Exposure to air pollution is a major contributor to the pathogenesis of COPD worldwide. Indeed, most recent estimates suggest that 50% of the total attributable risk of COPD may be related to air pollution. In response, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Scientific Committee performed a comprehensive review on this topic, qualitatively synthesised the evidence to date and proffered recommendations to mitigate the risk. The review found that both gaseous and particulate components of air pollution are likely contributors to COPD. There are no absolutely safe levels of ambient air pollution and the relationship between air pollution levels and respiratory events is supra-linear. Wildfires and extreme weather events such as heat waves, which are becoming more common owing to climate change, are major threats to COPD patients and acutely increase their risk of morbidity and mortality. Exposure to air pollution also impairs lung growth in children and as such may lead to developmental COPD. GOLD recommends strong public health policies around the world to reduce ambient air pollution and for implementation of public warning systems and advisories, including where possible the use of personalised apps, to alert patients when ambient air pollution levels exceed acceptable minimal thresholds. When household particulate content exceeds acceptable thresholds, patients should consider using air cleaners and filters where feasible. Air pollution is a major health threat to patients living with COPD and actions are urgently required to reduce the morbidity and mortality related to poor air quality around the world.

Executive summary of the Global Strategy for Prevention, Diagnosis and Management of COPD 2023: the latest evidence-based strategy document from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) https://bit.ly/3KCaTGe

Background: This study compared management of high-risk COPD patients in the UK to national and international management recommendations and quality standards, including the COllaboratioN on QUality improvement initiative for achieving Excellence in STandards of COPD care (CONQUEST). The primary comparison was in 2019, but trends from 2000 to 2019 were also examined. Methods: Patients identified in the Optimum Patient Care Research Database were categorised as newly diagnosed (≤12 months after diagnosis), already diagnosed, and potential COPD (smokers having exacerbation-like events). High-risk patients had a history of ≥2 moderate or ≥1 severe exacerbations in the previous 12 months. Findings: for diagnosed patients, the median time between diagnosis and first meeting the high-risk criteria was 617 days (Q1-Q3: 3246). The use of spirometry for diagnosis increased dramatically after 2004 before plateauing and falling in recent years. In 2019, 41% (95% CI 39–44%; n = 550/1343) of newly diagnosed patients had no record of spirometry in the previous year, and 45% (95% CI 43–48%; n = 352/783) had no record of a COPD medication review within 6 months of treatment initiation or change. In 2019, 39% (n = 6893/17,858) of already diagnosed patients had no consideration of exacerbation rates, 46% (95% CI 45–47%; n = 4942/10,725) were not offered or referred for pulmonary rehabilitation, and 41% (95% CI 40–42%; n = 3026/7361) had not had a COPD review within 6 weeks of respiratory hospitalization. Interpretation: Opportunities for early diagnosis of COPD patients at high risk of exacerbations are being missed. Newly and already diagnosed patients at high-risk are not being assessed or treated promptly. There is substantial scope to improve the assessment and treatment optimisation of these patients. Funding: This study is conducted by the Observational & Pragmatic Research International Ltd and was co-funded by Optimum Patient Care and AstraZeneca. No funding was received by the Observational & Pragmatic Research Institute Pte Ltd (OPRI) for its contribution.

Asthma, rhinitis, and atopic dermatitis (AD) are interrelated clinical phenotypes that partly overlap in the human interactome. The concept of "one-airway-one-disease," coined over 20 years ago, is a simplistic approach of the links between upper- and lower-airway allergic diseases. With new data, it is time to reassess the concept. This article reviews (i) the clinical observations that led to Allergic Rhinitis and its Impact on Asthma (ARIA), (ii) new insights into polysensitization and multimorbidity, (iii) advances in mHealth for novel phenotype definitions, (iv) confirmation in canonical epidemiologic studies, (v) genomic findings, (vi) treatment approaches, and (vii) novel concepts on the onset of rhinitis and multimorbidity. One recent concept, bringing together upper- and lower-airway allergic diseases with skin, gut, and neuropsychiatric multimorbidities, is the "Epithelial Barrier Hypothesis." This review determined that the "one-airway-one-disease" concept does not always hold true and that several phenotypes of disease can be defined. These phenotypes include an extreme "allergic" (asthma) phenotype combining asthma, rhinitis, and conjunctivitis. Rhinitis alone and rhinitis and asthma multimorbidity represent two distinct diseases with the following differences: (i) genomic and transcriptomic background (Toll-Like Receptors and IL-17 for rhinitis alone as a local disease; IL-33 and IL-5 for allergic and non-allergic multimorbidity as a systemic disease), (ii) allergen sensitization patterns (mono- or pauci-sensitization versus polysensitization), (iii) severity of symptoms, and (iv) treatment response. In conclusion, rhinitis alone (local disease) and rhinitis with asthma multimorbidity (systemic disease) should be considered as two distinct diseases, possibly modulated by the microbiome, and may be a model for understanding the epidemics of chronic and autoimmune diseases.

Rationale: Medication for treatment of chronic obstructive pulmonary disease (COPD) is available in many different delivery systems; however, national and international guidelines do not provide recommendations on how to select the optimal system for an individual patient. Objectives: to perform a systematic review of published algorithms for inhaler selection in outpatients with COPD. Methods: PubMed, EMBASE, PsycINFO, Cochrane, and Google Scholar were searched for articles on inhaler selection published between January 1, 1990, and March 10, 2021. The results were reviewed for articles containing an algorithm for inhaler selection. The quality of publications containing an algorithm was assessed using the Joanna Briggs Institute's System for the Unified Management, Assessment and Review of Information text and opinion critical appraisal checklist. Individual steps recommended in the algorithms and the order in which they were considered were extracted independently by the two authors using the Joanna Briggs Institute's text and opinion data extraction tool. Textual syntheses and a table of factors included were used to appraise and compare algorithms. Results: the search identified 1,016 publications. After removing duplicate studies (n = 409), 607 abstracts were examined. Nine different algorithms or hierarchical recommendations for device selection were identified. All nine publications were considered of good quality. Most algorithms contain only a few decision steps. There were significant differences between the algorithms. None of the algorithms have been validated. Three domains for factors included in the algorithms were identified: patient factors, device attributes, and healthcare professional (HCP) factors. Patient factors were considered most frequently (19 times) compared with device attributes (10 times) and HCP factors (7 times). Five specific attributes/factors with at least three rankings in different algorithms were identified as key factors for device selection: ability to perform the required inspiratory maneuver and handle device correctly, sufficient inspiratory flow for dry powder inhalers, availability of molecule(s) in the device, and continuity of device. Conclusions: Although the algorithms generally provide step-by-step approaches based on a literature review and/or the experiences of the different authors, none were developed using item generation/reduction methodology or included input from patients with COPD. However, the review identified key factors that should be considered by HCPs when selecting therapy. Registration: PROSPERO (CRD42021244475).

Purpose: Triple therapy comprising a long-acting muscarinic antagonist, long-acting β2-agonist and inhaled corticosteroid is recommended for patients with chronic obstructive pulmonary disease (COPD) who continue to experience frequent exacerbations or symptoms whilst receiving dual therapy. Adherence and persistence to multiple-inhaler triple therapy (MITT) is known to be poor. This study assessed comparative adherence to single-inhaler triple therapy (SITT) versus MITT in a real-world setting in England. Patients and Methods: This was a retrospective cohort study using linked primary care (Clinical Practice Research Datalink Aurum) and secondary care (Hospital Episode Statistics [HES] Admitted Patient Care) data to identify patients with COPD who were newly initiated on SITT or MITT between November 2017 and June 2019. Eligible patients were aged ≥35 years and had a forced expiratory volume in 1 second/forced vital capacity 30 days between the end of a prescription and the following refill used to determine non-persistence. Results: Overall, 4080 SITT and 6579 MITT users comprised the study cohort. After weighting, the baseline characteristics between the cohorts were comparable (absolute standardized mean difference

Introduction: Few randomised controlled trials (RCTs) have directly compared long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) dual maintenance therapies for patients with chronic obstructive pulmonary disease (COPD). This systematic literature review and network meta-analysis (NMA) compared the efficacy of umeclidinium/vilanterol (UMEC/VI) versus other dual and mono-bronchodilator therapies in symptomatic patients with COPD. Methods: a systematic literature review (October 2015–November 2020) was performed to identify RCTs ≥ 8 weeks long in adult patients with COPD that compared LAMA/LABA combinations against any long-acting bronchodilator-containing dual therapy or monotherapy. Data extracted on changes from baseline in trough forced expiratory volume in 1 s (FEV1), St George’s Respiratory Questionnaire (SGRQ) total score, Transitional Dyspnoea Index (TDI) focal score, rescue medication use and moderate/severe exacerbation rate were analysed using an NMA in a frequentist framework. The primary comparison was at 24 weeks. Fixed effects model results are presented. Results: the NMA included 69 full-length publications (including 10 GSK clinical study reports) reporting 49 studies. At 24 weeks, UMEC/VI provided statistically significant greater improvements in FEV1 versus all dual therapy and monotherapy comparators. UMEC/VI provided similar improvements in SGRQ total score compared with all other LAMA/LABAs, and significantly greater improvements versus UMEC 125 μg, glycopyrronium 50 μg, glycopyrronium 18 μg, tiotropium 18 μg and salmeterol 50 μg. UMEC/VI also provided significantly better outcomes versus some comparators for TDI focal score, rescue medication use, annualised moderate/severe exacerbation rate, and time to first moderate/severe exacerbation. Conclusion: UMEC/VI provided generally better outcomes compared with LAMA or LABA monotherapies, and consistent improvements in lung function (measured by change from baseline in trough FEV1 at 24 weeks) versus dual therapies. Treatment with UMEC/VI may improve outcomes for symptomatic patients with COPD compared with alternative maintenance treatments.

In the original article the disclosures for the author MeiLan K. Han are missing. MeiLan K. Han’s disclosures should read as “MeiLan K. Han has received personal fees from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Merck and Mylan. Research support was also received from Novartis and Sunovion”.

Purpose: the 24-week INTREPID trial demonstrated the clinical benefits of once-daily single-inhaler triple therapy (SITT) with fluticasone furoate, umeclidinium, and vilanterol (FF/UMEC/VI) versus non-ELLIPTA multiple-inhaler triple therapy (MITT) in patients with symptomatic chronic obstructive pulmonary disease (COPD). This analysis assessed the cost-effectiveness of FF/UMEC/VI versus non-ELLIPTA MITT for the treatment of symptomatic COPD from a United Kingdom (UK) National Health Service (NHS) perspective. Patients and Methods: the analysis was conducted using the validated GALAXY COPD disease progression model. Baseline characteristics, treatment effect parameters (forced expiratory volume in 1 second and St. George’s Respiratory Questionnaire score [derived from exploratory COPD Assessment Test score mapping]), and discontinuation data from INTREPID were used to populate the model. UK healthcare resource and drug costs (2020 British pounds) were applied, and costs and outcomes were discounted at 3.5%. Analyses were conducted over a lifetime horizon from a UK NHS perspective. Model outputs included exacerbation rates, total costs, life years (LYs), quality-adjusted LYs (QALYs) and incremental cost-effectiveness ratio per QALY. Sensitivity analyses were conducted to assess the robustness of the results by varying parameter values and assumptions. Results: over a lifetime horizon, FF/UMEC/VI provided an additional 0.174 (95% confidence interval [CI]: 0.024, 0.344) LYs (approximately 2 months), and 0.253 (95% CI: 0.167, 0.346) QALYs (approximately 3 months), at a cost saving of £1764 (95% CI: −£2600, −£678) per patient, compared with non-ELLIPTA MITT. FF/UMEC/VI remained the dominant treatment option, meaning greater benefits at lower costs, across all scenario and sensitivity analyses. Conclusion: Based on this analysis, in a UK setting, FF/UMEC/VI would improve health outcomes and reduce costs compared with non-ELLIPTA MITT for the treatment of patients with symptomatic COPD. SITT may help to reduce the clinical and economic burden of COPD and should be considered by physicians as a preferred treatment option.

BACKGROUND AND OBJECTIVE: Chronic mucus hypersecretion (CMH) is a clinical phenotype of COPD. This exploratory post hoc analysis assessed relationship between CMH status and treatment response in IMPACT. METHODS: Patients were randomized to once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 μg, FF/VI 100/25 μg or UMEC/VI 62.5/25 μg and designated CMH+ if they scored 1/2 in St George's Respiratory Questionnaire (SGRQ) questions 1 and 2. Endpoints assessed by baseline CMH status included on-treatment exacerbation rates, change from baseline in trough forced expiratory volume in 1 second, SGRQ total score, COPD Assessment Test (CAT) score, proportion of SGRQ and CAT responders at Week 52 and safety. RESULTS: of 10,355 patients in the intent-to-treat population, 10,250 reported baseline SGRQ data (CMH+: 62% [n = 6383]). FF/UMEC/VI significantly (p 

PURPOSE: There has been concern that asthma and chronic obstructive pulmonary disease [COPD] increase the risk of developing and exacerbating COVID-19. The effect of medications such as inhaled corticosteroids (ICS) and biologics on COVID-19 is unclear. This systematic literature review analyzed the published evidence on epidemiology and the burden of illness of asthma and COPD, and the use of baseline medicines among COVID-19 populations. PATIENTS AND METHODS: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, Embase®, MEDLINE® and Cochrane were searched (January 2019-August 2021). The prevalence of asthma or COPD among COVID-19 populations was compared to the country-specific populations. Odds ratios (ORs) were estimated to compare healthcare resource utilization (HCRU) rates, and meta-analyses of outcomes were estimated from age-adjusted ORs (aORs) or hazard ratios (aHRs). Meta-analyses of COVID-19 outcomes were conducted using random effects models for binary outcomes. RESULTS: Given the number and heterogeneity of studies, only 183 high-quality studies were analyzed, which reported hospitalization, intensive care unit (ICU) admissions, ventilation/intubation, or mortality. Asthma patients were not at increased risk for COVID-19-related hospitalization (OR = 1.05, 95% CI: 0.92 to 1.20), ICU admission (OR = 1.21, 95% CI: 0.99 to 1.1.48), ventilation/intubation (OR = 1.24, 95% CI: 0.95 to 1.62), or mortality (OR = 0.85, 95% CI: 0.75 to 0.96). Accounting for confounding variables, COPD patients were at higher risk of hospitalization (aOR = 1.45, 95% CI: 1.30 to 1.61), ICU admission (aOR = 1.28, 95% CI: 1.08 to 1.51), and mortality (aOR = 1.41, 95% CI: 1.37 to 1.65). Sixty-five studies reported outcomes associated with ICS or biologic use. There was limited evidence that ICS or biologics significantly impacted the risk of SARS-CoV-2 infection, HCRU, or mortality in asthma or COPD patients. CONCLUSION: in high-quality studies included, patients with asthma were not at significantly higher odds for adverse COVID-19-related outcomes, while patients with COPD were at higher odds. There was no clear evidence that baseline medication affected outcomes. REGISTRATION: PROSPERO (CRD42021233963).

BACKGROUND: in the InforMing the PAthway of COPD Treatment (IMPACT) trial, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) reduced moderate/severe exacerbation rates versus FF/VI and UMEC/VI in patients with chronic obstructive pulmonary disease (COPD). This post hoc analysis tested the relationship between baseline health status, risk of future exacerbations, and efficacy outcomes. METHODS: IMPACT was a Phase 3, double-blind, 52-week trial in patients with symptomatic COPD (COPD Assessment Test [CAT] score ≥10) and ≥1 moderate/severe exacerbation in the prior year randomized 2:2:1 to FF/UMEC/VI 100/62.5/25mcg, FF/VI 100/25mcg, or UMEC/VI 62.5/25mcg. Annual rate of on-treatment moderate/severe exacerbations, lung function, and safety were analyzed by continuous baseline CAT score. RESULTS: Moderate/severe exacerbation rates increased with increasing baseline CAT scores in FF/UMEC/VI and UMEC/VI arms. There was a very small increase in on-treatment pneumonia rates at higher baseline CAT scores across all treatment arms. FF/UMEC/VI reduced moderate/severe exacerbation rates versus UMEC/VI (i.e. the inhaled corticosteroid effect) consistently across the range of CAT scores. The reduction with FF/UMEC/VI versus FF/VI (i.e. the long-acting muscarinic antagonist effect) was greatest at lower CAT scores and appeared lesser at higher CAT scores. Improvements in lung function were observed with FF/UMEC/VI versus FF/VI and UMEC/VI, regardless of baseline CAT score. CONCLUSIONS: the CAT score was predictive of exacerbation risk. Worse baseline health status was associated with higher moderate/severe exacerbation and pneumonia rates. Irrespective of baseline CAT score, FF/UMEC/VI improved lung function, and reduced the annual moderate/severe exacerbation rates versus dual therapy. Results indicate an overall favorable benefit-risk profile of triple versus dual therapy, irrespective of CAT score. Clinical Trial Registration:GSK (CTT116855/NCT02164513).

OBJECTIVES: in the IMPACT trial (NCT02164513), triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) showed clinical benefit compared with dual therapy with either FF/VI or UMEC/VI in the treatment of chronic obstructive pulmonary disease (COPD). We used data from IMPACT to determine whether this translated into differences in COPD-related healthcare resource utilization (HRU) costs in a United Kingdom (UK) setting. METHODS: in a within-trial analysis, individual patient data from the IMPACT intention-to-treat (ITT) population were analyzed to estimate rates of COPD-related HRU with FF/UMEC/VI, FF/VI, or UMEC/VI. A Bayesian approach was applied to address issues typically encountered with this kind of data, namely data missing due to early study withdrawal, subjects with zero reported HRU, and skewness. Rates of HRU were estimated under alternate assumptions of data being missing at random (MAR) or missing not at random (MNAR). UK-specific unit costs were then applied to estimated HRU rates to calculate treatment-specific costs. RESULTS: Under each MNAR scenario, per patient per year (PPPY) rates of COPD-related HRU were lowest amongst those patients who received treatment with FF/UMEC/VI compared with those receiving either FF/VI or UMEC/VI. Although absolute HRU rates and costs were typically higher for all treatment groups under MNAR scenarios versus MAR, final economic conclusions were robust to patient withdrawals. CONCLUSIONS: PPPY rates were typically lower with FF/UMEC/VI versus FF/VI or UMEC/VI.

Background the association between chronic obstructive pulmonary disease exacerbations and increased cardiovascular event risk has not been adequately studied in a heterogenous population with both low and high cardiovascular risk. Methods and Results This post hoc analysis of the IMPACT (Informing the Pathway of COPD Treatment) trial (N=10 355 symptomatic patients with chronic obstructive pulmonary disease at risk of exacerbations) evaluated time-dependent risk of cardiovascular adverse events of special interest (CVAESI) following exacerbations and impact of exacerbation history, cardiovascular risk factors, and study treatment on this association. Risk (time-to-first) of CVAESI or CVAESI resulting in hospitalization or death was assessed during and 1 to 30, 31 to 90, and 91 to 365 days after resolution of moderate or severe exacerbations. CVAESI risk was compared between the period before and during/after exacerbation. CVAESI risk increased significantly during a moderate (hazard ratio [HR], 2.63 [95% CI, 2.08-3.32]) or severe (HR, 21.84 [95% CI, 17.71-26.93]) exacerbation and remained elevated for 30 days following an exacerbation (moderate: HR, 1.63 [95% CI, 1.28-2.08]; severe: HR, 1.75 [95% CI, 0.99-3.11; nonsignificant]) and decreased over time, returning to baseline by 90 days. Risk of CVAESI resulting in hospitalization or death also increased during an exacerbation (moderate: HR, 2.46 [95% CI, 1.53-3.97]; severe: HR, 41.29 [95% CI, 30.43-56.03]) and decreased in a similar time-dependent pattern. Results were consistent regardless of exacerbation history, cardiovascular risk at screening, or study treatment. Conclusions Overall risk of cardiovascular events was higher during and in the 30 days following chronic obstructive pulmonary disease exacerbations, even among those with low cardiovascular risk, highlighting the need for exacerbation prevention and vigilance for cardiovascular events following exacerbations. Registration URL: https://clinicaltrials.gov/ct2/show/NCT02164513; Unique identifier: NCT02164513.

Chronic obstructive pulmonary disease (COPD) is the end result of a series of dynamic and cumulative gene-environment interactions over a lifetime. The evolving understanding of COPD biology provides novel opportunities for prevention, early diagnosis, and intervention. To advance these concepts, we propose therapeutic trials in two major groups of subjects: "young" individuals with COPD and those with pre-COPD. Given that lungs grow to about 20 years of age and begin to age at approximately 50 years, we consider "young" patients with COPD those patients in the age range of 20-50 years. Pre-COPD relates to individuals of any age who have respiratory symptoms with or without structural and/or functional abnormalities, in the absence of airflow limitation, and who may develop persistent airflow limitation over time. We exclude from the current discussion infants and adolescents because of their unique physiological context and COPD in older adults given their representation in prior randomized controlled trials (RCTs). We highlight the need of RCTs focused on COPD in young patients or pre-COPD to reduce disease progression, providing innovative approaches to identifying and engaging potential study subjects. We detail approaches to RCT design, including potential outcomes such as lung function, patient-reported outcomes, exacerbations, lung imaging, mortality, and composite endpoints. We critically review study design components such as statistical powering and analysis, duration of study treatment, and formats to trial structure, including platform, basket, and umbrella trials. We provide a call to action for treatment RCTs in 1) young adults with COPD and 2) those with pre-COPD at any age.

Rationale: the IMPACT trial demonstrated a significant reduction in on-/off-treatment all-cause mortality (ACM) risk with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus UMEC/VI in patients with symptomatic chronic obstructive pulmonary disease (COPD) and a history of exacerbations. To identify whether this mortality benefit finding was associated with specific patient characteristics, the time to on-/off-treatment ACM by patient subgroups was investigated. Method(s): IMPACT was a Phase III, randomized, double-blind, 52-week trial comparing once-daily FF/UMEC/VI 100/62.5/25 mcg with FF/VI 100/25 mcg and UMEC/VI 62.5/25 mcg. Eligible patients (aged >=40 years) had symptomatic COPD (COPD Assessment Test score >=10), and a forced expiratory volume in 1 second (FEV1) =1 moderate or severe exacerbation in the prior year, or a FEV1 50-=2 moderate or >=1 severe exacerbations in the prior year. This post hoc analysis analyzed time to on-/off-treatment ACM, including additional vital status data, for FF/UMEC/VI versus UMEC/VI using a Cox proportional hazards model with covariates of treatment group, age (at screening), and sex. On-/offtreatment deaths were defined as those occurring between study treatment start date and the latest of study treatment stop date or projected Week 52 date (based on treatment start date) +7 days, inclusive. Subgroups included pneumonia history, cardiovascular risk, smoking status, age, sex, body mass index, race, geographical region, and exacerbation history in the prior year. Result(s): the intent-to-treat (ITT) population comprised 10,355 patients (FF/UMEC/VI, n=4151; FF/VI n=4134; UMEC/VI, n=2070); vital status at Week 52 was obtained for 99.6% of the ITT population. There were 98 (2.36%) and 66 (3.19%) on-/off-treatment deaths reported in the FF/UMEC/VI and UMEC/VI arms, respectively. FF/UMEC/VI demonstrated a significant reduced risk of on-/offtreatment ACM compared with UMEC/VI in some subgroups, including patients with >=2 cardiovascular risk factors (39.4% reduction; 95% confidence interval [CI]: 7.1, 60.5; P=0.022), a past history of pneumonia (49.1% reduction; 95% CI: 10.4, 71.1; P=0.019), or with

Rationale the IMPACT trial demonstrated that fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) single-inhaler triple therapy significantly reduced severe exacerbations rates and all-cause mortality risk versus UMEC/VI in patients with chronic obstructive pulmonary disease (COPD). However, concerns have been raised about an increased risk of pneumonia with inhaled corticosteroid-containing regimens as well as cardiovascular effects with dual bronchodilation. To better determine the benefit-risk profile of FF/UMEC/VI versus FF/VI and UMEC/VI in the IMPACT population, a composite adverse event outcome was examined. Methods the IMPACT trial (NCT02164513, CTT116855) was a 52-week, randomized, doubleblind, multicenter study comparing FF/UMEC/VI 100/62.5/25mug with FF/VI 100/25mug and UMEC/VI 62.5/25mug in patients aged >=40 years with symptomatic COPD (COPD Assessment Test score >=10) and forced expiratory volume in 1 second (FEV1) =1 moderate or severe exacerbation in the prior year, or FEV1 50-=2 moderate or >=1 severe exacerbations in the prior year. This post hoc analysis evaluated time-to-first composite event, comprising on-treatment severe exacerbation, on-treatment cardiovascular adverse event of special interest (AESI) resulting in hospitalization or death, on-treatment pneumonia AESI resulting in hospitalization or death, or on-treatment death from any cause. For patients with multiple events, only the first event contributed to this analysis. Severe exacerbations were defined as worsening of symptoms resulting in hospitalization or death. The analysis was conducted using a Cox proportional hazards model with covariates of treatment group, sex, exacerbation history (=2 moderate/severe), geographical region, smoking status (screening) and post bronchodilator percent predicted FEV1 (screening). Results the overall intent-to-treat population comprised 10,355 patients (FF/UMEC/VI, n=4151; FF/VI, n=4134; UMEC/VI, n=2070). Composite events occurred in 647 (16%), 636 (15%), and 356 (17%) patients receiving FF/UMEC/VI, FF/VI, and UMEC/VI, respectively. The probability of experiencing an event before Day 365 with FF/UMEC/VI, FF/VI, and UMEC/VI was 16.7%, 17.5%, and 19.1%, respectively (Figure). FF/UMEC/VI significantly reduced composite event risk versus UMEC/VI by 16.5% (95% confidence interval [CI]: 5.0, 26.7; p=0.006). The point estimates for the reduction in the risk of a composite event favored FF/UMEC/VI over FF/VI (6.2% reduction [-4.7, 15.9]; p=0.255), and FF/VI over UMEC/VI (11.1% reduction [-1.3, 21.9]; p=0.077), but differences were not statistically significant. Conclusions FF/UMEC/VI significantly reduced the risk of a composite adverse event versus UMEC/VI and numerically reduced the risk versus FF/VI, demonstrating a favorable benefit-risk profile of once-daily FF/UMEC/VI triple therapy compared with dual therapy in patients with symptomatic COPD and a history of exacerbations. Funding GSK (NCT02164513/CTT116855).

Early in the COVID pandemic there were concerns about the outcomes for patients with COPD who developed COVID-19. Although the pandemic has made the diagnosis and routine management of COPD more difficult, the risk of patients developing COVID or of having poor outcomes is less than anticipated and there have been some unexpected findings that may lead to significant improvements in the management of COPD in future.

BACKGROUND: Data to better understand and manage the COVID-19 pandemic is urgently needed. However, there are gaps in information stored within even the best routinely-collected electronic health records (EHR) including test results, remote consultations for suspected COVID-19, shielding, physical activity, mental health, and undiagnosed or untested COVID-19 patients. Observational and Pragmatic Research Institute (OPRI) Singapore and Optimum Patient Care (OPC) UK established Platform C19, a research database combining EHR data and bespoke patient questionnaire. We describe the demographics, clinical characteristics, patient behavior, and impact of the COVID-19 pandemic using data within Platform C19. METHODS: EHR data from Platform C19 were extracted from 14 practices across UK participating in the OPC COVID-19 Quality Improvement program on a continuous, monthly basis. Starting 7th August 2020, consenting patients aged 18-85 years were invited in waves to fill an online questionnaire. Descriptive statistics were summarized using all data available up to 22nd January 2021. FINDINGS: from 129,978 invitees, 31,033 responded. Respondents were predominantly female (59.6%), white (93.5%), and current or ex-smokers (52.6%). Testing for COVID-19 was received by 23.8% of respondents, of which 7.9% received positive results. COVID-19 symptoms lasted ≥4 weeks in 19.5% of COVID-19 positive respondents. Up to 39% respondents reported a negative impact on questions regarding their mental health. Most (67%-76%) respondents with asthma, Chronic Obstructive Pulmonary Disease (COPD), diabetes, heart, or kidney disease reported no change in the condition of their diseases. INTERPRETATION: Platform C19 will enable research on key questions relating to COVID-19 pandemic not possible using EHR data alone.

Inhaled corticosteroids (ICS) have a class effect of increasing pneumonia risk in patients with COPD. However, pneumonia incidence varies widely across clinical trials of ICS use in COPD. This review clarifies methodological differences in defining and recording pneumonia events in these trials and discusses factors that could contribute to the varying pneumonia incidence. Literature searches and screening yielded 40 relevant references for inclusion. Methods used to capture pneumonia events in these studies included investigator-reported pneumonia adverse events, standardised list of signs or symptoms, radiographic confirmation of suspected cases and/or confirmation by an independent clinical end-point committee. In general, more stringent pneumonia diagnosis criteria led to lower reported pneumonia incidence rates. In addition, studies varied in design and population characteristics, including exacerbation history and lung function, factors that probably contribute to the varying pneumonia incidence. As such, cross-trial comparisons are problematic. A minimal set of standardised criteria for diagnosis and reporting of pneumonia should be used in COPD studies, as well as reporting of patients’ pneumonia history at baseline, to allow comparison of pneumonia rates between trials. Currently, within-trial comparison of ICS-containing versus non-ICS-containing treatments is the appropriate method to assess the influence of ICS on pneumonia incidence.

Background: in the Informing the Pathway of COPD Treatment (IMPACT) trial, single-inhaler triple-therapy fluticasone furoate (FF), umeclidinium (UMEC), and vilanterol (VI) reduced moderate/severe exacerbation rates vs FF/VI and UMEC/VI in patients with symptomatic COPD and a history of exacerbations, with a similar safety profile. Research Question: Are trial outcomes with single-inhaler triple-therapy FF/UMEC/VI vs FF/VI and UMEC/VI affected by age in patients with symptomatic COPD and a history of exacerbations? Study Design and Methods: IMPACT was a phase III, double-blind, 52-week trial. Patients ≥ 40 years of age with symptomatic COPD and ≥ 1 moderate/severe exacerbation in the previous year were randomly assigned 2:2:1 to FF/UMEC/VI 100/62.5/25 μg, FF/VI 100/25 μg, or UMEC/VI 62.5/25 μg. End points assessed by age included annual rate of moderate/severe exacerbations, change from baseline (CFB) in trough FEV1, proportion of St. George's Respiratory Questionnaire (SGRQ) responders (≥ 4 units decrease from baseline in SGRQ total score), and safety. Results: the intention-to-treat population comprised 10,355 patients; 4,724 (46%), 4,225 (41%), and 1,406 (14%) were ≤ 64, 65 to 74, and ≥ 75 years of age, respectively. FF/UMEC/VI reduced on-treatment moderate/severe exacerbation rates vs FF/VI (% reduction [95% CI]: ≤ 64 years, 8% [−1 to 16]; P =. 070; 65-74 years, 22% [14-29]; P <. 001; ≥ 75 years, 18% [3-31]; P =. 021) and vs UMEC/VI (≤ 64 years, 16% [7-25]; P =. 002; 65-74 years, 33% [25-41]; P <. 001; ≥ 75 years, 24% [6-38]; P =. 012), with greatest rate reduction seen in the 65 to 74 and ≥ 75 years subgroups. Post hoc analyses of CFB in trough FEV1 and proportion of SGRQ responders at week 52 were significantly greater with FF/UMEC/VI than with FF/VI or UMEC/VI in all subgroups. No new safety signals were identified. Interpretation: FF/UMEC/VI reduced the rate of moderate/severe exacerbations and improved lung function and health status vs FF/VI and UMEC/VI irrespective of age for most end points, with a similar safety profile. Clinical Trial Registration: ClinicalTrials.gov; No.: NCT02164513; URL: www.clinicaltrials.govCTT116855

Inhaled corticosteroids have proven to be less effective in asthmatic patients who smoke; however, there is limited information on the efficacy of inhaled corticosteroid-containing regimens in COPD patients who continue smoking. We evaluate the differential efficacy of once-daily indacaterol/glycopyrronium 110/50 µg compared with twice-daily salmeterol/fluticasone 50/500 µg in current smokers and ex-smokers with COPD. A pooled analysis of data from ILLUMINATE, LANTERN and FLAME studies was conducted to assess the efficacy of indacaterol/glycopyrronium compared with salmeterol/fluticasone in current smokers and ex-smokers with COPD. Efficacy was assessed in terms of improvements in trough forced expiratory volume in 1 s (FEV1), transition dyspnoea index (TDI) focal score, St George’s Respiratory Questionnaire (SGRQ) total score, reduced rescue medication use and exacerbation prevention at 26 weeks after the start of the therapy. In total, 1769 (38%) current smokers and 2848 (62%) ex-smokers were included. Patients treated with indacaterol/glycopyrronium experienced greater improvements in trough FEV1 versus salmeterol/ fluticasone in both current and ex-smokers (least squares mean treatment difference, 105 mL and 78 mL, respectively). Improvements in TDI focal score, SGRQ total score and reduction in rescue medication use were also greater with indacaterol/glycopyrronium versus salmeterol/fluticasone in current and ex-smokers. Furthermore, indacaterol/glycopyrronium reduced all exacerbations (moderate/severe) compared with salmeterol/fluticasone, irrespective of smoking status. The difference in efficacy in favour of indacaterol/ glycopyrronium was more prominent in current smokers in most cases. Indacaterol/glycopyrronium demonstrated greater efficacy versus salmeterol/fluticasone, and the differences were generally more prominent in current smokers suggesting smoking may reduce the effects of salmeterol/fluticasone.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has raised many questions about the management of patients with chronic obstructive pulmonary disease (COPD) and whether modifications of their therapy are required. It has raised questions about recognizing and differentiating coronavirus disease (COVID-19) from COPD given the similarity of the symptoms. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) Science Committee used established methods for literature review to present an overview of the management of patients with COPD during the COVID-19 pandemic. It is unclear whether patients with COPD are at increased risk of becoming infected with SARS-CoV-2. During periods of high community prevalence of COVID-19, spirometry should only be used when it is essential for COPD diagnosis and/or to assess lung function status for interventional procedures or surgery. Patients with COPD should follow basic infection control measures, including social distancing, hand washing, and wearing a mask or face covering. Patients should remain up to date with appropriate vaccinations, particularly annual influenza vaccination. Although data are limited, inhaled corticosteroids, long-acting bronchodilators, roflumilast, or chronic macrolides should continue to be used as indicated for stable COPD management. Systemic steroids and antibiotics should be used in COPD exacerbations according to the usual indications. Differentiating symptoms of COVID-19 infection from chronic underlying symptoms or those of an acute COPD exacerbation may be challenging. If there is suspicion for COVID-19, testing for SARS-CoV-2 should be considered. Patients who developed moderate-to-severe COVID-19, including hospitalization and pneumonia, should be treated with evolving pharmacotherapeutic approaches as appropriate, including remdesivir, dexamethasone, and anticoagulation. Managing acute respiratory failure should include appropriate oxygen supplementation, prone positioning, noninvasive ventilation, and protective lung strategy in patients with COPD and severe acute respiratory distress syndrome. Patients who developed asymptomatic or mild COVID-19 should be followed with the usual COPD protocols. Patients who developed moderate or worse COVID-19 should be monitored more frequently and accurately than the usual patients with COPD, with particular attention to the need for oxygen therapy.

BACKGROUND: Poor treatment adherence in COPD patients is associated with poor clinical outcomes and increased healthcare burden. Personalized approaches for adherence management, supported with technology-based interventions, may offer benefits to patients and providers but are currently unproven in terms of clinical outcomes as opposed to adherence outcomes. METHODS: Maximizing Adherence and Gaining New Information for Your COPD (MAGNIFY COPD study), a pragmatic cluster randomized trial, aims to evaluate the impact of an adherence technology package (interventional package), comprising an adherence review, ongoing provision of a dual bronchodilator but with an add-on inhaler sensor device and a connected mobile application. This will compare time to treatment failure and other clinical outcomes in patients identified at high risk of exacerbations with historic poor treatment adherence as measured by prescription collection to mono/dual therapy over one year (1312 patients) versus usual care. Treatment failure is defined as the first occurrence of one of the following: (1) moderate/severe COPD exacerbation, (2) prescription of triple therapy (inhaled corticosteroid/long-acting β2-agonist/long-acting muscarinic antagonist [ICS/LABA/LAMA]), (3) prescription of additional chronic therapy for COPD, or (4) respiratory-related death. Adherence, moderate/severe exacerbations, respiratory-related healthcare resource utilization and costs, and intervention package acceptance rate will also be assessed. Eligible primary care practices (N=176) participating in the Optimum Patient Care Quality Improvement Program will be randomized (1:1) to either adherence support cluster arm (suitable patients already receiving or initiated Ultibro® Breezhaler® [indacaterol/glycopyrronium] will be offered interventional package) or the control cluster arm (suitable patients continue to receive usual clinical care). Patients will be identified and outcomes collected from anonymized electronic medical records within the Optimum Patient Care Research Database. On study completion, electronic medical record data will be re-extracted to analyze outcomes in both study groups. REGISTRATION NUMBER: ISRCTN10567920. CONCLUSION: MAGNIFY will explore patient benefits of technology-based interventions for electronic adherence monitoring.

Introduction: Clinically important deterioration (CID) is a multicomponent measure for assessing disease worsening in chronic obstructive pulmonary disease (COPD). This analysis investigated the prognostic value of a CID event on future clinical outcomes and the effect of single-inhaler triple versus dual therapy on reducing CID risk in patients in the IMPACT trial. Methods: IMPACT was a phase III, double-blind, 52-week, multicentre trial. Patients with symptomatic COPD and at least one moderate/severe exacerbation in the prior year were randomised 2:2:1 to fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 µg, FF/VI 100/25 µg or UMEC/VI 62.5/25 µg. CID at the time-point of interest was defined as a moderate/severe exacerbation, ⩾100 mL decrease in trough forced expiratory volume in 1 s or deterioration in health status (increase of ⩾4.0 units in St George’s Respiratory Questionnaire total score or increase of ⩾2.0 units in COPD Assessment Test score) from baseline. A treatment-independent post hoc prognostic analysis compared clinical outcomes up to week 52 in patients with/without a CID by week 28. A prospective analysis evaluated time to first CID with each treatment. Results: Patients with a CID by week 28 had significantly increased exacerbation rates after week 28, smaller improvements in lung function and health status at week 52 (all p

Rationale: ED visits and hospitalizations associated with COPD place a burden on healthcare systems, and account for most COPD-related healthcare costs in the US. In the IMPACT trial, fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) significantly reduced rates of severe exacerbations (resulting in hospitalization or death) versus UMEC/VI in patients with COPD. The rate of ED visits in patients enrolled in IMPACT has not been published; this analysis investigated the annual rate of ED visits by treatment arm for patients with COPD in the IMPACT trial. Method(s): IMPACT was a Phase 3, randomized, double-blind, 52-week trial comparing once-daily FF/UMEC/VI 100/62.5/25mug with FF/VI 100/25mug and UMEC/VI 62.5/25mug. Eligible patients (aged >=40 years) had symptomatic COPD (COPD Assessment Test score >=10), a forced expiratory volume in 1 second (FEV1) =1 moderate or severe exacerbation in the prior year, or a FEV1 50-=2 moderate or >=1 severe exacerbation in the prior year. Unscheduled healthcare resource utilization, including ED visits, was recorded in patients' electronic case report form. This post hoc analysis quantified annual rates of ED visits for any reason by treatment arm, using a generalized linear model assuming a negative binomial distribution. Result(s): the intent-to-treat population comprised 10,355 patients of which data on ED visits were available for 10,351 patients (FF/UMEC/VI, n=4148; FF/VI, n=4134; UMEC/VI, n=2069). Overall, 11.5% (n=477/4148) of patients on FF/UMEC/VI, 10.4% (n=432/4134) on FF/VI, and 12.2% (n=252/2069) on UMEC/VI had 1 ED visit, and 4.4% (n=182/4148), 4.8% (n=199/4134), and 4.2% (n=86/2069), respectively, had >=2 ED visits. The model estimated annual event rates (95% confidence interval [CI]) were 0.27 (0.24, 0.29), 0.29 (0.26, 0.32), and 0.33 (0.28, 0.37) for FF/UMEC/VI, FF/VI, and UMEC/VI, respectively (Figure). The rate of ED visits for patients on FF/UMEC/VI was significantly lower versus UMEC/VI (18% reduction; rate ratio: 0.82; 95% CI: 0.70, 0.97; p=0.017) but there was no statistically significant difference versus FF/VI (7% reduction; rate ratio: 0.93; 95% CI: 0.81, 1.06; p=0.256). Conclusion(s): the rate of ED visits was significantly lower for patients on FF/UMEC/VI compared with UMEC/VI and similar to the FF/VI arm. In addition to the reduction in severe exacerbation rates with FF/UMEC/VI versus UMEC/VI seen in the IMPACT trial, this reduction in ED visits for any reason highlights the benefits of single-inhaler FF/UMEC/VI triple therapy over UMEC/VI dual therapy in patients with symptomatic COPD and a history of exacerbations. Funding(s): GSK (CTT116855/NCT02164513).

INTRODUCTION: Symptoms may persist after the initial phases of COVID-19 infection, a phenomenon termed long COVID. Current knowledge on long COVID has been mostly derived from test-confirmed and hospitalized COVID-19 patients. Data are required on the burden and predictors of long COVID in a broader patient group, which includes both tested and untested COVID-19 patients in primary care. METHODS: This is an observational study using data from Platform C19, a quality improvement program-derived research database linking primary care electronic health record data (EHR) with patient-reported questionnaire information. Participating general practices invited consenting patients aged 18-85 to complete an online questionnaire since 7th August 2020. COVID-19 self-diagnosis, clinician-diagnosis, testing, and the presence and duration of symptoms were assessed via the questionnaire. Patients were considered present with long COVID if they reported symptoms lasting ≥4 weeks. EHR and questionnaire data up till 22nd January 2021 were extracted for analysis. Multivariable regression analyses were conducted comparing demographics, clinical characteristics, and presence of symptoms between patients with long COVID and patients with shorter symptom duration. RESULTS: Long COVID was present in 310/3151 (9.8%) patients with self-diagnosed, clinician-diagnosed, or test-confirmed COVID-19. Only 106/310 (34.2%) long COVID patients had test-confirmed COVID-19. Risk predictors of long COVID were age ≥40 years (adjusted Odds Ratio [AdjOR]=1.49 [1.05-2.17]), female sex (adjOR=1.37 [1.02-1.85]), frailty (adjOR=2.39 [1.29-4.27]), visit to A&E (adjOR=4.28 [2.31-7.78]), and hospital admission for COVID-19 symptoms (adjOR=3.22 [1.77-5.79]). Aches and pain (adjOR=1.70 [1.21-2.39]), appetite loss (adjOR=3.15 [1.78-5.92]), confusion and disorientation (adjOR=2.17 [1.57-2.99]), diarrhea (adjOR=1.4 [1.03-1.89]), and persistent dry cough (adjOR=2.77 [1.94-3.98]) were symptom features statistically more common in long COVID. CONCLUSION: This study reports the factors and symptom features predicting long COVID in a broad primary care population, including both test-confirmed and the previously missed group of COVID-19 patients.

Rationale: Severe exacerbations are associated with an increased risk of mortality in patients with chronic obstructive pulmonary disease (COPD). In the IMPACT trial, fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy was associated with a 34% reduction in the annual rate of severe exacerbations versus the long-acting muscarinic antagonist/long-acting beta2-agonist (LAMA/LABA) UMEC/VI in patients with symptomatic COPD and a history of exacerbations. Furthermore, FF/UMEC/VI also reduced on-treatment allcause mortality (ACM) risk by 42% when compared with UMEC/VI. This analysis investigated the risk of ACM during and following a moderate or severe exacerbation in patients enrolled in the IMPACT trial. Method(s): IMPACT was a Phase III, randomized, double-blind, 52-week trial comparing once-daily FF/UMEC/VI 100/62.5/25 mcg with FF/VI 100/25 mcg and UMEC/VI 62.5/25 mcg. Eligible patients (>=40 years of age) had symptomatic COPD (COPD Assessment Test score >=10), and a forced expiratory volume in 1 second (FEV1) =1 moderate or severe exacerbation in the prior year, or a FEV1 50-=2 moderate or >=1 severe exacerbations in the prior year. This post hoc analysis analyzed the risk of on-treatment ACM during and 1-90 and 91-365 days post moderate or severe exacerbations, versus baseline using a time-dependent repeated measures Cox model. Moderate exacerbations were those requiring treatment with antibiotics or systemic/oral corticosteroids. Severe exacerbations were those resulting in hospitalization or death. Result(s): 10,355 patients were included in the intent-to-treat population. 5034 (48.6%) patients experienced moderate/severe exacerbations. The risk of ACM was significantly increased during a severe exacerbation event compared with baseline (hazard ratio [HR] 41.22, 95% confidence interval [CI] 26.49, 64.15; P

Rationale: in the IMPACT (Informing the Pathway of COPD Treatment) trial, single-inhaler fluticasone furoate/umeclidinium/ vilanterol (FF/UMEC/VI) triple therapy reduced exacerbation risk versus FF/VI and UMEC/VI and mortality risk versus UMEC/VI. However, pneumonia incidence was higher in the inhaled corticosteroid (FF)–containing arms, raising questions about the relative benefit of exacerbation reduction compared with the increased risk of pneumonia. Objectives: Determine benefit–risk of the three treatments by evaluating time-to-first and rates of composite exacerbation or pneumonia outcomes. Methods: We evaluated time-to-first (prespecified) and rates (post hoc) of investigator-reported pneumonia, serious pneumonia leading to hospitalization or death, and the composite endpoints of 1) moderate (required antibiotics/corticosteroids)/ severe (hospitalized) exacerbation or pneumonia and 2) severe exacerbation or serious (hospitalized) pneumonia. Analyses were repeated for radiographically confirmed pneumonia (post hoc). Results: Moderate/severe exacerbations occurred in 47%, 49%, and 50% of patients randomized to FF/UMEC/VI, FF/VI and UMEC/VI, and pneumonias in 8%, 7%, and 5%, respectively. FF/UMEC/VI reduced the risk of combined moderate/severe exacerbation or pneumonia (time-to-first) versus FF/VI (hazard ratio, 0.87 [95% confidence interval (CI), 0.82–0.92]) and UMEC/VI (0.87 [0.81–0.94]), as well as the risk of combined severe exacerbation or serious pneumonia versus UMEC/VI (0.83 [0.72–0.96]). FF/UMEC/VI reduced the rate of combined moderate/severe exacerbation or pneumonia (rate ratio, 0.78 [0.72–0.84]) and combined severe exacerbation or serious pneumonia (rate ratio, 0.76 [0.65–0.89]) versus UMEC/VI. Results were similar for radiographically confirmed pneumonia endpoints. Conclusions: Despite higher incidence of pneumonia in FF-containing arms, these composite exacerbation/pneumonia outcomes support a favorable benefit–risk profile of FF/UMEC/VI versus FF/VI and UMEC/VI in patients with symptomatic chronic obstructive pulmonary disease and a history of exacerbations.

This document is the direct transcription of a Webinar organized by Prof. L. Corbetta of the University of Florence on December 17th, 2020.

Introduction: in the IMPACT trial, single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) reduced moderate/severe exacerbation rates versus FF/VI or UMEC/VI dual therapy in patients with chronic obstructive pulmonary disease (COPD); however, pneumonia incidence was higher in FF-containing arms. As COPD is a growing problem in Asia, we compared the efficacy and safety of FF/UMEC/VI in Asia versus non-Asia regions. Methods: IMPACT was a double-blind, 52-week trial in symptomatic COPD patients with ≥ 1 moderate/severe exacerbation in the prior year. This pre-specified analysis evaluated the annual rate of moderate/severe exacerbations, change from baseline in trough forced expiratory volume in 1 s, and St George’s Respiratory Questionnaire total score, mortality, and safety (including pneumonia) in Asia versus non-Asia regions. Results: the intent-to-treat population comprised 10,355 patients (Asia n = 1644 [16%]). Rate ratios (95% confidence intervals) for moderate/severe exacerbations with FF/UMEC/VI were 0.89 (0.76–1.05) versus FF/VI and 0.86 (0.71–1.04) versus UMEC/VI in Asia, and 0.84 (0.79–0.90) and 0.74 (0.68–0.80) in non-Asia. Efficacy of FF/UMEC/VI on other endpoints was similar in both regions. There was an increased incidence of investigator-reported pneumonia in patients in Asia (FF/UMEC/VI: 13%; FF/VI: 14%; UMEC/VI: 6%) compared with non-Asia (FF/UMEC/VI: 6%; FF/VI: 5%; UMEC/VI: 4%). The increased risk of pneumonia in patients in Asia was most marked in patients with lower body mass index, lower lung function, and taking inhaled corticosteroids. In post hoc analysis of adjudicated on-treatment all-cause mortality, probabilities of death were numerically lower in both regions with FF/UMEC/VI (Asia: 1.16%; non-Asia: 1.35%) and FF/VI (Asia: 1.77%; non-Asia: 1.21%) versus UMEC/VI (Asia: 1.91%; non-Asia: 2.23%). Conclusions: FF/UMEC/VI provides similar benefits in COPD patients in Asia and non-Asia regions. Clinical benefits of treatment, including reduction in mortality risk, should be weighed against risk of pneumonia, taking account of all known risk factors. Trial Registration: ClinicalTrials.gov identification, NCT02164513.

Introduction: the Fostair® 100/6 (BDP/FF) pressurized metered-dose inhaler, delivering an extrafine formulation, is licensed for asthma and COPD in the UK. However, its real-life effectiveness for COPD has not been evaluated. This study compared the clinical effectiveness of BDP/FF against other licensed ICS/LABA combination inhalers: the Seretide® Accuhaler® (FP/SAL) and the Symbicort® Turbohaler® (BUD/FF). Methods: a matched historical cohort study was conducted using records of patients with diagnostic codes for COPD from the Optimum Patient Care Research Database (OPCRD). Patients who had received BDP/FF as their first ICS/LABA were matched 1:1 with patients who had received FP/SAL or BUD/FF, resulting in two matched comparisons. Additional analysis was conducted on patients who had never had diagnostic codes for asthma. Noninferiority in terms of the proportion of patients with moderate/severe COPD exacerba-tions on the different inhalers in the following year was assessed. Noninferiority was achieved if the upper CI limit were ≤1.2. Results: This study included 537 and 540 patient pairs in the BDP/FF vs FP/SAL cohort and the BDP/FF vs BUD/FF cohort, respectively. The proportion of patients with COPD exacer-bations in the BDP/FF group was not significantly different from either the FP/SAL (68.7% vs 70.2%, AOR 0.89, 95% CI 0.67–1.19) or BUD/FF group (68.5% vs 69.4%, AOR 0.79, 95% CI 0.58–1.08). Noninferiority of BDP/FF in preventing COPD exacerbations was fulfilled in both comparisons. In patients without asthma, BDP/FF was also noninferior to BUD/FF (proportion with COPD exacerbations, 67.8% vs 64.7%, AOR 0.79, 95% CI 0.51– 1.1997). Additionally, a significantly lower proportion of patients prescribed BDP/FF had COPD exacerbations than FP/SAL (64.8% vs 73.7%, AOR 0.64 95% CI 0.43–0.96). Conclusion: Initiating ICS/LABA treatment of COPD with extrafine-formulation BDP/ FF was noninferior in preventing moderate/severe exacerbations compared to FP/SAL and BUD/FF.

This paper offers practical and feasible actions to be implemented at patient, healthcare provider and community level to combat COVID-19 while attending, maintaining and strengthening ongoing health management in people with lung diseases https://bit.ly/30yNyhP

We examined associations between blood eosinophil counts (BEC) and risk of treatment failure or hospital readmission following acute oral corticosteroid (OCS)-treated COPD exacerbations. We conducted studies from the Optimum Patient Care Research Database (OPCRD) (www.optimumpatientcare.org/opcrd) and Clinical Practice Research Datalink (CPRD) (www.cprd.com/home/), validated databases for medical research, with linked Hospital Episode Statistics (HES) data for ∼20 000 COPD patients aged ≥40�
years. For patients with OCS-treated COPD exacerbations treated in primary care, with BECs recorded on first day of OCS treatment (Cohort 1), we assessed treatment failure (COPD-related hospitalisations and OCS prescriptions beyond index OCS course). For patients hospitalised for COPD exacerbations, with BEC measured over an exacerbation-free period during the year prior to admission (Cohort 2), we assessed readmission rate. Cox proportional hazards regression analysis was adjusted for confounders to estimate the association between BEC and treatment outcomes. of patients treated with OCS for COPD exacerbations in primary care (Cohort 1), 44% experienced treatment failure following single OCS courses, and 10% (255/2482) were hospitalised for ≤6�
weeks. Greater BEC was associated with reduced hospital-admission risk (hazard ratio [HR]=0.26; 95% CI: 0.12-0.56, per 100 cells·µL-1 increase). BEC increases of ≥200�
cells·µL-1 from exacerbation-free periods to exacerbations were associated with least hospitalisation risk (HR=0.32; 95% CI: 0.15-0.71) versus no BEC change. For patients hospitalised for COPD exacerbations (Cohort 2), 4-week hospital readmission was 12% (1189/10 245). BEC increases during an exacerbation-free period within the past year were associated with reduced risk of short-term readmission (HR=0.78; 95% CI: 0.63-0.96). Greater BEC predicted better outcomes for patients with OCS-treated COPD exacerbations, whether community or hospital managed. Eosinopenia predicted worse outcomes.

Comorbid conditions (comorbidities) can complicate the diagnosis and management of asthma. In different age groups, comorbid conditions can present varying challenges, including diagnostic confusion due to mimicking asthma symptoms, exacerbation of asthma symptoms, therapy for comorbid conditions affecting asthma or therapy for asthma affecting these conditions. This review aims to summarise some common comorbid conditions with asthma, such as rhinitis, vocal cord dysfunction, gastro-oesophageal reflux, psychiatric disorders, obesity and obstructive sleep apnoea, and discuss their prevalence, symptoms, diagnosis and treatment, highlighting any differences in how they impact children and adults. Overall, there is a lack of data on the impact of treating comorbid conditions on asthma outcomes and further studies are needed to guide age-appropriate asthma management in the presence of these conditions.

Rationale: in patients with chronic obstructive pulmonary disease (COPD), use of multiple inhalers is associated with more errors and worse adherence than single-inhaler regimens, which could result in worse outcomes. Real-world effectiveness data on single-inhaler versus multiple-inhaler regimens on health status in COPD are lacking. We evaluated the impact of single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy versus multiple-inhaler triple therapy (MITT; inhaled corticosteroid+long-acting muscarinic antagonist+long-acting beta2-agonist [ICS+LAMA+LABA] combination) on health status, measured using the COPD Assessment Test (CAT), over 24 weeks in usual clinical care in five European countries. Method(s): INTREPID (NCT03467425), a randomized, open-label, phase IV effectiveness study, enrolled patients with COPD who had continuously received non-ELLIPTA maintenance therapy (MITT, or dual therapy with documented clinical indication for step-up to triple therapy) for >=16 weeks prior to randomization, CAT score >=10, and >=1 moderate/severe exacerbation in the prior 3 years. Patients were randomized to FF/UMEC/VI 100/62.5/25mug via ELLIPTA (FF/UMEC/VI cohort) or their clinician's choice of any ICS+LAMA+LABA combination in non-ELLIPTA devices (MITT cohort) for 24 weeks; patients randomized to MITT who entered on triple therapy at study entry were to remain on their previous regimen. To minimize interventions and reflect usual clinical care, commercial study medication was prescribed and only 2 study visits were mandated. The primary endpoint was the proportion of CAT responders (>=2-unit decrease in CAT score from baseline) at Week 24. Secondary endpoints in a subset were change from baseline in forced expiratory volume in 1 second (FEV1) and proportion of patients making >=1 critical error in inhalation technique at 24 weeks. Safety was evaluated descriptively. Result(s): the intent-to-treat population comprised 3092 patients (FF/UMEC/VI N=1545; MITT N=1547). The odds of being a CAT responder at Week 24 were statistically significantly greater with FF/UMEC/VI than MITT (odds ratio 1.31; p

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPARγ:Peroxisome proliferator-activated receptor, NFκB: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2α:Elongation initiation factor 2α). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT1R axis (AT1R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity.

Rationale: the IMPACT (Informing the Pathway of Chronic Obstructive Pulmonary Disease Treatment) trial demonstrated a significant reduction in all-cause mortality (ACM) risk with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus UMEC/VI in patients with chronic obstructive pulmonary disease (COPD) at risk of future exacerbations. Five hundred seventy-four patients were censored in the original analysis owing to incomplete vital status information.Objectives: Report ACM and impact of stepping down therapy, following collection of additional vital status data.Methods: Patients were randomized 2:2:1 to FF/UMEC/VI 100/62.5/25 μg, FF/VI 100/25 μg, or UMEC/VI 62.5/25 μg following a run-in on their COPD therapies. Time to ACM was prespecified. Additional vital status data collection and subsequent analyses were performed post hoc.Measurements and Main Results: We report vital status data for 99.6% of the intention-to-treat population (n = 10,355), documenting 98 (2.36%) deaths on FF/UMEC/VI, 109 (2.64%) on FF/VI, and 66 (3.19%) on UMEC/VI. For FF/UMEC/VI, the hazard ratio for death was 0.72 (95% confidence interval, 0.53-0.99; P = 0.042) versus UMEC/VI and 0.89 (95% confidence interval, 0.67-1.16; P = 0.387) versus FF/VI. Independent adjudication confirmed lower rates of cardiovascular and respiratory death and death associated with the patient's COPD.Conclusions: in this secondary analysis of an efficacy outcome from the IMPACT trial, once-daily single-inhaler FF/UMEC/VI triple therapy reduced the risk of ACM versus UMEC/VI in patients with symptomatic COPD and a history of exacerbations.

Introduction: the phase 3 InforMing the PAthway of COPD (chronic obstructive pulmonary disease) Treatment (IMPACT) trial, single-inhaler therapy with fluticasone furoate (FF) 100 μg, umeclidinium (UMEC) 62.5 μg, and vilanterol (VI) 25 μg demonstrated a reduction in the rate of moderate or severe exacerbations compared with FF/VI or UMEC/VI in patients with symptomatic COPD at risk of exacerbations. This article reports additional evidence of improvements in symptoms and health-related quality of life (HRQoL) with FF/UMEC/VI compared with either FF/VI or UMEC/VI from the IMPACT study. Methods: Patient-reported HRQoL assessments and symptom measures included as pre-specified IMPACT end points were the St George's Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT), and Baseline Dyspnea Index (BDI) as the anchor for the Transitional Dyspnea Index (TDI) focal score (BDI/TDI) in a subset of patients enrolled at study sites in North America and Europe. Change from baseline was assessed at weeks 4, 28, and 52. Results: the intent-to-treat population included 10,355 patients (TDI population: 5058 patients). Clinically meaningful improvements in SGRQ total score between baseline and week 52 favored FF/UMEC/VI over FF/VI (− 1.8 units, p < 0.001) and UMEC/VI (− 1.8 units, p < 0.001). Similar improvements in the CAT and TDI focal score were also observed with FF/UMEC/VI versus FF/VI or UMEC/VI. Conclusions: This study demonstrates that in patients with symptomatic COPD at risk of exacerbations, once-daily FF/UMEC/VI, compared with FF/VI or UMEC/VI, improves patient-perceived HRQoL and symptoms. Trial Registration Number: NCT02164513.

Background: This analysis of the IMPACT study assessed the cardiovascular (CV) safety of single-inhaler triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus FF/VI and UMEC/VI dual therapy. Methods: IMPACT was a 52-week, randomized, double-blind, multicenter Phase III study comparing the efficacy and safety of FF/UMEC/VI 100/62.5/25 mcg with FF/VI 100/25 mcg or UMEC/VI 62.5/25 mcg in patients ≥40 years of age with symptomatic chronic obstructive pulmonary disease (COPD) and ≥1 moderate/severe exacerbation in the previous year. The inclusion criteria for the study were intentionally designed to permit the enrollment of patients with significant concurrent CV disease/risk. CV safety assessments included proportion of patients with and exposure-adjusted rates of on-treatment CV adverse events of special interest (CVAESI) and major adverse cardiac events (MACE), as well as time-to-first (TTF) CVAESI, and TTF CVAESI resulting in hospitalization/prolonged hospitalization or death. Results: Baseline CV risk factors were similar across treatment groups. Overall, 68% of patients (n = 7012) had ≥1 CV risk factor and 40% (n = 4127) had ≥2. At baseline, 29% of patients reported a current/past cardiac disorder and 58% reported a current/past vascular disorder. The proportion of patients with on-treatment CVAESI was 11% for both FF/UMEC/VI and UMEC/VI, and 10% for FF/VI. There was no statistical difference for FF/UMEC/VI versus FF/VI or UMEC/VI in TTF CVAESI (hazard ratio [HR]: 0.98, 95% confidence interval [CI]: 0.85, 1.11; p = 0.711 and HR: 0.92, 95% CI: 0.78, 1.08; p = 0.317, respectively) nor TTF CVAESI leading to hospitalization/prolonged hospitalization or death (HR: 1.19, 95% CI: 0.93, 1.51; p = 0.167 and HR: 0.96, 95% CI: 0.72, 1.27; p = 0.760, respectively). On-treatment MACE occurred in ≤3% of patients across treatment groups, with similar prevalence and rates between treatments. Conclusions: in a symptomatic COPD population with a history of exacerbations and a high rate of CV disease/risk, the proportion of patients with CVAESI and MACE was 10-11% and 1-3%, respectively, across treatment arms, and the risk of CVAESI was low and similar across treatment arms. There was no statistically significant increased CV risk associated with the use of FF/UMEC/VI versus FF/VI or UMEC/VI, and UMEC/VI versus FF/VI. Trial registration: NCT02164513 (GSK study number CTT116855).

IMPACT, a 52-week, randomised, double-blind trial, assessed the efficacy and safety of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy versus FF/VI or UMEC/VI in patients with symptomatic COPD and a history of exacerbations. Subgroup analyses assessed whether the efficacy of FF/UMEC/VI versus FF/VI or UMEC/VI and UMEC/VI versus FF/VI varies according to prior exacerbation history, and the combined effects of exacerbation history and blood eosinophil counts. Three subgroups were defined: single moderate (1 moderate/no severe; n=3056 (30%)), frequent moderate (≧2 moderate/no severe; n=4628 (45%)) and severe (≧1 severe/any moderate; n=2671 (26%)). End-points included annual on-treatment moderate/severe exacerbation rate (pre-specified), lung function and health status (both post-hoc). Moderate/severe exacerbation rates (reduction % (95% CI)) were reduced in the FF/UMEC/VI group versus FF/VI (single moderate 20% (10–29), frequent moderate 11% (2–19), severe 17% (7–26)) and versus UMEC/VI (single moderate 18% (5–29), frequent moderate 29% (21–37), severe 26% (14–35)). Moderate/severe exacerbation rates were reduced in the FF/VI group versus UMEC/VI in the frequent moderate subgroup; a numerical reduction was observed in the severe subgroup (single moderate 2% (-12–18), frequent moderate 21% (11–29), severe 11% (-3–22)). Moderate/severe exacerbation rates were lower in the FF/VI group compared with UMEC/VI in patients with higher eosinophil counts. FF/UMEC/VI improved lung function and health status versus both dual therapies irrespective of exacerbation subgroup. UMEC/VI improved lung function versus FF/VI in all subgroups. Triple therapy was more effective than dual regardless of exacerbation history, consistent with results in the intent-to-treat population. Comparisons between dual therapies were influenced by prior exacerbation history and eosinophil counts.

Rationale: in the IMPACT (Informing the Pathway of Chronic Obstructive Pulmonary Disease Treatment) trial, fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) significantly reduced exacerbations compared with FF/VI or UMEC/VI in patients with symptomatic chronic obstructive pulmonary disease and a history of exacerbations. Objectives: to understand whether inhaled corticosteroid (ICS) withdrawal affected IMPACT results, given direct transition from prior maintenance medication to study medication at randomization. Methods: Exacerbations and change from baseline in trough FEV1 and St. George’s Respiratory Questionnaire results were analyzed by prior ICS use. Exacerbations were also analyzed while excluding data from the first 30 days. Measurements and Main Results: FF/UMEC/VI significantly reduced the annual moderate/severe exacerbation rate compared with UMEC/VI in prior ICS users (29% reduction; P, 0.001), but only a numerical reduction was seen among prior ICS nonusers (12% reduction; P = 0.115). To minimize impact from ICS withdrawal, in an analysis excluding the first 30 days, FF/UMEC/VI continued to significantly reduce the annual on-treatment moderate/severe exacerbation rate (19%; P, 0.001) compared with UMEC/VI. The benefit of FF/UMEC/VI compared with UMEC/VI was seen for severe exacerbation rates, regardless of prior ICS use (prior ICS users, 35% reduction; P, 0.001; non-ICS users, 35% reduction; P = 0.018), and overall when excluding the first 30 days (29%; P, 0.001). Improvements from baseline with FF/UMEC/VI compared with UMEC/VI were also maintained throughout the study for both trough FEV1 and St. George’s Respiratory Questionnaire, regardless of prior ICS use. Conclusions: These data support the important treatment effects of FF/UMEC/VI combination therapy on exacerbation reduction, lung function, and quality of life that do not appear to be related to abrupt ICS withdrawal.

The term asthma chronic obstructive pulmonary disease (COPD) overlap (ACO) has been popularized to describe people who simultaneously have features of both diseases. Analysis of the basis of disease classification and comparison of the clinical, pathophysiological, and therapeutic features of asthma and COPD concludes that it is not useful to use the term ACO. Rather, it is important to make the individual diagnoses, recognizing that both diseases may coexist. If a concurrent diagnosis of COPD is suspected in people with asthma, pharmacotherapy should primarily follow asthma guidelines, but pharmacologic and nonpharmacologic approaches also may be needed for COPD.

Background: Blood eosinophil count (BEC) and fractional exhaled nitric oxide (FeNO) concentration are established biomarkers in asthma, associated particularly with the risk of exacerbations. We evaluated the relationship of BEC and FeNO as complementary and independent biomarkers of severe asthma exacerbations. Methods: This observational study included data from the Optimum Patient Care Research Database. Asthma patients (18-80 years) with valid continuous data for 1 year before FeNO reading, ≥ 1 inhaled corticosteroid prescription, and BEC recorded ≤ 5 years before FeNO reading were separated into cohorts. Categorisation 1 was based on the American Thoracic Society criteria for elevated FeNO concentration (high: ≥ 50 ppb; non-high: < 25 ppb) and BEC (high: ≥ 0.300 × 109 cells/L; non-high: < 0.300 × 109 cells/L). Categorisation 2 (FeNO concentration, high: ≥ 35 ppb; non-high: < 35 ppb) was based on prior research. Reference groups included patients with neither biomarker raised. Results: in categorisation 1, patients with either high FeNO or high BEC (n = 200) had a numerically greater exacerbation rate (unadjusted rate ratio, 1.31 [95% confidence interval: 0.97, 1.76]) compared with patients in the reference group. Combination of high FeNO and high BEC (n = 27) resulted in a significantly greater exacerbation rate (3.67 [1.49, 9.04]). Similarly, for categorisation 2, when both biomarkers were raised (n = 53), a significantly greater exacerbation rate was observed (1.72 [1.00, 2.93]). Conclusion: the combination of high FeNO and high BEC was associated with significantly increased severe exacerbation rates in the year preceding FeNO reading, suggesting that combining FeNO and BEC measurements in primary care may identify asthma patients at risk of exacerbations.

Background: Previous studies have highlighted a relationship between reduction in rate of exacerbations with therapies containing inhaled corticosteroids (ICS) and baseline blood eosinophil count in patients with chronic obstructive pulmonary disease (COPD). The IMPACT trial showed that once-daily single-inhaler triple therapy significantly reduced exacerbations versus dual therapies. Blood eosinophil counts and smoking status could be important modifiers of treatment response to ICS. We aimed to model these relationships and their interactions, including outcomes other than exacerbations. Methods: IMPACT was a phase 3, randomised, double-blind, parallel-group, 52-week global study comparing once-daily single-inhaler triple therapy (fluticasone furoate–umeclidinium–vilanterol) with dual inhaled therapy (fluticasone furoate–vilanterol or umeclidinium–vilanterol). Eligible patients had moderate-to-very-severe COPD and at least one moderate or severe exacerbation in the previous year. We used fractional polynomials to model continuous blood eosinophil counts. We used negative binomial regression for numbers of moderate and severe exacerbations, severe exacerbations, and pneumonia. We modelled differences at week 52 in trough FEV1, St George's Respiratory Questionnaire (SGRQ) total score, and Transition Dyspnoea Index using repeated measurements mixed effect models. IMPACT was registered with ClinicalTrials.gov, number NCT02164513. Findings: the magnitude of benefit of regimens containing ICS (fluticasone furoate–umeclidinium–vilanterol n=4151 and fluticasone furoate–vilanterol n=4134) in reducing rates of moderate and severe exacerbations increased in proportion with blood eosinophil count, compared with a non-ICS dual long-acting bronchodilator (umeclidinium–vilanterol n=2070). The moderate and severe exacerbation rate ratio for triple therapy versus umeclidinium–vilanterol was 0·88 (95% CI 0·74 to 1·04) at blood eosinophil count less than 90 cells per μL and 0·56 (0·47 to 0·66) at counts of 310 cells per μL or more; the corresponding rate ratio for fluticasone furoate–vilanterol versus umeclidinium–vilanterol was 1·09 (0·91 to 1·29) and 0·56 (0·47 to 0·66), respectively. Similar results were observed for FEV1, Transition Dyspnoea Index, and SGRQ total score; however, the relationship with FEV1 was less marked. At blood eosinophil counts less than 90 cells per μL and at counts of 310 cells per μL or more, the triple therapy versus umeclidinium–vilanterol treatment difference was 40 mL (95% CI 10 to 70) and 60 mL (20 to 100) for trough FEV1, −0·01 (–0·68 to 0·66) and 0·30 (–0·37 to 0·97) for Transition Dyspnoea Index score, and −0·01 (–1·81 to 1·78) and −2·78 (–4·64 to −0·92) for SGRQ total score, respectively. Smoking status modified the relationship between observed efficacy and blood eosinophil count for moderate or severe exacerbations, Transition Dyspnoea Index, and FEV1, with former smokers being more corticosteroid responsive at any eosinophil count than current smokers. Interpretation: This analysis of the IMPACT trial shows that assessment of blood eosinophil count and smoking status has the potential to optimise ICS use in clinical practice in patients with COPD and a history of exacerbations. Funding: GlaxoSmithKline.

The abstract will be presented as an ENCORE by Dr. Marcel Reeh on behalf of the authors with their permissions. It was presented at ERS 2018 in Paris. Advertorial Background IMPACT is a landmark > 10,000 patient study that simplifies patient care in COPD and prospectively identifies phenotypes/endotypes associated with preferential response to inhaled maintenance treatments. Previous studies have shown a relation between ICS-associated reduction in the rate of acute exacerbation of COPD (AECOPD) and baseline blood eosinophil count (BEC). Methods IMPACT is a randomised, double-blind, parallel-group, 52-week, global study comparing once-daily fluticasone furoate(FF)/umeclidinium(UMEC)/vilanterol(VI) to components FF/VI and UMEC/VI. Eligible patients had moderate to severe COPD and experienced > 1 moderate/severe AECOPD in the past 12 months. We used negative binomial regression with fractional polynomials for modelling of continuous BEC, to model the number of moderate/severe AECOPD, comparing subjects in the 3 treatment groups. Results the magnitude of benefit of ICS containing arms (FF/UMEC/VI [N = 4,151] and FF/VI [N = 4,134]) compared to non-ICS (UMEC/VI [N = 2,070]) in reducing the rate of moderate/severe AECOPD increased in proportion to BEC ([Fig. 1]). Modeled data showing relationship between BEC and rate of moderate/severe exacerbations by treatment, point estimates show data fitted in quintiles. Conclusions in exacerbating COPD patients treated with UMEC/VI but not in those receiving FF (ICS), exacerbation rate increases with increasing BEC. Baseline BEC is linked with FF-associated exacerbation reduction on a continuous scale. This analysis prospectively confirms the value of BEC in the management of COPD.

Effectiveness studies complement conventional randomised controlled trials by providing a holistic view of treatments in the setting of usual clinical practice. We present the protocol for the ongoing INTREPID (INvestigation of TRelegy Effectiveness: usual PractIce Design; ClinicalTrials.gov identifier: NCT03467425) study, a randomised, open-label, 24-week effectiveness study of once-daily fluticasone furoate/ umeclidinium/vilanterol (FF/UMEC/VI; Trelegy) delivered by the ELLIPTA inhaler versus non-ELLIPTA multiple-inhaler triple therapy in patients with chronic obstructive pulmonary disease (COPD) in usual practice settings. INTREPID was designed to provide evidence of FF/UMEC/VI effectiveness in patients with COPD managed in routine healthcare systems across multiple European countries. Between study initiation and endof- study visits, patients will receive their medication and care as they would ordinarily receive it, from their usual healthcare provider at their usual healthcare centre. Study-specific intervention will be minimal. The primary end-point will be the proportion of COPD assessment test (CAT) responders, defined as a clinically meaningful improvement from baseline of ≥2 units, at week 24. The CAT was chosen as it provides health status information relevant to patients, physicians, health technology agencies and payers. Lung function (forced expiratory volume in 1 s) and critical inhaler errors will also be assessed in a subgroup of patients. The strengths and weaknesses of the protocol and some of the challenges associated with conducting this multicountry study, such as differences in healthcare systems and treatment practices across sites, will also be discussed.

The abstract will be presented as an ENCORE by Dr. Sven Micklisch on behalf of the authors with their permissions. It was presented at ERS 2018 in Paris. Rationale Current GOLD strategy document positions both combination regimens of inhaled corticosteroid plus a long-acting p2 -agonist [i.e. ICS/LABA] and long-acting muscarinic antagonist plus LABA [i.e. LAMA/LABA] for symptomatic patients with recurrent exacerbations. Methods the InforMing the PAthway of COPD Treatment (IMPACT) study was a phase III, double-blind, parallel-group, multicenter study that compared the efficacy and safety of single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 ug (FF/UMEC/VI), FF/VI 100/25 u.g or UMEC/VI 62.5/25 ug, all using the ELLIPTA inhaler in symptomatic patients with COPD and exacerbation history, randomised 2 :2 : 1, respectively to 52 weeks of treatment. The primary efficacy results on the annual rate of moderate or severe exacerbations are presented separately. Additional endpoints included change from baseline [CFB] in forced expiratory volume in 1 s (trough FEV1), St George's Respiratory Questionnaire (SGRQ) for FF/VI compared with UMEC/VI. Results of the 10 355 patients enrolled, 4134 received FF/VI and 2070 received UMEC/VI. At Week 52, there was a statistically significant improvement in trough FEV1 with UMEC/VI vs. FF/VI (mean CFB 40 mL and -3 mL, treatment difference 43 mL [95% CI: 28, 58 mL]; p < 0.001). The mean CFB in SGRQ Total score at week 52 was similar for both treatments (-3.7 units). Conclusions UMEC/VI improved lung function compared with the once daily ICS/LABA FF/VI in patients with symptomatic COPD and at risk of exacerbations whereas the SGRQ Total score was similar. These results may help to inform treatment choices for this patient population.

Background: the 2019 Global Initiative for Chronic Obstructive Lung Disease (GOLD) report made recommendations for the assessment, initial and subsequent treatment chronic obstructive pulmonary disease (COPD) based on biomarkers, including blood eosinophil counts. Methods: We evaluated the distribution of UK COPD patients initiating maintenance therapy and established patients by GOLD group, the prevalence of comorbidities and appropriateness of therapy using electronic patient records from the Optimum Patient Care Research Database (OPCRD). Changes in effective GOLD group, therapy and exacerbation rates over the next 2 years were analysed. Findings: 11,409 established COPD patients and 699 starting therapy were studied. 44·3%, 25·7%, 13·8% & 16·2% of established COPD patients and 45·2%, 28·5%, 15·7% & 10·6% initiating therapy were in GOLD groups A, B, C & D respectively. The overall proportion in each GOLD group was similar after 2 years but there was substantial movement of patients between groups. Diabetes and cardiovascular disease were the most common comorbidities in all groups in both cohorts. LAMA monotherapy was the commonest initial therapy in all GOLD groups. In both cohorts there was over-treatment with escalation, de-escalation or switching in nearly 50% during follow-up. In both cohorts, exacerbation rates were highest in group D and appeared higher in over-treated patients. Interpretation: Most patients are not at risk of exacerbations and co-morbidities are common. Many patients change effective GOLD group and therapy over time. Prescribing is not in accordance with guideline recommendations and many patients still appear over treated.

The abstract will be presented as an ENCORE by Dr. Friederike Klein on behalf of the authors with their permissions. It was presented at ERS 2018 in Paris. Advertorial Rationale Current GOLD strategy document positions both combination regimens of inhaled corticosteroid plus a long-acting p2 -agonist [ICS/LABA] and LABA plus long-acting muscarinic antagonist [LAMA/LABA] for symptomatic patients with recurrent exacerbations (GOLD D) but only LAMA/LABA for persistently symptomatic patients with < 1 non-hospitalized exacerbations (GOLD B). A recent study suggests superiority of LABA/LAMA over ICS/LABA (NEJM 2016;374 :23) Methods the InforMing the PAthway of COPD Treatment (IMPACT) study evaluated the annual rate of moderate/severe exacerbations on fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 jg vs. UMEC/VI (LAMA/LABA) 62.5/25 jg and FF/VI (ICS/LABA) 100/25 jg over 52-weeks in symptomatic patients with > 1 exacerbation. This analysis compared annual rate and time to first (TTF) exacerbation between UMEC/VI and FF/VI in the intention-to-treat (ITT) population and within subgroups (some analyses were post-hoc). Findings in the ITT analysis, FF/VI reduced exacerbation rate vs. UMEC/VI (p < 0.01); subgroups analyses are shown in the figure. Conclusion in IMPACT, exacerbation rate reduction favoured FF/VI vs. UMEC/VI in the ITT, GOLD D and baseline triple therapy-treated patients. In baseline LAMA-treated patients, and consistent with FLAME findings, there was a trend favouring UMEC/VI but low statistical power limited confirmation.

Rationale: the 52-week, randomized, double-blind, multicenter IMPACT study compared fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25mcg with FF/VI 100/25mcg and UMEC/VI 62.5/25mcg in patients aged >=40 years with symptomatic chronic obstructive pulmonary disease (COPD) and a history of exacerbations (N=10,355). The primary endpoint was annual on-treatment moderate/severe exacerbation rate. Here we present analyses based on COPD medication use at screening. Method(s): Post hoc analyses of annual moderate/severe and severe exacerbation rates, lung function (trough forced expiratory volume in 1 second [FEV1], Week 52) and health-related quality of life (St George's Respiratory Questionnaire [SGRQ], Week 52) were conducted for FF/UMEC/VI versus UMEC/VI and FF/VI in the following COPD medication subgroups (defined by use within 3 days prior to screening): inhaled corticosteroid+long-acting muscarinic antagonist+long-acting beta2-agonist (ICS+LAMA+LABA), LAMA+LABA, ICS+LABA, and LAMA. The study was not powered to analyze between-treatment differences in these outcomes by subgroups. Exacerbation rates were analyzed using a generalized linear model assuming negative binomial distribution. Trough FEV1 and SGRQ were analyzed using a repeated measures model. Result(s): in all treatment arms, annual moderate/severe exacerbation rates varied with therapy at screening (Figure). In patients on ICS+LAMA+LABA or ICS+LABA at screening, FF/UMEC/VI significantly reduced annual moderate/severe exacerbation rates versus FF/VI and UMEC/VI (Figure). In patients on LAMA+LABA at screening, FF/UMEC/VI significantly reduced annual moderate/severe exacerbation rates versus FF/VI; a reduction was also seen versus UMEC/VI but was not statistically significant (Figure). There were no statistically significant differences in annual moderate/severe exacerbation rates with FF/UMEC/VI versus both comparators in patients on LAMA at screening (Figure). Significant reductions in annual severe exacerbation rates were seen with FF/UMEC/VI versus both comparators in patients on ICS+LAMA+LABA at screening, and versus UMEC/VI in patients on ICS+LABA at screening; other comparisons were not statistically significant. Significant improvements in lung function were seen with FF/UMEC/VI versus both comparators regardless of COPD medication use at screening. FF/UMEC/VI significantly improved SGRQ versus both comparators in patients on ICS+LAMA+LABA or ICS+LABA at screening, and versus FF/VI in patients on LAMA at screening; SGRQ results were in favor of FF/UMEC/VI for other comparisons but not statistically significant. Conclusion(s): Benefits of FF/UMEC/VI versus FF/VI and UMEC/VI were demonstrated across several COPD endpoints in patients on ICS+LAMA+LABA or ICS+LABA at screening, consistent with the overall intent-to-treat population results. Benefits were also seen in patients on LAMA/LABA at screening for FF/UMEC/VI versus FF/VI, while no significant between-treatment differences were observed in patients on LAMA at screening.

Rationale: the IMPACT trial (NCT02164513, CTT116855), demonstrated a statistically significant and clinically relevant reduction in the risk of on-treatment all-cause-mortality (ACM), and in ACM including off-treatment data in the Intention-to-Treat (ITT) population, comparing FF/UMEC/VI with UMEC/VI. However, 574 subjects (5.5%) were censored from the original analysis including off-treatment data because of incomplete vital status information at Week 52, suggesting that the mortality reduction finding could be fragile. We now report the findings of ACM following collection of additional vital status data from the trial. Method(s): IMPACT (N=10,355) was a 52-week phase III, randomized, double-blind, parallel group, multicenter trial in 37 countries that compared the efficacy, safety and tolerability of single-inhaler ICS/LAMA/LABA triple therapy (FF/UMEC/VI) versus ICS/LABA (FF/VI) or LABA/LAMA (UMEC/VI) dual therapy. Subjects were randomized in a 2:2:1 fashion to these arms. Time to ACM was a prespecified endpoint. Additional vital status data collection and subsequent analyses were performed post-hoc. Result(s): the IMPACT trial demonstrated a 42.1% reduction in the risk of on-treatment ACM (95% CI: 11.9, 61.9; p=0.011), and a 28.6% reduction in the risk of ACM (95% CI: 1.0, 48.6; p=0.043) including off-treatment data, in the Intention-to-Treat (ITT) population, comparing FF/UMEC/VI with UMEC/VI. The initial analyses censored 574 subjects (5.5%) from the ITT, as previously reported. Additional data collection now provides data for 99.6% of the population (42 subjects censored). The on-treatment findings are not affected by this data collection and these analyses. Twenty-seven additional off-treatment deaths were identified in the post-hoc collection of vital status information and included in the analyses. There were 98 deaths (2.36%) on FF/UMEC/VI, 109 (2.64%) on FF/VI and 66 (3.19%) on UMEC/VI. For patients randomized to FF/UMEC/VI, the hazard ratio (HR) for death was 0.89 (11% reduction; 95% CI 0.67, 1.16; p=0.387) compared to FF/VI, and 0.72 (27.7% reduction; 95% CI 0.53, 0.99; p=0.042) compared to UMEC/VI, using a Cox proportional hazards model (Figure). Sensitivity analyses supported the findings. Conclusion(s): Once-daily single-inhaler triple therapy with FF/UMEC/VI reduced the risk of all-cause-mortality compared to UMEC/VI in a large patient population with symptomatic COPD and a history of exacerbations. These results confirm the robustness of the originally reported findings.

The abstract will be presented as an ENCORE by Dr. Christina Hermsen on behalf of the authors with their permissions. It was presented at ERS 2018 in Paris. Advertorial Background to determine overall benefit-risk, we examined the effect of single inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus UMEC/VI and FF/VI on the composite outcome of acute exacerbation of COPD or pneumonia in the IMPACT study (NCT02164513, CTT116855), a 52-week, randomized, multicentre study in patients with symptomatic COPD and a history of exacerbations Methods We defined two composite outcomes: time to first moderate (required antibiotics and/or oral/systemic corticosteroids)/severe (required hospitalisation) exacerbation or pneumonia; and time to first severe exacerbation/hospitalised pneumonia. Analyses were based on a proportional hazards model. Results Moderate/severe exacerbations occurred in 47% of patients randomized to FF/UMEC/VI, 49% in those randomized to FF/VI and 50% in those randomized to UMEC/VI. Pneumonias occurred in 8%, 7%, and 5% of patients in these groups, respectively. FF/UMEC/VI reduced the risk of first moderate/severe exacerbation or pneumonia vs. FF/VI by 13.2% (95%CI 7.8 - 18.3%; p < 0.001) and vs. UMEC/VI by 13.1% (95%CI 6.3 - 19.3%; p < 0.001) as determined by a time to first analysis. There was no difference in the risk of a moderate/severe exacerbation or pneumonia between FF/VI and UMEC/VI. FF/UMEC/VI reduced the risk of a severe exacerbation or hospitalized pneumonia vs. UMEC/VI by 16.9% (95%CI 4.2 -27.8%, p = 0.011) as determined by a time to first analysis. There was no statistically significant difference in the risk of a severe exacerbation or hospitalized pneumonia between FF/UMEC/VI and FF/VI or between FF/VI and UMEC/VI. Conclusion These composite exacerbation/pneumonia outcomes support a favourable benefit-risk profile of once-daily FF/UMEC/VI compared with FF/VI and UMEC/VI in patients with moderate to severe COPD and a history of exacerbations.

Chronic obstructive pulmonary disease (COPD) is one of the top three causes of death worldwide, but governments and non-governmental organisations have not given its prevention and treatment the priority it requires. This is particularly true in low- and middle-income countries, where most of the people suffering from this disease live. The United Nations (UN) has targeted a reduction of premature deaths from noncommunicable diseases (NCDs) by a third by 2030; however, a coordinated UN/World Health Organization (WHO) strategy to address the burden of COPD (one of the most important NCDs) is still lacking. To explore the extent of the problem and inform the development of policies to improve the situation, the Board of Directors of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) held a 1-day Summit. The key themes that emerged were the need to ensure accurate data on prevalence, raise awareness of the disease among the public, healthcare professionals and governments, including the fact that COPD aetiology goes beyond smoking (and other inhaled pollutants) and includes poor lung development in early life, and ensure that spirometry and both pharmacological and non-pharmacological therapies are available and affordable. Here, we present the actions that must be taken to address the impact of COPD. We believe that the WHO is particularly well-positioned to co-ordinate an attack on COPD, and GOLD will do all it can to help and rally support.

Clinical practice guidelines are ubiquitous and are developed to provide recommendations for the management of many diseases, including chronic obstructive pulmonary disease. The development of these guidelines is burdensome, demanding a significant investment of time and money. In Europe, the majority of countries develop their own national guidelines, despite the potential for overlap or duplication of effort. A concerted effort and consolidation of resources between countries may alleviate the resource-intensity of maintaining individual national guidelines. Despite significant resource investment into the development and maintenance of clinical practice guidelines, their implementation is suboptimal. Effective strategies of guideline dissemination must be given more consideration, to ensure adequate implementation and improved patient care management in the future.

RATIONALE: in adults and adolescents FEV1 is generally viewed as the preferred lung function assessment in asthma clinical trials. PEF was assessed as an alternative endpoint. METHOD(S): FEV1 and PEF outcomes from 7 trials with tiotropium Respimat add-on to ICS +/- additional controllers were compared. Change from baseline in peak FEV1(0-3h), trough FEV1 and PEFam/pm with tiotropium 5mug, 2.5mug and placebo, delivered by Respimat (2 puffs once daily), were analyzed from studies in patients with symptomatic asthma (adults: GraziaTinA-asthma, MezzoTinA-asthma and PrimoTinA-asthma; 12-17-year-olds: PensieTinA-asthma and RubaTinA-asthma). Correlation of in-clinic and weekly mean home measurements (AM3 Home Spirometer and eDiary) of FEV1 and PEF was also analyzed post hoc. RESULT(S): Improvements in both measures of lung function were seen in all studies with tiotropium Respimat: FEV1(0-3h), 90-185mL and 111- 223mL with 5mug and 2.5mug, respectively; and PEFam, 15.8-25.6L/min and 9.7-26.3L/min with 5mg and 2.5mg, respectively. PEF appeared better able to identify tiotropium dose-response relationships. Measurements at home versus those in-clinic correlated better for PEF (intraclass correlation coefficient [ICC] 0.724-0.839) than for FEV1 (ICC 0.575-0.818), atWeek 12 or 24, depending on the study, indicating that home assessed PEF as an endpoint may give additional information over and above FEV1. CONCLUSION(S): FEV1 and PEF both improved with tiotropium added to ICS other controllers versus placebo in all studies. However, home PEF measurements may have certain advantages over home FEV1 measurements such as identification of dose ordering, ease of use and increasing convenience for the study subject.

BACKGROUND: the benefits of triple therapy for chronic obstructive pulmonary disease (COPD) with an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting β2-agonist (LABA), as compared with dual therapy (either inhaled glucocorticoid-LABA or LAMA-LABA), are uncertain. METHODS: in this randomized trial involving 10,355 patients with COPD, we compared 52 weeks of a once-daily combination of fluticasone furoate (an inhaled glucocorticoid) at a dose of 100 μg, umeclidinium (a LAMA) at a dose of 62.5 μg, and vilanterol (a LABA) at a dose of 25 μg (triple therapy) with fluticasone furoate-vilanterol (at doses of 100 μg and 25 μg, respectively) and umeclidinium-vilanterol (at doses of 62.5 μg and 25 μg, respectively). Each regimen was administered in a single Ellipta inhaler. The primary outcome was the annual rate of moderate or severe COPD exacerbations during treatment. RESULTS: the rate of moderate or severe exacerbations in the triple-therapy group was 0.91 per year, as compared with 1.07 per year in the fluticasone furoate-vilanterol group (rate ratio with triple therapy, 0.85; 95% confidence interval [CI], 0.80 to 0.90; 15% difference; P

Rationale: Lung function, health status, and exacerbations are important measures of chronic obstructive pulmonary disease (COPD) progression. So far, treatments in COPD have failed to demonstrate a reduction in rate of decline of trough forced expiratory volume in 1 second (FEV1) or mortality, which may be related to the multicomponent nature of COPD. This post hoc analysis assessed the suitability to predict long-term outcomes using a composite endpoint in patients with moderate to very severe COPD in the UPLIFT trial that may better reflect the multifactorial disease progression in COPD. Method(s): in the 4 year UPLIFT study (NCT00144339) Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stage 2-4 COPD patients were randomized to receive tiotropium 18 mug once daily (via Handihaler) or placebo. A composite endpoint of clinically important deterioration (CID: first confirmed =100mL decrease in FEV1, confirmed increase in St. George's Respiratory Questionnaire (SGRQ) total score of =4units, or time to first moderate/severe exacerbation) was tested and treatment arms were pooled. Result(s): CID events were highly variable across patients. Confirmed FEV1 deterioration and confirmed SGRQ deterioration were observed at the same assessment in only 18% of patients. Time intervals between a first event and subsequent, different, event type were also highly variable. CID events at 6 and 12 months were a good predictor of moderate/severe and severe exacerbation, but a weaker, predictor for death [CID at 6 months HR: 1.21,95% CI: 1.06, 1.39; CID at 12 months HR 1.31, 95% CI: 1.13, 1.53]. When CID events were analyzed as time-varying covariate to predict death, it was associated with a HR of 1.69 [95% CI 1.42, 2.01]. Importantly, tiotropium significantly lowered Hazard ratios for time to first CID in GOLD 2 [HR: 0.70, 95% CI: 0.65, 0.77] and GOLD 3 patients [HR: 0.69, 95% CI: 0.63, 0.75]. Conclusion(s): Here we show that CID is a clinically meaningful parameter in order to predict long-term outcome in COPD, including mortality. CID may therefore have a significant impact on future clinical trial designs, e.g. by reducing the optimal number of participants to show a clinically relevant effect of therapeutic intervention. CID may also change future treatment strategies by taking into account the multicomponent nature of COPD.

Triple inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) therapy is recommended for symptomatic patients with chronic obstructive pulmonary disease (COPD) and at risk of exacerbations. However, the benefits versus side-effects of triple inhaled therapy for COPD, based on distinct patient clinical profiles, are unclear. FULFIL, a phase III, randomised, double-blind study, compared 24 weeks of once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 µg using the Ellipta inhaler with twice-daily budesonide/formoterol (BUD/FOR) 400/12 µg using the Turbuhaler. Subgroup analyses of forced expiratory volume in 1 s (FEV1), St George’s Respiratory Questionnaire (SGRQ) Total score and exacerbation rates were carried out. Subgroups were defined by COPD medication at screening (ICS+LABA, BUD+FOR, ICS+LABA+LAMA, LAMA alone, tiotropium alone and LAMA+LABA), by disease severity (lung function and exacerbations) and by exacerbation history (exacerbation severity and frequency). In the intent-to-treat population (n=1810) at week 24, FF/UMEC/VI (n=911) versus BUD/FOR (n=899) improved FEV1 and SGRQ Total score and reduced mean annual exacerbation rates in all disease severity and exacerbation history subgroups. FF/UMEC/VI versus BUD/FOR improved FEV1 and SGRQ Total score in all medication subgroups and reduced mean annual exacerbation rates in all medication subgroups, except LAMA+LABA. Adverse events were similar across subgroups. These findings support the benefit of FF/UMEC/VI compared with dual ICS/LABA therapy in patients with symptomatic COPD regardless of disease severity or prior treatment and may help to inform clinical decision making.

Bronchodilator therapy is central to the management of chronic obstructive pulmonary disease and are recommended as the preferred treatment by the Global Obstructive Lung Disease Initiative (GOLD). Long acting anti-muscarinics (LAMA) and long acting ?2 agonists (LABA) are both more effective than regular short-acting drugs but many patients remain symptomatic despite monotherapy with these drugs. Combination therapy with LAMA and LABA increases the therapeutic benefit while minimizing dose-dependent side effects of long-acting bronchodilator therapy. The TOviTO programme has investigated the benefits of treatment with a combination of tiotropium and olodaterol administered via a single inhaler. Tiotropium+olodaterol 5/5 µg significantly improved forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 3 hours, trough FEV1 health status and breathlessness versus the mono-components and placebo. Tiotropium+olodaterol 5/5 µg also increased endurance time and reduced dynamic hyperinflation during constant work rate cycle ergometry. On the basis of these and other studies the 2017 GOLD report recommends escalating to dual bronchodilator therapy in patients in groups B and C if they remain symptomatic or continue to have exacerbations and as initial therapy for patients in group D.

RATIONALE We performed a comprehensive assessment of the effect of tiotropium Respimat add-on therapy on episodes of asthma worsening in adult patients with symptomatic asthma despite inhaled corticosteroid (ICS)/long-acting beta2-agonist (LABA) treatment. METHODS the PrimoTinA-asthma studies (NCT00772538/NCT00776984) were two replicate 48-week, Phase III trials, which, when pooled, were powered to investigate the effect of tiotropium Respimat 5mug (as 2 puffs once daily) or placebo on episodes of asthma worsening and exacerbations when added onto ICS >=800mug budesonide equivalent/day + LABA +/- additional controller medication. Endpoints included time to first episode of asthma worsening during the 48-week treatment period - defined as either a progressive increase in symptoms (as compared with usual day-to-day asthma symptoms), or a decline of 30% or more in morning peak expiratory flow for 2 or more consecutive days - and number of episodes of asthma worsening per patient. Time to first asthma worsening was also analyzed by baseline patient characteristics, and number of episodes was analyzed by month in order to determine any seasonality effect. RESULTS in pooled data from the two studies (N=912), time to first asthma worsening was longer in the tiotropium group compared with placebo, with a 31% risk reduction (hazard ratio 0.69; 95% confidence interval [CI] 0.58, 0.82; P

AIMS: a discussion of methodological issues and social media recruitment to a feasibility study to investigate mHealth resources for asthma and pregnancy care. BACKGROUND: Pregnant women with asthma are reported to be poorly supported according to an international research. We sought to establish if a mHealth intervention might be feasible and acceptable to them. DESIGN: a Phase I or modelling study. METHODS: a project team designed an intervention to address UK national guidelines for the management of asthma during pregnancy, using other resources already accessible on the web. This was made available on a project website optimized for mobile phone usage. Links were Tweeted and advertised on Facebook, asking participants to access the project website, which included links to the resources and before- and after-use questionnaires to establish baseline symptom data and participant views of the resources. RESULTS: Despite 55,700 Twitter impressions in a 76-day period over winter 2016-2017, this recruitment strategy garnered 402 engagements but only seven respondents for questionnaire 1 and zero respondents for questionnaire 2. CONCLUSIONS: We could not recruit to this study despite believing that social media recruitment would be effective and we recommend that social media recruitment be used cautiously. Apparently, we did not sufficiently address the theoretical aspects of communications theory and were not clear enough about our key messages. Publication bias may exist about the non-publication of other failed telemedicine studies using social media; this goes largely unreported in some systematic reviews and may influence researchers' decision-making about social media recruitment.

Background COPD exacerbations are associated with accelerated lung function decline, but whether they are causal is unknown. We evaluated the effect of a single exacerbation on rate of lung function change using data from the 4-year Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) trial. Methods Retrospective analysis of annual rates of decline in FEV1 and FVC before and after a single (and the only) moderate-to-severe exacerbation in patients during UPLIFT® (exacerbator subgroup), compared with changes between the first and second half of the study in a non-exacerbator subgroup. A sensitivity analysis examined annual rates of decline in matched pairs of exacerbators and non-exacerbators. Results Following the single moderate-to-severe exacerbation, mean annual decline in post-bronchodilator lung function increased compared with the rate of decline before the exacerbation (FEV1 76.5 vs. 39.1 mL/year, p = 0.003; FVC 106.5 vs. 34.7 mL/year, p = 0.011). In non-exacerbators, there were no differences in rates of decline between the first and second halves of the study (post-bronchodilator FEV1 38.2 vs. 41.8 mL/year, FVC 45.3 vs. 43.9 mL/year. Before the single (moderate-to-severe) exacerbation in the exacerbator subgroup, declines in post-bronchodilator FEV1 or FVC were similar to non-exacerbators in the first half of the study; after the single exacerbation they were significantly higher than for non-exacerbators in the second half of the study. The sensitivity analysis showed similar results. Conclusion a single COPD exacerbation may result in significant increase in the rate of decline in lung function.

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: (i) 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; (ii) for each of the groups a to D, escalation strategies for pharmacological treatments are proposed; (iii) the concept of de-escalation of therapy is introduced in the treatment assessment scheme; (iv)non-pharmacological therapies are comprehensively presented and (v) the importance of co-morbid conditions in managing COPD is reviewed.

The quality of care can be improved by the development and implementation of evidence-based treatment guidelines. Different national guidelines for chronic obstructive pulmonary disease (COPD) exist in Europe and relevant differences may exist among them.This was an evaluation of COPD treatment guidelines published in Europe and Russia in the past 7�
years. Each guideline was reviewed in detail and information about the most important aspects of patient diagnosis, risk stratification and pharmacotherapy was extracted following a standardised process. Guidelines were available from the Czech Republic, England and Wales, Finland, France, Germany, Italy, Poland, Portugal, Russia, Spain and Sweden. The treatment goals, criteria for COPD diagnosis, consideration of comorbidities in treatment selection and support for use of long-acting bronchodilators, were similar across treatment guidelines. There were differences in measures used for stratification of disease severity, consideration of patient phenotypes, criteria for the use of inhaled corticosteroids and recommendations for other medications (e.g. theophylline and mucolytics) in addition to bronchodilators.There is generally good agreement on treatment goals, criteria for diagnosis of COPD and use of long-acting bronchodilators as the cornerstone of treatment among guidelines for COPD management in Europe and Russia. However, there are differences in the definitions of patient subgroups and other recommended treatments.

Despite increased interest and awareness of chronic obstructive pulmonary disease (COPD), nearly half of the people with COPD remain undiagnosed. Inviting people at risk for screening is unlikely to be effective as many will not attend. Co-morbidities are common in people with COPD but COPD is also a comorbidity of other long-term conditions and people with these conditions are under regular review in primary care clinics. This study aimed to develop a pilot programme to case find people with COPD among patients attending other long-term clinics in primary care. Twenty-three general practices were recruited to participate in South West England. All current or ex-smokers aged ≥35 attending a long-term condition clinic who were not known to have COPD were asked to complete a questionnaire designed to help identify people with COPD and to perform microspirometry. Practices were asked to collect data on up to 100 patients. One thousand three hundred and thirty-three patients were assessed. Four hundred and ten people (31%) were current smokers. Six hundred and thirteen (46%) had high questionnaire scores and 287 (22%) of these also had a forced expiratory volume in 1 second (FEV1) below the lower limit of normal (LLN). The mean FEV1 in these patients was 59.0% of predicted (range 22-79.0%). Two hundred and twenty-four had an FEV1 between 50% and 80% of predicted, 50 had an FEV1 between 30% and 50% of predicted. One hundred and sixteen (40%) of the people with an FEV1 below the LLN were still smoking and 55 accepted referral to cessation services. A total of 56% of the other smokers assessed but not thought to have COPD also accepted referral. Assessing symptoms and performing microspirometry in people attending long-term condition clinics in primary care is feasible and has a high yield of identifying people likely to have previously undiagnosed COPD.

Clinical phenotyping is currently used to guide pharmacological treatment decisions in chronic obstructive pulmonary disease (COPD), a personalized approach to care. Precision medicine integrates biological (endotype) and clinical (phenotype) information for a more individualized approach to pharmacotherapy, to maximize the benefit versus risk ratio. Biomarkers can be used to identify endotypes. To evolve toward precision medicine in COPD, the most appropriate biomarkers and clinical characteristics that reliably predict treatment responses need to be identified. FEV1 is a marker of COPD severity and has historically been used to guide pharmacotherapy choices. However, we now understand that the trajectory of FEV1 change, as an indicator of disease activity, is more important than a single FEV1 measurement. There is a need to develop biomarkers of disease activity to enable a more targeted and individualized approach to pharmacotherapy. Recent clinical trials testing commonly used COPD treatments have provided new information that is likely to influence pharmacological treatment decisions both at initial presentation and at follow up. In this Perspective, we consider the impact of recent clinical trials on current COPD treatment recommendations. We also focus on the movement toward precision medicine and propose how this field needs to evolve in terms of using clinical characteristics and biomarkers to identify the most appropriate patients for a given pharmacological treatment.

COPD is now widely recognized as a complex heterogeneous syndrome, having both pulmonary and extrapulmonary features. In clinical practice, the diagnosis of COPD is based on the presence of chronic airflow limitation, as assessed by post-bronchodilator spirometry. The severity of the airflow limitation, as measured by percent predicted FEV1, provides important information to the physician to enable optimization of management. However, in order to accurately assess the complexity of COPD, there need to be other measures made beyond FEV1. At present, there is a lack of reliable and simple blood biomarkers to confirm and further assess the diagnosis of COPD. However, it is possible to identify patients who display different phenotypic characteristics of COPD that relate to clinically relevant outcomes. Currently, validated phenotypes of COPD include alpha-1 antitrypsin deficiency, and “frequent exacer-bators”. Recently, a definition and assessment of a new phenotype comprising patients with overlapping features of asthma and COPD has been suggested and is known as “asthma COPD overlap syndrome”. Several other phenotypes have been proposed, but require validation against clinical outcomes. Defining phenotypes requires the assessment of multiple factors indicating disease severity, its impact, and its activity. Recognition and validation of COPD phenotypes has an important role to play in the selection of evidence-based targeted therapy in the future management of COPD, but regardless of the diagnostic terms, patients with COPD should be assessed and treated according to their individual treatable characteristics.

Background: a review of the effectiveness of relaxation techniques for chronic obstructive pulmonary disease patients has shown inconsistent results, but studies have varied in terms of technique and outcome measures. Aim: to determine patient preference for different relaxation techniques. Methods: Chronic obstructive pulmonary disease patients were presented with six techniques via a DVD and asked to rate the techniques in terms of effectiveness, rank in order of likely use, and comment. Results: Patients differed in the technique preferred and reason for that preference, but the most commonly preferred technique both for effectiveness and ease of use was “thinking of a nice place” followed by progressive relaxation and counting. Familiarity and ease of activity were commonly given reasons for preference. Conclusion: Rather than providing patients with a single technique that they might find difficult to implement, these results suggest that it would be better to give a choice. “Thinking of a nice place” is a popular but under-investigated technique.

BACKGROUND: Tiotropium, a long-acting anticholinergic bronchodilator, has demonstrated efficacy and safety as add-on therapy to inhaled corticosteroids (ICS), with or without other maintenance therapies, in patients with symptomatic asthma. OBJECTIVE: to evaluate safety and tolerability of tiotropium delivered via the Respimat(®) device, compared with placebo, each as add-on to at least ICS therapy, in a pooled sample of adults with symptomatic asthma at different treatment steps. METHODS: Data were pooled from seven Phase II and III, randomised, double-blind, parallel-group trials of 12-52 weeks' treatment duration, which investigated once-daily tiotropium Respimat(®) (5 μg, 2.5 μg) versus placebo as add-on to different background maintenance therapy including at least ICS. Adverse events (AEs) including serious AEs were assessed throughout treatment + 30 days after the last dose of trial medication. RESULTS: of 3474 patients analysed, 2157 received tiotropium. The percentage of patients with AEs was comparable between treatment groups: tiotropium 5 μg, 60.8%; placebo 5 μg pool, 62.5%; tiotropium 2.5 μg, 57.1%; placebo 2.5 μg pool, 55.1%. Consistent with the disease profile, the most frequent AEs overall were asthma, decreased peak expiratory flow rate (both less frequent with tiotropium) and nasopharyngitis. Overall incidence of dry mouth, commonly associated with use of anticholinergics, was low: tiotropium 5 μg, 1.0%; placebo 5 μg pool, 0.5%; tiotropium 2.5 μg, 0.4%; placebo 2.5 μg pool, 0.5%. The percentage of cardiac disorder AEs was comparable between tiotropium and placebo: tiotropium 5 μg, 1.4%; placebo 5 μg pool, 1.4%; tiotropium 2.5 μg, 1.4%; placebo 2.5 μg pool, 1.1%. The proportions of patients with serious AEs were balanced across groups: tiotropium 5 μg, 4.0%; placebo 5 μg pool, 4.9%; tiotropium 2.5 μg, 2.0%; placebo 2.5 μg pool, 3.3%. CONCLUSION: Tiotropium Respimat(®) demonstrated safety and tolerability comparable with those of placebo, as add-on to at least ICS therapy, at different treatment steps in adults with symptomatic asthma.

Background: Tiotropium, a once-daily long-acting anticholinergic bronchodilator, has demonstrated efficacy in patients with asthma who were symptomatic despite treatment with medium- to high-dose inhaled corticosteroids (ICS). Objective: the objective of this study was to evaluate the efficacy and safety of once-daily tiotropium Respimat (5 μg or 2.5 μg), compared with placebo Respimat, as add-on therapy to low- to medium-dose ICS for adults with symptomatic asthma. Methods: a phase III, double-blind, placebo-controlled trial was conducted (NCT01316380). Adults with symptomatic asthma receiving low- to medium-dose ICS (200-400 μg budesonide or equivalent dose) and a pre-bronchodilator forced expiratory volume in 1 second (FEV1) ≥60% and ≤90% of predicted normal were randomized to 12 weeks of treatment with once-daily tiotropium Respimat 5 μg or 2.5 μg, or placebo Respimat, as add-on therapy to ICS. The primary endpoint was peak FEV1(0-3h) response. Results: in total, 464 patients were randomized (61% female; mean age 43 years; mean baseline FEV1 78% of predicted normal). After 12 weeks, both tiotropium Respimat doses were superior to placebo (adjusted mean difference from placebo: 5 μg, 128 mL; 2.5 μg, 159 mL; both P

Despite current therapeutic approaches asthma remains uncontrolled in a significant proportion of patients. Short-acting anticholinergic bronchodilators have a very long history of use in asthma, and recent data confirms the importance of acetylcholine as both a bronchoconstrictor and as a regulator of inflammation and remodeling in the lungs. Data from a comprehensive clinical trial programme, as well as use in primary care, show the efficacy and safety of tiotropium in adults with mild to moderate asthma when it is added to ICS and in severe asthma when it is added to high doses of ICS plus LABA, as well as in adolescents. Tiotropium is cost effective and its benefits are not restricted to particular phenotypes, making it a useful addition to the therapeutic options recommended by the Global Initiative for Asthma (GINA) for people with poorly controlled asthma at steps 4 & 5.

Introduction: Phenotyping patients with COPD using relative eosinophil blood count (EBC) as a biomarker is a topical issue. To evaluate whether EBC might serve as a useful biomarker in COPD, a retrospective analysis on data from the tiotropium Respimat study programme was performed. Method(s): Analysis of baseline EBC and its relation to tiotropium's effect on exacerbation risk in patients with and without ICS at baseline was performed using data from 3 long term placebocontrolled tiotropium Respimat studies (NCT00168844, NCT00168831 and NCT00387088). 5134 patients were categorized according to their relative baseline EBC (

OBJECTIVES: to determine the importance of fear and anxiety at the time of an exacerbation of chronic obstructive pulmonary disease. To assess the influence of carers and health professionals on this fear and anxiety. DESIGN: a qualitative study to elicit the views of patients and their carers during a hospital admission for exacerbations of chronic obstructive pulmonary disease. SETTING: Interviews were conducted in a District General Hospital. PARTICIPANTS: Twenty patients were interviewed shortly after admission to hospital with an exacerbation. MAIN OUTCOME MEASURES: Key themes were identified using cross-sectional thematic analysis of transcripts where commonalities and differences were identified. RESULTS: Four themes emerged: panic and fear; anxiety management techniques used during an exacerbation; intervention from family members and carers; response to medical services. CONCLUSION: Panic and fear are important emotions prior to admission. Many patients recognised the link between panic-fear and a worsening of symptoms, and some were able to use self-management techniques to reduce their panic-fear. Some relatives were seen as helping and others exacerbating the symptoms of panic-fear. The emergency services were seen as positive: providing reassurance and a sense of safety. How best to help patients with chronic obstructive pulmonary disease manage panic and fear remains a challenge.

BACKGROUND: Healthy Outlook is a service delivered by the UK Met Office directly to patients with chronic obstructive pulmonary disease (COPD) that has been in place since 2006. Its objective is to reduce the severity and length of COPD exacerbations, hence improving the quality of life and life expectancy. AIMS: to assess the effect of the Healthy Outlook service on hospital admission rates of all general practitioners that have used the service. METHODS: Control practices were selected for each of the 661 participating practices. The number of hospital admissions for each practice was extracted from the Hospital Episode Statistics database. The differences in admission rates per practice between the first year of use of the Healthy Outlook service and the previous year were compared by paired t-test analyses. RESULTS: for admissions with a primary diagnosis of COPD, the difference between participating and control practices was -0.8% (95% confidence interval (CI)=-1.8 to 0.2%; P=0.13). For admissions with a primary or co-morbid diagnosis of COPD, the difference was -2.3% (95% CI=-4.2 to -0.4%; P=0.02). CONCLUSIONS: Participation in the Healthy Outlook service reduces hospital admission rates for patients coded on discharge with COPD (including co-morbid).

BACKGROUND: We previously reported a progressive decline in absolute responses of FEV1 and FVC to a near-maximal dose of 2 different short-acting bronchodilators over 4 years. Since varying host factors and the method of expressing the response may impact the time trend of acute bronchodilator responses, we now examined the potential influence of salient host characteristics on changes in bronchodilator responses over time expressed in different ways. METHODS: As part of the 4-year, placebo-controlled Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) trial, pre- and post-bronchodilator spirometry was performed at baseline and 1 month and every 6 months thereafter. Post-bronchodilator values for FEV1 and FVC were analyzed for subjects completing at least the 1 year visit (Placebo - N = 2463; Tiotropium - N = 2579), stratified by GOLD stage, age, gender and smoking status and expressed as absolute, relative (%) and % predicted changes from pre-bronchodilator values. Annual changes in bronchodilator response were estimated using linear mixed effects models. RESULTS: for all subjects analyzed, FEV1 and FVC bronchodilator responses showed progressive and highly significant (p 

Background: Patterns of health-care use and comorbidities present in patients in the period before diagnosis of chronic obstructive pulmonary disease (COPD) are unknown. We investigated these factors to inform future case-finding strategies. Methods: We did a retrospective analysis of a clinical cohort in the UK with data from Jan 1, 1990 to Dec 31, 2009 (General Practice Research Database and Optimum Patient Care Research Database). We assessed patients aged 40 years or older who had an electronically coded diagnosis of COPD in their primary care records and had a minimum of 3 years of continuous practice data for COPD (2 years before diagnosis up to a maximum of 20 years, and 1 year after diagnosis) and at least two prescriptions for COPD since diagnosis. We identified missed opportunites to diagnose COPD from routinely collected patient data by reviewing patterns of health-care use and comorbidities present before diagnosis. We assessed patterns of health-care use in terms of lower respiratory consultations (infective and non-infective), lower respiratory consultations with a course of antibiotics or oral steroids, and chest radiography. If these events did not lead to a diagnosis of COPD, they were deemed to be missed opportunities. This study is registered with ClinicalTrials.gov, number NCT01655667. Findings: We assessed data for 38859 patients. Opportunities for diagnosis were missed in 32900 (85%) of 38859 patients in the 5 years immediately preceding diagnosis of COPD; in 12856 (58%) of 22286 in the 6-10 years before diagnosis, in 3943 (42%) of 9351 in the 11-15 years before diagnosis; and in 95 (8%) of 1167 in the 16-20 years before diagnosis. Between 1990 and 2009, we noted decreases in the age at diagnosis (0·05 years of age per year, 95% CI 0·03-0·07) and yearly frequency of lower respiratory prescribing consultations (rate ratio 0·982 opportunities per year, 95% CI 0·979-0·985). Prevalence of all comorbidities present at COPD diagnosis increased except for asthma and bronchiectasis, which decreased between 1990 and 2007, from 281 (33·4%) of 842 patients to 451 of 1465 (30·8%) for asthma, and from 53 of 842 (6·3%) to 53 of 1465 (3·6%) for bronchiectasis. In the 2 years before diagnosis, of 6897 patients who had had a chest radiography, only 2296 (33%) also had spirometry. Interpretation: Opportunities to diagnose COPD at an earlier stage are being missed, and could be improved by case-finding in patients with lower respiratory tract symptoms and concordant long-term comorbidities. Funding: UK Department of Health, Research in Real Life. © 2014 Elsevier Ltd.

While the slope of decline in FEV1 has traditionally been calculated from the post- rather than the pre-bronchodilator measurement in COPD interventional trials, it is not clear whether and to what extent these two slopes differ in symptomatic patients with COPD. Therefore, we used data from the 4-year UPLIFT trial of tiotropium 18 mcg QD vs. placebo to compare annual rates of change in pre- vs. post-bronchodilator FEV1 in 5041 patients with moderate to very severe COPD (mean FEV1 48% pred) in whom the post-bronchodilator FEV1 was measured after 4 inhalations of two different classes of short-acting inhaled bronchodilators at baseline and 1 month and every 6 months post-randomization over 4 years. Linear mixed effects models were used to estimate annual rates of decline in FEV1 and FVC pre- and post-bronchodilator in each treatment group separately, after adjusting for height, gender, smoking status, baseline % predicted FEV1 or FVC, and baseline acute % improvement in lung function. The slopes of the post-bronchodilator FEV1 and FVC were significantly steeper than the pre-bronchodilator slopes regardless of treatment arm (p < 0.001), while the estimated variances of the slopes were similar. Post-bronchodilator increases in FEV1 and FVC diminished progressively and significantly (p < 0.0001) over the 4-year trial, suggesting a possible explanation for the significant differences between the pre- and post-bronchodilator slopes. While the reasons for these differences are not completely clear, they are important to consider when assessing treatment effects on rates of decline in FEV1 and FVC.

BACKGROUND: Long-term acute care (LTAC) hospitals provide specialized care for survivors of critical illness who require prolonged mechanical ventilation. These chronically ill patients often have multiple comorbidities and are colonized with antibiotic-resistant organisms. We investigated the association of comorbidities and colonization status with outcomes in patients requiring prolonged mechanical ventilation in an LTAC facility. We hypothesized that comorbidity burden and colonization with multiple drug resistant organisms would be associated with worse clinical outcomes. METHODS: We performed a retrospective, cohort study of 157 mechanically ventilated subjects in an urban LTAC facility admitted from January 2007 to September 2009. Comorbidity burden was documented from pre-admission data using the Charlson Comorbidity Index. Colonization data were obtained from surveillance cultures. Outcomes studied included transfer back to acute care facilities, stay, and ventilator weaning status. RESULTS: Within 60 days, 58.6% of subjects were transferred back to an acute care facility. The most common reason for transfer was infection/sepsis (37%). The Charlson Comorbidity Index of subjects transferred to acute care, versus those who were not, was 4.9 ± 3.1 versus 3.6 ± 2.7 (P =. 01), an odds ratio of 1.1 for each 1-point increase in Charlson Comorbidity Index (95% CI 1.03-1.71, P =. 02). Colonization with acinetobacter was associated with higher incidence of transfer (71% vs 51%, P =. 01). The odds ratio for transfer to acute care was 1.3 for each additional organism colonizing a subject (95% CI 1.11-1.53, P =. 006). CONCLUSIONS: Higher comorbidity burden and colonization status were associated with increased risk of transfer to acute care. Further investigation is needed to clarify this relationship between comorbidity burden and colonization with change in clinical status.

We report patients, family members and health professionals' experiences of Chronic Obstructive Pulmonary Disease (COPD) in Barnsley, northern England. A widespread belief that having "bad lungs" is part of normal ageing shapes everyday experience in this former mining town. People with COPD, and their families, link its cause to the areas industrial past and are sceptical of a medical orthodoxy that attributes cause to smoking. They doubt doctors' objectivity. Encouraging uptake of care, promoting smoking cessation, and developing care planning would be enhanced by engaging with the significance of place in the social narrative of health evident in this town.

Background: the impact of interventions on the progressive course of COPD is currently assessed by the slope of the annual decline in FEV 1 determined from serial measurements of the post-, in preference to the pre-, bronchodilator FEV 1. We therefore compared the yearly slope and the variability of the slope of the pre- versus the post-bronchodilator FEV 1 in men and women with mild to moderate COPD who participated in the 5-year Lung Health Study (LHS).Methods: Data were analyzed from 4484 of the 5887 LHS participants who had measurements of pre- and post-bronchodilator FEV 1 at baseline (screening visit 2) and all five annual visits. The annual rate of decline in FEV 1 (±SE) measured pre- and post-bronchodilator from the first to the fifth annual visit was estimated separately using a random coefficient model adjusted for relevant covariates. Analyses were performed separately within each of the three randomized intervention groups. In addition, individual rates of decline in pre- and post-bronchodilator FEV 1 were also determined for each participant. Furthermore, sample sizes were estimated for determining the significance of differences in slopes of decline between different interventions using pre- versus post-bronchodilator measurements.Results: Within each intervention group, mean adjusted and unadjusted slope estimates were slightly higher for the pre- than the post-bronchodilator FEV 1 (range of differences 2.6-5.2 ml/yr) and the standard errors around these estimates were only minimally higher for the pre- versus the post-bronchodilator FEV 1 (range 0.05-0.11 ml/yr). Conversely, the standard deviations of the mean FEV 1 determined at each annual visit were consistently slightly higher (range of differences 0.011 to 0.035 L) for the post- compared to the pre-bronchodilator FEV 1. Within each group, the proportion of individual participants with a statistically significant slope was similar (varying by only 1.4 to 2.7%) comparing the estimates from the pre- versus the post-bronchodilator FEV 1. However, sample size estimates were slightly higher when the pre- compared to the post-bronchodilator value was used to determine the significance of specified differences in slopes between interventions.Conclusion: Serial measurements of the pre-bronchodilator FEV 1 are generally sufficient for comparing the impact of different interventions on the annual rate of change in FEV 1. © 2012 Tashkin et al.; licensee BioMed Central Ltd.

CONTEXT: the end of Life Care Strategy for England highlights effective communication between patients and professionals as key to facilitating patient involvement in advance care planning. The strategy emphasizes that, currently, communication in patients with noncancer life-limiting conditions is likely to be inadequate, and research has identified that patients with chronic obstructive pulmonary disease and heart failure have a poor understanding of their condition. OBJECTIVES: to identify existing interventions of patient-professional communication developed for life-limiting conditions and explore the applicability of interventions developed within a cancer framework to other diagnostic groups. METHODS: a comprehensive literature review of studies describing communication interventions for patients receiving end-of-life care was undertaken. Ten electronic databases were searched. Inclusion criteria were all English language studies relating to patient-professional communication interventions for patients with life-limiting conditions receiving end-of-life care. RESULTS: of the 755 articles initially identified, 16 met the inclusion criteria. Three core themes emerged from the synthesis of the literature: using education to enhance professional communication skills, using communication to improve patient understanding, and using communication skills to facilitate advance care planning. CONCLUSION: Although limited, evidence relating to the development and evaluation of communication interventions for patients with life-limiting illnesses would suggest that a successful intervention should include combined components of training, patient discussion, and education. In a context of limited resources and an increasing number of patients living and dying with chronic life-limiting conditions, the need for appropriate and effective communication strategies should be seen as a priority for both research and policy.

Background: Exacerbations affect morbidity in chronic obstructive pulmonary disease (COPD). We sought to evaluate the association between exacerbation frequency and spirometric and health status changes over time using data from a large, long-term trial. Methods: This retrospective analysis of data from the 4-year UPLIFT® (Understanding Potential Long-term Impacts on Function with Tiotropium) trial compared tiotropium with placebo. Annualized rates of decline and estimated mean differences at each time point were analyzed using a mixed-effects model according to subgroups based on exacerbation frequency (events per patient-year: 0,≥0-1, ≥1-2, and≥2). Spirometry and the St George's Respiratory Questionnaire (SGRQ) were performed at baseline and every 6 months (also at one month for spirometry). Results: in total, 5992 patients (mean age 65 years, 75% male) were randomized. Higher exacerbation frequency was associated with lower baseline postbronchodilator forced expiratory volume in one second (FEV1) (1.40, 1.36, 1.26, and 1.14 L) and worsening SGRQ scores (43.7, 44.1, 47.8, and 52.4 units). Corresponding rates of decline in postbronchodilator FEV1 (mL/year) were 40, 41, 43, and 48 (control), and 34, 38, 48, and 49 (tiotropium). Values for postbronchodilator forced vital capacity decline (mL/year) were 45, 56, 74, and 83 (control), and 43, 57, 83, and 95 (tiotropium). The rates of worsening in total SGRQ score (units/year) were 0.72, 1.16, 1.44, and 1.99 (control), and 0.38, 1.29, 1.68, and 2.86 (tiotropium). The proportion of patients who died (intention-to-treat analysis until four years [1440 days]) for the entire cohort increased with increasing frequency of hospitalized exacerbations. Conclusion: Increasing frequency of exacerbations worsens the rate of decline in lung function and health-related quality of life in patients with COPD. Increasing rates of hospitalized exacerbations are associated with increasing risk of death. © 2012 Halpin et al, publisher and licensee Dove Medical Press Ltd.

Background: Being able to identify patients at risk of exacerbations is useful as it enables resources to be targeted at these patients. Aims: to test the theoretically-derived prediction that the frequency of non-asthma related visits to the general practitioner (GP) predicts exacerbations. Methods: Clinical and demographic data and both self-report and prescription-based adherence data were obtained from 166 patients diagnosed with asthma attending a GP clinic, all of whom were prescribed inhaled corticosteroids (ICS). Asthma exacerbations (treated by the GP or in hospital) and non-asthma visits and symptoms were assessed from notes for the subsequent 5 years. Results: Exacerbations correlated with non-asthma visits (0.35), severity as measured by BTS step (0.28), and with prescription-based adherence (0.28). Asthma severity correlated with non-asthma visits (0.35). Receiver operating curves showed that ≥2 non-asthma visits per year provided 79% sensitivity and 58% specificity for detecting ≥3 exacerbations over 5 years. Poor adherence predicted outcomes only for patients with high levels of non-asthma visits (≥3) and only for those reporting regular-but-less ICS use but not symptom-directed ICS use. Conclusions: Non-asthma visits are a good predictor of asthma exacerbations, particular in non-adherent patients. These results are consistent with a mechanism where exacerbations result from a combination of random oscillating specific and non-specific inflammatory processes. It is important to consider the total patient rather than just the lung when managing patients with asthma. © 2012 Primary Care Respiratory Society UK. All rights reserved.

Background: There is growing recognition that patients with COPD should have the chance to discuss end of life care and advance care planning (ACP). Admission to hospital with an exacerbation of COPD has been seen as a possible opportunity to initiate such discussions.
Aim: to examine whether or not an admission to hospital for an exacerbation of COPD is an opportunity for advance care planning. To understand from a patient perspective the optimum circumstances for ACP.
Design: Qualitative study involving interviews with patients and their carers.
Setting: Two general practices in Devon one urban and one semi-rural.
Method: Qualitative analysis of 16 interviews with patients and carers after admission with an exacerbation of COPD
Results: During the period of severe illness no patients recalled having discussions about resuscitation or planning for the future. Hospital admission and discharge was seen as chaotic and lacking in continuity. On reflection some patients welcomed the opportunity to discuss ACP and felt that their general practitioner would be the best person for this. Others wished to avoid end of life care discussions, but there was evidence that with empathetic and knowledgeable support these discussions could be initiated.
Conclusion: Even though the period of hospitalization may not be an appropriate time to initiate discussion on ACP the admission itself is a milestone that can lead to discussion after discharge. GPs should be alert to that opportunity after discharge from hospital.

Background: We have developed a winter forecasting service to predict when patients with COPD are at higher risk of an exacerbation and alert them via an automated telephone call. Aims: to assess the effect of the service and its ability to predict periods of increased risk. Methods: a 4-month prospective randomised controlled trial using clinical criteria and the EXACT PRO questionnaire to identify exacerbations. Patients were randomly allocated to receive alert calls. All patients completed a diary including the EXACT PRO questionnaire on a BlackBerry Smartphone each day. They were contacted and assessed if they appeared to be exacerbating. Results: 79 patients participated, 40 received alert calls. The exacerbation frequency per patient per week was significantly greater during periods of predicted high risk (0.086±0.010 v 0.055±0.010). The exacerbation frequency (± standard error of the mean, SEM) in patients receiving alert calls was lower (0.95±0.27 v 1.17±0.29) but this was not statistically significant. Fewer patients receiving alert calls had one or more EXACT event compared to the controls (34% v 53%, p=0.11), their duration was shorter (8.2±2.0 v10.1±1.9 days, p=0.481) and they were less severe (AUC 65±21 v 115±22, p=0.118). There were no significant differences in the mean change (±SEM) in SGRQ scores between the groups. Conclusions: the ability of the forecast to predict high risk periods was confirmed unequivocally. Alert calls appeared to reduce the frequency and severity of exacerbations but these effects did not reach statistical significance, perhaps because of the number of participants, lower than expected exacerbation rates, and the fact that there was contact with patients in both groups whenever they appeared to be exacerbating. (ClinicalTrials.gov number NCT00788645) © 2011 Primary Care Respiratory Society UK. All rights reserved.

Objectives: the UK Meteorological Office (Met Office) has developed a health forecasting service for chronic obstructive pulmonary disease (COPD) patients, combining a rule-based model predicting risk based on environmental conditions with an anticipatory care intervention providing information on self-management and warnings via an interactive telephone call. Our aim was to explore the acceptability and utility of such a service to patients with COPD and its perceived impact on their behaviour and disease management. Methods: a cross-sectional questionnaire survey of service users drawn from 189 general practices in England, Scotland and Wales at the end of the winter of 2007/8. Results: Completed questionnaires were received from 3288 COPD patients, representing a response rate of 40%. Eighty-five percent of those returning a questionnaire reported at least one exacerbation during the study period and 8% had been admitted to hospital on one occasion or more. The majority of respondents deemed the information pack (comprising a booklet and thermometers) useful while the automated calls were generally said to be convenient, easy to understand and reassuring. Those less satisfied with the service felt they were already sufficiently aware of the prevailing weather conditions or felt more detailed information was needed. Most benefit was reported by those patients who were willing to be pro-active in the management of their condition, with the service encouraging 36% of respondents to seek a repeat prescription, 28% to reread their information pack and 12% to consult their GP for worsening of symptoms. Conclusions: Patients found the automated interactive calling, combined with a health risk forecast, both viable and useful, welcoming the information and tools it offered. In many cases, it added to patients' understanding of their illness and promoted better self-management. Future research should focus on the potential impact of the service in terms of health outcomes and cost-effectiveness. © the Royal Society of Medicine Press Ltd 2010.

Chronic obstructive pulmonary disease (COPD) is a highly prevalent condition worldwide and is associated with significant mortality. This paper gives an overview of the relevant literature regarding care needs in advanced COPD from the perspective of the patient or carer, and aims to explore the appropriateness of a palliative care approach in this group. Publications revealed that patients with COPD have a high symptom burden that impacts on quality of life and social functioning. Information provision in COPD is often lacking and the implications of diagnosis and prognosis are not routinely discussed. The impact on families and carers is considerable, many patients have significant care requirements which can affect family relationships. Although patients with COPD have regular contact with health services, access to specialist services and palliative care is poor. This paper highlights the need for increased provision for palliative care in COPD, alongside dedicated education and training for health professionals, and continued research to identify the most appropriate ways of delivering this care.

Translating the growing evidence base on COPD management into practice can be challenging and understanding the strengths and weakness of published studies is crucial. Studies should conform to the standards of CONSORT statement; they should be sufficiently powered, participants should be randomised, there should be assignment concealment, and the outcome measures and analyses should be decided in advance. The interpretation of the results may be affected by age and severity inclusion criteria for the study and the exclusion of patients with co-morbid illnesses. Whether previous medication is continued or stopped can affect the interpretation of the results. Secondary analyses in sub-groups should be viewed with caution unless pre-specified and accommodated in the trial design and power calculations. Real world observational studies may be confounded by non-randomisation of participants but can sometimes yield valuable insights. The way in which the results are presented can influence their interpretation and their magnitude with respect to minimal important differences as well as statistical significance is important. Research studies help formulate management algorithms but often the questions they address are too specific to allow evidence-based sequencing of therapies. © 2010 Primary Care Respiratory Society UK.

The challenges associated with patient-based research in palliative care are well documented. This paper focuses on the ethical challenges and discusses them in the context of a pilot study to explore the palliative-care needs of patients with moderate and severe chronic obstructive pulmonary disease. The main ethical challenge encountered related to problems surrounding the use of terminology, specifically the terms 'palliative care' and 'chronic obstructive pulmonary disease'. The approving ethics committee specified that these terms be removed from all patient materials in order to protect patients from undue distress. The impact of this ethical advice on patients' ability to give fully informed consent is discussed. This paper highlights a requirement for appropriately resourced and well-managed studies in palliative care, and identifies a need for the development of appropriate strategies in order to ensure the informed participation of patients with non-cancer diagnoses in palliative-care research.

Introduction: Harold Shipman, a general practitioner (GP) working near Manchester in England, is thought to have killed 250 of his patients by diamorphine overdose between 1975 and 1998. Opiates are recommended for relieving dyspnoea in end stage chronic obstructive pulmonary disease (COPD). Little is known about the effect of the Shipman case on clinician attitudes to prescribing of opiates in advanced COPD. Subjects and methods: Focus groups were held with a total of 39 health professionals in primary (n = 3) and secondary care settings (n = 2) in two sociodemographically contrasting areas of England. Results: Participants identified that the experience of dyspnoea in end-stage COPD was often distressing for patients, their families and their professional carers. Whilst opiates were recognised to be effective in relieving dyspnoea, the Shipman case, and associated fears of litigation, was identified as the key barrier to prescribing. Whilst this was seen as a particular problem within primary care settings leading, for example, GPs to admit patients to hospital rather than prescribe opiates, it was also considered an issue within acute hospital settings. of particular concern to participants was recognising when an exacerbation was 'terminal' and hence opiate prescribing appropriate. Conclusions: There is evidence to show that opiates are effective in managing end-stage dyspnoea in COPD without hastening death. However, participants did not perceive this to be the case and expressed considerable anxiety about appropriate prescribing in this situation. Given the significant burden of dyspnoea on patients with advanced COPD, there is an urgent need for appropriate training to increase clinician confidence regarding opiate use in this patient group which is sensitive to the concerns raised by the Shipman murders. © 2010 W.S. Maney & Son Ltd.

The English end of Life Care Strategy promises that all patients with advanced, life limiting illness will have the opportunity to participate in Advance Care Planning (ACP). For patients with Chronic Obstructive Pulmonary Disease (COPD), the barriers to this being achieved in practice are under-explored. Five focus groups were held with a total of 39 health care professionals involved in the care of patients with COPD. Participants reported that discussions relating to ACP are very rarely initiated with patients with COPD and identified the following barriers: inadequate information provision about the likely course of COPD at diagnosis; lack of consensus regarding who should initiate ACP and in which setting; connotations of comparing COPD with cancer; ACP discussions conflicting with goals of chronic disease management; and a lack of understanding of the meaning of 'end of life' within the context of COPD. The findings from this study indicate that, for patients with COPD, significant service improvement is needed before the objective of the end of Life Care Strategy regarding patient participation in end of life decision-making is to be achieved. Whilst the findings support the Strategy's recommendations regarding an urgent for both professional education and increased public education about end of life issues, they also indicate that these alone will not be enough to effect the level of change required. Consideration also needs to be given to the integration of chronic disease management and end of life care and to developing definitions of end of life care that fit with concepts of 'continuous palliation'.

Chronic obstructive pulmonary disease (COPD) is a debilitating condition characterized by airflow limitation that is not fully reversible. It is a major cause of morbidity and mortality and represents substantial economic and social burden throughout the world. A range of interventions has been developed that decrease symptoms and address complications associated with COPD. However, to date few interventions have been unequivocally demonstrated to modify disease progression. Assessment of the potential for interventions to modify disease progression is complicated by the lack of a clear definition of disease modification and disagreement over appropriate markers by which modification should be evaluated. To clarify these issues, a working group of physicians and scientists from the USA, Canada and Europe was convened. The proposed working definition of disease modification resulting from the group discussions was "an improvement in, or stabilization of, structural or functional parameters as a result of reduction in the rate of progression of these parameters which occurs whilst an intervention is applied and may persist even if the intervention is withdrawn". According to this definition, pharmacologic interventions may be considered disease-modifying if they provide consistent and sustained improvements in structural and functional parameters. Smoking cessation and lung volume reduction surgery would both qualify as disease-modifying interventions. © 2009 Informa UK Ltd all rights reserved.

BACKGROUND: Recent clinical trials suggest that intermittent use of inhaled corticosteroids (ICS) is safe for mild persistent asthma. Intermittent ICS use is inconsistent with current guidelines but is a common form of non-compliance. The aim of this study was to investigate how asthma nurses advise patients to use ICS. METHODS: Practice managers of 241 GP surgeries in the southwest of England were sent questionnaires to distribute to practice nurses. RESULTS: Questionnaires were returned by 105 nurses (104 had asthma-specific training). There was a wide variation in attitudes to guideline-based care and advice given to patients. 97% indicated that they sometimes advised patients to decrease their ICS use, 85% sometimes advised patients to stop their ICS when their asthma was well controlled, and 70% reported sometimes advising intermittent use. CONCLUSION: Asthma nurse recommendations are often inconsistent with guidelines. There is considerable variation between different asthma nurses in the advice given to patients.

Prognosis in COPD is poor and many patients perceive shortcomings in the education they receive about aspects of their condition. This study explores the experiences of patients with COPD, particularly fears surrounding death and dying. Semi-structured interviews were conducted with 21 patients with moderate or severe COPD. Findings revealed that patient understanding of COPD was poor, most patients were unaware of the progressive nature of the condition, and few were aware they could die of COPD. Despite this, patients often expressed concerns that their condition might deteriorate. Patients had particular concerns regarding the manner of their death; the overriding fear was dying of breathlessness or suffocation. None of the patients' had discussed these fears with a health care professional. Improved patient education is needed in order to improve patients understanding of their condition and prognosis. Open communication regarding death, as advocated in a palliative care approach, is also appropriate to alleviate patients fears and to allow them to make decisions regarding the management of their care at the end of life.

AIM: to assess the effect of tiotropium 18 mcg once daily on chronic obstructive pulmonary disease (COPD) exacerbations and exacerbation-related hospitalisations using a patient-level pooled analysis. METHODS: all completed randomised, placebo-controlled, parallel-group tiotropium trials with a duration of >or=24 weeks were included (n=9). An exacerbation was defined in each study as >or=2 respiratory symptoms lasting >or=3 days, and requiring treatment with antibiotics and/or systemic steroids and/or hospitalisation. RESULTS: Compared with placebo (2,862 patients), tiotropium (3,309 patients) significantly reduced by 21% both the risk of COPD exacerbation (95% confidence interval [CI] 0.73-0.86; p

Phosphodiesterases (PDEs) are important enzymes that hydrolyze the cyclic nucleotides adenosine 3′5′-cyclic monophosphate (cAMP) and guanosine 3′5′-cyclic monophosphate (cGMP) to their inactive 5′ monophosphates. They are highly conserved across species and as well as their role in signal termination, they also have a vital role in intra-cellular localization of cyclic nucleotide signaling and integration of the cyclic nucleotide pathways with other signaling pathways. Because of their pivotal role in intracellular signaling, they are now of considerable interest as therapeutic targets in a wide variety diseases, including COPD where PDE inhibitors may have bronchodilator, anti-inflammatory and pulmonary vasodilator actions. This review examines the diversity and cellular localization of the isoforms of PDE, the known and speculative relevance of this to the treatment of COPD, and the range of PDE inhibitors in development together with a discussion of their possible role in treating COPD. © 2008 Dove Medical Press Limited. All rights reserved.

Aliskiren is the first of a new class of orally active, non-peptide, renin inhibitors. The enzyme renin is involved in the first step of the renin - angiotensin - aldosterone system (RAAS), which helps regulate blood pressure. Inhibition of renin activity suppresses the RAAS at an earlier point than that targeted by the angiotensin converting enzyme (ACE) inhibitors. Short-term, placebo-controlled studies in patients with mild-to-moderate hypertension show aliskiren monotherapy to be well tolerated and effective; it lowers blood pressure at least as effectively as the diuretic hydrochlorothiazide and the angiotensin II receptor antagonists (blockers: ARBs) irbesartan and losartan. In a 26-week study, aliskiren-based treatment had a greater antihypertensive effect than treatment based on the ACE inhibitor ramipril. Aliskiren in combination with an ACE inhibitor, an ARB, a calcium-channel blocker or with hydrochlorothiazide reduced blood pressure more effectively than the respective monotherapies in most instances. Whereas ACE inhibitors and ARBs increase plasma renin concentration and activity as a consequence of interrupting angiotensin II-mediated negative feedback on renin release, renin inhibitors decrease plasma renin activity. This is illustrated best in studies in which aliskiren neutralises the increase in plasma renin activity caused by an ACE inhibitor and an ARB. The net reduction in renin activity occurs despite the increase in plasma renin concentration that aliskiren causes. These increases are slightly larger with aliskiren than those occurring with other blockers of the renin pathway, consistent with inhibition at the rate-limiting step causing the greatest inhibition of the angiotensin II-mediated negative feedback. © 2008 CSF Medical Communications Ltd.

Human papillomavirus (HPV) is the pathological agent required for the development and progression of precancerous lesions in the cervical epithelium. Just two HPV types account for around 70% of all cases of cervical cancer. Therefore, there is a clear rationale for the development of prophylactic vaccines that protect against infection by these oncogenic HPV strains in order that the substantial burden of cervical cancer can be reduced. Two vaccines have been developed which comprise type-specific virus-like particles (VLPs) of the L1 capsid protein produced in recombinant expression systems. These VLPs are structurally similar to the native virus, but as they contain no viral DNA, they are non-infectious and non-oncogenic. Cervarix is a bivalent vaccine, which targets the two HPV typed (HPV 16 and 18) responsible for the majority of cervical cancers. Clinical trials have shown that Cervarix, formulated with a proprietary adjuvant (ASO4), stimulates a robust immune response in vaccinated women, such that virtually all vaccinees seroconvert within 1 month of completing the vaccine schedule. High titres of type-specific antibodies lead to a significant reduction in the number of incident and persistent HPV 16 and 18 infections. Clinically, this manifests as a reduction in the incidence of pre-cancerous cervical lesions. Cervarix has no efficacy in clearing pre-existing HPV infections, but should continue to protect against infection by the remaining vaccine type to which women have not been exposed. The vaccine has a favourable safety profile, with localised injection-site reactions the most common adverse event. The introduction of Cervarix has the potential to substantially reduce the burden of HPV infection, and thus reduce the morbidity, mortality and socioeconomic burden associated with cervical cancer. © 2008 CSF Medical Communications Ltd.

Many patients with hypertension require combination therapy to reduce their blood pressure to target levels. Treatment with an angiotensin-converting enzyme (ACE) inhibitor such as perindopril, plus a diuretic such as indapamide, is frequently used to control hypertension. Coversyl Plus combines perindopril, 4 mg, and indapamide, 1.25 mg, in a single tablet, taken once daily, and thus can simplify treatment schedules and increase patient compliance. Coversyl Plus can reduce blood pressure to a greater extent than monotherapy with some other antihypertensive agents, and to an equivalent extent to certain other combination regimens. Results from a recent, large-scale clinical outcomes study have also shown that Coversyl Plus reduces the risk of premature death, micro- and macrovascular outcomes, and renal outcomes (such as the development of microalbuminuria) in hypertensive patients with type 2 diabetes. Importantly, these benefits appear to be independent of a range of treatments and the presence or absence of hypertension at baseline. Coversyl Plus is associated with an excellent safety and tolerability profile, and thus remains a valuable treatment option for hypertension. In addition, Coversyl Plus has been shown to be of particular benefit in significantly reducing risk in hypertensive patients with type 2 diabetes. © 2008 CSF Medical Communications Ltd.

Although statins are first-line treatment for most patients with dyslipidaemia, some people require additional or alternative treatment to modify their lipid profile. Many patients treated with statins still fail to achieve increasingly stringent LDL-C goals in clinical practice, and can benefit from add-on ezetimibe therapy, which has a complementary mechanism of action to other drugs in current use. Many clinical studies have demonstrated that combinations of ezetimibe with statins, fibrates, and other lipid-modifying therapies, provide better normalisation of lipid profiles than these drugs given as monotherapy. Moreover, ezetimibe is also effective as a monotherapy. The safety and tolerability profile of ezetimibe as monotherapy is similar to placebo, and is also excellent when given in combination with other lipid-modifying agents. Ezetimibe may also provide a cost-effective alternative to statin titration. These findings suggest that ezetimibe represents a useful alternative and adjunct to other lipid management strategies. © 2008 CSF Medical Communications Ltd.

Human papillomavirus (HPV) is absolutely required for the development and progression of precancerous lesions in the cervical epithelium, and has been isolated in more than 99% of cervical cancers sampled. Given that the majority (∼70%) of cases of cervical cancer are caused by only two HPV types, appropriately designed vaccines are an attractive proposition for preventing HPV infection and thus, by extension, cervical cancer. Gardasil is a recombinant quadrivalent HPV vaccine comprising a mixture of highly purified virus-like particles (VLPs) of the major capsid protein (L1) derived from HPV types 6, 11, 16 and 18. Gardasil prevents persistent infection by the vaccine HPV types for at least 5 years. More pertinently, in HPV-naïve women, Gardasil provides complete protection against high-grade cervical dysplasia. The vaccine also prevents vulval precancers, reduces the incidence of vaginal precancerous lesions and protects against genital warts caused by the vaccine HPV types. The vaccine stimulates a robust immune response, with serum anti-HPV antibody titres substantially higher than those associated with a natural HPV infection, whilst immune responses in children are non-inferior to those of older adolescents and young women, suggesting that Gardasil also prevents HPV infection in this population. Gardasil is well tolerated with a favourable safety profile. In summary the introduction of Gardasil in conjunction with cervical screening has the potential to substantially reduce the burden of cervical cancer and other HPV-related diseases. © 2008 CSF Medical Communications Ltd.

Background: Identifying chronic obstructive pulmonary disease (COPD) patients at increased risk of mortality is an important component of effective disease management. Methods: a pooled analysis of patients with severe COPD, from two well-controlled 1-year studies, was conducted using Cox regression and spline analysis to evaluate predictability of baseline demographic data and in-study variables for mortality risk, and to evaluate the effect of treatment allocation to budesonide and formoterol, versus their respective control groups, on these outcomes. Results: in the pooled analysis, a Cox regression model reported a higher baseline St George's Respiratory Questionnaire (SGRQ) total score as a significant predictor of mortality (hazard ratio 1.037 [95% confidence interval 1.021-1.054]; p < 0.0001). The 36-item short-form health survey (SF-36) mental and physical component scores were also predictive of an increased mortality risk (p < 0.05). Age, forced expiratory volume in 1 s (FEV1), body mass index and smoking status were not significant predictors. Spline analysis of baseline variables revealed a linear association between SGRQ total score and mortality risk over 1 year (logarithmic scale). Other baseline variables, including FEV1, showed different bimodal patterns in the spline analysis. There was no difference in mortality in the formoterol versus the non-formoterol treatment group while budesonide-containing treatment was associated with reduced 1-year, all-cause, in-study mortality compared with non-budesonide therapy. Conclusion: Health status measured by SGRQ and SF-36 may be important for predicting COPD patients at increased mortality risk, with SGRQ total score emerging as the strongest predictor compared with other baseline covariates. © 2008 Elsevier Ltd. All rights reserved.

Aggressive lipid lowering can improve cardiovascular outcomes, particularly among high-risk patients. However, many patients fail to achieve increasingly stringent LDL-C goals when treated in clinical practice. Consequently, novel approaches to lipid management are required. Inegy (Vytorin in the USA) combines two lipid-modifying drugs, ezetimibe and simvastatin, which have complementary mechanisms of action. By inhibiting two independent pathways of plasma cholesterol generation - the exogenous pathway of cholesterol absorption from the gut (via ezetimibe) and the endogenous pathway of cholesterol biosynthesis in the liver (via simvastatin) - Inegy reduces plasma LDL-C levels and also improves other elements of the lipid profile. A number of clinical studies have consistently demonstrated that Inegy provides more potent LDL-C lowering than statin monotherapy. Indeed, the reductions in LDL-C associated with low-dose Inegy appear to be similar to those achieved by monotherapy with maximum doses of even the most potent statins. Thus, Inegy reduces the need for statin dose titration, potentially reducing the adverse events associated with high-dose statin monotherapy. Moreover, the safety and tolerability profile of Inegy appears to be similar to low-dose statin monotherapy. These findings suggest that Inegy represents a useful addition to the lipid management strategies that are currently available to clinicians. © 2008 CSF Medical Communications Ltd.

Objective: This systematic review examines the published evidence on the pharmacoecomonics of Symbicort®. Symbicort is a combination inhaler used in asthma and chronic obstructive pulmonary disease (COPD) that contains budesonide and formoterol. In asthma, Symbicort can be used as fixed or adjustable dose maintenance therapy as well as for both maintenance and reliever therapy (SMART). Method: a literature search of PubMed was carried out to find all publications on the pharmacoeconomics of Symbicort. Additional studies were searched for in the reference lists of the papers retrieved and by searching tables of contents of relevant journals. A total of 13 studies on Symbicort in asthma and 2 studies on Symbicort in COPD were found. Results: Total costs were lower with Symbicort than with separate inhalers containing budesonide and formoterol. Adjustable dosing maintained control of asthma using less medication and was associated with lower treatment costs than fixed dosing with Symbicort or the combination of fluticasone/salmeterol. SMART improves asthma control, reduces exacerbations and reduces direct and indirect costs compared to fixed maintenance therapy with either Symbicort or fluticasone/ salmeterol. In COPD, Symbicort offers clinical advantages over therapy with the monocomponents and these are achieved at little or no extra cost. © 2008 Informa UK Ltd.

Hypertension can be managed effectively with a wide range of drugs from different classes. However, different combinations of these agents are frequently required for blood pressure to be sufficiently controlled for patients to reach guideline targets. Telmisartan, an angiotensin II receptor antagonist (AIIRA), is effective in controlling hypertension in a broad population of hypertensive patients, including the elderly and those with comorbid conditions (type 2 diabetes and renal impairment), when used as monotherapy or in combination with the thiazide diuretic, hydrochlorothiazide (HCTZ). Telmisartan, like other AIIRAs, blocks the effects of angiotensin II by competitively binding to angiotensin II type 1 (AT1) receptors. It has a longer plasma half-life than all of the other AIIRAs currently available, which accounts for its extended control of blood pressure over a 24-hour period. This has implications for the control of the early morning surge in blood pressure and thus may help to prevent excess cardiovascular mortality and morbidity (e.g. myocardial infarction [MI] or strokes) which occur at a greater frequency between 6 am and noon. Evidence from clinical trials has shown that telmisartan, with or without HCTZ, has a good tolerability and safety profile, and is better tolerated than angiotensin-converting enzyme (ACE) inhibitors. Taken together, these observations indicate that telmisartan represents a valuable first-line treatment option for the management of hypertension. © 2008 CSF Medical Communications Ltd.

Inhaled anticholinergic bronchodilators are a treatment of choice for chronic obstructive pulmonary disease (COPD). Tiotropium is currently the only long-acting inhaled anticholinergic bronchodilator available and works by selectively inhibiting muscarinic receptors involved in mucus hypersecretion and bronchoconstriction, two characteristic features of COPD. Clinical trials have demonstrated the efficacy of tiotropium across all degrees of severity of stable COPD. Tiotropium improves airway function, symptoms of dyspnoea, exercise endurance and health status. Treatment with tiotropium also reduces acute exacerbations associated with COPD as well as associated hospitalisations. The clinical improvements observed with tiotropium are associated with changes in airway volume, particularly inspiratory capacity, which translate into improvements in patient-centred outcomes, such as breathlessness during exercise. Emerging evidence indicates that tiotropium may exert additive effects when used in combination with the long-acting β2-agonist (LABA), formoterol, consistent with the current recommendations for combination therapy in patients who do not respond to a single bronchodilator. Encouraging results have also been obtained with tiotropium in triple combination with salmeterol/ fluticasone propionate. Furthermore, post hoc analyses suggest that tiotropium may slow the rate of decline in lung function characteristic of COPD. Recent studies indicate that combining tiotropium therapy with pulmonary rehabilitation programmes can yield significant improvements in exercise endurance time. In safety evaluations, tiotropium was generally well tolerated with a similar safety profile to ipratropium, a short-acting anticholinergic bronchodilator. Dry mouth is the most common adverse event reported with tiotropium, although this is generally transient and does not lead to treatment discontinuation. © 2008 CSF Medical Communications Ltd.

Exacerbations key are important events in the natural history of chronic obstructive pulmonary disease (COPD). They are common and occur with greater frequency as disease severity increases. They produce distressing symptoms and are often frightening events for patients. They affect patients' health-related quality of life and wellbeing, lead to a significant the risk of death and hospitalisation and account for a large proportion of the costs of managing the disease. This article discusses the evidence on prevention and treatment of exacerbations. Prevention of exacerbations is a vital part of COPD management. Inhaled corticosteroids, long-acting beta agonists and long-acting anticholinergics reduce exacerbation rates as does stopping smoking, pulmonary rehabilitation and influenza vaccination. Exacerbations should be managed with increased doses or frequency of bronchodilators, oral corticosteroids and antibiotics if there is evidence of infection. Most exacerbations can be treated in the community, but some require hospital admission. Investigations are not required for exacerbations managed in the community, but patients with exacerbations severe enough to require hospitalisation should have a chest radiograph and arterial blood gas tensions measured. Oxygen therapy is important to treat episodes of respiratory failure, but, if patients are acidotic, they may require noninvasive ventilation. Hospital at home and assisted discharge schemes are effective and can be used to facilitate home care. Undertaking pulmonary rehabilitation shortly after an admission for an exacerbation speeds functional recovery and may reduce readmission rates.

Chronic obstructive pulmonary disease (COPD) is associated with important extrapulmonary, or systemic, effects. There is systemic as well as pulmonary inflammation in COPD and this, together with systemic oxidative stress, contributes to their development. Skeletal muscle dysfunction contributes to exercise limitation. There is a loss of muscle mass and a reduction in the proportion of type 1 fibers. Sedentarism, hypoxia, corticosteroid therapy, nutritional depletion and systemic inflammation may contribute to its development. Weight loss is another important effect. It is associated with a worse prognosis, which changes with therapy and may be due to reductions in calorie intake, changes in intermediate metabolism and effects of systemic inflammation. Cardiovascular disease is a frequent cause of death in COPD and coronary artery disease, left ventricular failure and arrhythmias are systemic effects of COPD, as well as comorbidities sharing a common etiology. Exacerbations of COPD may increase the risk of coronary events by increasing the level of systemic inflammation. Osteoporosis is more common in COPD (even after adjusting for corticosteroid usage) and may be due to a combination of inactivity and the effects of systemic inflammation. COPD is also associated with systemic endothelial dysfunction and CNS abnormalities (including depression), which may also be due to the effects of systemic inflammation. These systemic effects respond to COPD treatments, including pulmonary rehabilitation, nutritional supplementation and inhaled corticosteroids, as well as specific drugs, such as bisphosphonates or diuretics. There is growing evidence that novel approaches, such as the use of statins, may also be of value. © 2007, Future Drugs Ltd. All rights reserved.

BACKGROUND: Ciclesonide is a new inhaled corticosteroids licensed for the prophylactic treatment of persistent asthma in adults. Currently beclomethasone dipropionate, budesonide and fluticasone propionate are the most commonly prescribed inhaled corticosteroids for the treatment of asthma but there has been no systematic review comparing the effectiveness and safety ciclesonide to these agents. We therefore aimed to systematically review published randomised controlled trials of the effectiveness and safety of ciclesonide compared to alternative inhaled corticosteroids in people with asthma. METHODS: We performed literature searches on MEDLINE, EMBASE, PUBMED, the COCHRANE LIBRARY and various Internet evidence sources for randomised controlled trials or systematic reviews comparing ciclesonide to beclomethasone or budesonide or fluticasone in adult humans with persistent asthma. Data was extracted by one reviewer. RESULTS: Five studies met the inclusion criteria. Methodological quality was variable. There were no trials comparing ciclesonide to beclomethasone. There was no significant difference between ciclesonide and budesonide or fluticasone on the following outcomes: lung function, symptoms, quality of life, airway responsiveness to a provoking agent or inflammatory markers. However, the trials were very small in size, increasing the possibility of a type II error. One trial demonstrated that the combined deposition of ciclesonide (and its active metabolite) in the oropharynx was 47% of that of budesonide while another trial demonstrated that the combined deposition of ciclesonide (and its active metabolite) in the oropharynx was 53% of that of fluticasone. One trial demonstrated less suppression of cortisol in overnight urine collection after ciclesonide compared to fluticasone (geometric mean fold difference = 1.5, P < 0.05) but no significant difference in plasma cortisol response. CONCLUSION: There is very little evidence comparing CIC to other ICS, restricted to very small, phase II studies of low power. These demonstrate CIC has similar effectiveness and efficacy to FP and BUD (though equivalence is not certain) and findings regarding oral deposition and HPA suppression are inconclusive. There is no direct comparative evidence that CIC causes fewer side effects since none of the studies reported patient-based outcomes.

COPD causes considerable morbidity and mortality, particularly in the elderly, and often remains undiagnosed. The diagnosis cannot be made without spirometry. The NICE guideline provides an evidence-based approach to COPD management. Patients with stable disease may require pharmacotherapy with short- or long-acting bronchodilators, inhaled steroids to reduce exacerbation rates, mucolytics, diuretics, oxygen, and anti-depressants as well as non-pharmacological treatments such as pulmonary rehabilitation and nutritional supplements. It is also essential that they are encouraged to stop smoking. Exacerbations of COPD occur at all stages of the disease. Mortality following exacerbations requiring hospitalization is high. Exacerbations should be managed with increased doses of bronchodilators and oral corticosteroids unless contraindicated. Antibiotics should only be prescribed if there is a history of purulent sputum. Hospital at home and assisted discharge schemes provide safe and effective alternatives to hospital therapy.

The effective prevention of exacerbations in patients with chronic obstructive pulmonary disease (COPD) has the potential to improve patients' health-related quality of life, reduce rates of hospitalisation and mortality and lower healthcare costs. Several pharmacological agents, including inhaled corticosteroid/long-acting β2-agonist combination therapies, have demonstrated beneficial effects on COPD exacerbations. The number needed to treat (NNT) analysis is a simple, concise method that allows physicians to quantify directly the benefits that alternative treatment options have on disease outcomes in terms of the number of patients who need to be treated before a benefit is observed. This review evaluates the applicability and clinical relevance of NNT analysis for determining the effectiveness of combination therapies against COPD exacerbations, focusing on budesonide/formoterol in the same inhaler. Physicians are encouraged to consider NNT data within the context of their limitations and in conjunction with other analytical methods when selecting treatments for patients with COPD. © 2005 Blackwell Publishing Ltd.

AIMS: to identify specific patterns of corticosteroid use and examine their relationship with asthma outcomes. METHODS: an adherence questionnaire was developed and applied in a population-based observational survey; this compared unscheduled care visits and asthma quality of life for adherent and non-adherent patient groups within 176 patients from a semi-rural UK practice. RESULTS: Three main patterns of medication use were identified: Regular; Regular-but-less (Low-Dosing); and Symptom-Directed variation. For mild-to-moderate asthma (BTS treatment step 2), non-adherence produced acceptable outcomes, not significantly different from outcomes for adherent patients. For more severe asthma, regular adherence was more effective, resulting in significantly less unscheduled visits. CONCLUSIONS: the results suggest that flexible 'symptom-directed' medication use and patient-initiated dose reduction may be viable alternatives to regular medication for a number of lower severity patients. For milder asthma, clinicians should perhaps focus their efforts on patients with poor asthma outcomes, rather than poor adherence.

Background: Planned care of patients with chronic diseases in primary care depends on being able to identify them. A recorded label of asthma does not necessarily mean that the patient is currently symptomatic, and failure to record the diagnosis may influence future care. Aim: to determine the degree of under- and over-reporting of the diagnosis of asthma for patients aged 16-55 years inclusive in one large general practice. Design: a questionnaire validated for the detection of bronchial hyper-reactivity was sent to all patients recorded as having asthma and their matched controls. Patients with a diagnosis of asthma and symptomatic bronchial hyper-reactivity were considered to have asthma. Evidence of asthma in the written and computer records was sought for two groups: patients with asthma and without symptoms of bronchial hyper-reactivity, and controls with symptoms of bronchial hyper-reactivity. Setting: a semi-rural group practice with 14 830 patients. Method: Questionnaires were sent to 833 patients and 831 controls matched by age and sex. Results: Response rates were 79.1% (659/833) for patients with asthma and 70.6% (587/831) for control patients. of the patients with asthma who replied, 60.5% (399/659) had symptomatic bronchial hyper-reactivity. of those with asthma and a negative bronchial hyper-reactivity status (based on the questionnaire), 190/260 (73.1%) were considered to have had asthma when diagnosed, on review of their primary care records. There was no evidence to suggest asthma in 45 (17.3%) of the 260 patients who had a negative bronchial hyper-reactivity status. of the control patients, 41 (7.0%) of the 587 responders had symptomatic bronchial hyper-reactivity and nine of these may have asthma. By extrapolation, we estimate that there were possibly another 99 patients with symptoms of asthma, who had not been labelled as having asthma, and 362 patients with symptoms of bronchial hyper-reactivity who had not reported them to their doctors or had not had them recognised. Conclusions: There is an 89.4% chance that a patient recorded as having asthma has, or has had, asthma. © British Journal of General Practice.

Background: a study designed to explore the experiences of patients with severe chronic obstructive pulmonary disease (COPD) and their carers, particularly with regard to ongoing and palliative care needs. Methods: the participants were nine men and one woman with severe COPD and the carers of eight of the men, in East Devon, UK. Semi-structured interviews were undertaken, transcribed and analysed using interpretative phenomenological analysis (IPA). Results: the emergent themes were of losses, adaptation, relationships with health professionals and effect on carer. Losses reflected the loss of personal liberty and dignity and of previous expectations of the future. Adaptation included strategies to cope with the effects of the disease. Relationships related to both positive and negative aspects of contact with health professionals. There was appreciation for continuity of care and reassurance. The effect on the carer was evident particularly as they had to take on multiple roles. They also experienced some of the same losses as the patient and appeared enmeshed with the illness. Conclusions: This study confirmed the inexorable decline in activities of daily life and social isolation for patients with severe COPD. Adaptive strategies were common and some positive aspects were identified. Support from the primary health care team was appreciated. The strain on carers was very apparent. The concept of a more structured sharing of information and a surveillance role mediated by health care professionals known to the patient and carer would be a pragmatic approach to improving care. © Arnold 2004.

The need to manage the key symptoms of chronic obstructive pulmonary disease (COPD) (breathlessness, cough and sputum) is an important treatment objective. Viozan (sibenadet HCl, AR-C68397AA) is a novel dual D2 dopamine receptor, beta2-adrenoceptor agonist, which combines conventional bronchodilatory activity with the sensory nerve modulation afforded by dopamine agonism. The efficacy of this agent in relieving patient symptoms has been determined in a series of large-scale clinical studies; the results of a 3-month, placebo-controlled multi-centre study are reported. Effect on patient symptoms was determined using a novel patient-reported assessment instrument, the Breathlessness, Cough and Sputum Scale (BCSS). Patients with smoking-related COPD were required to complete a 2-week baseline period before being randomized to one of three treatment groups; sibenadet (500 microg three times daily) plus placebo (twice daily); salmeterol (50 microg twice daily) plus placebo (three times daily); placebo (twice daily) plus a second placebo (three times daily). All treatments were delivered via pressurized metered dose inhaler (pMDI) for 12 weeks. From enrolment, patients were required to complete daily diary cards to record symptoms of breathlessness, cough and sputum, medication use and adverse events. The primary outcome measure was the difference between the mean BCSS total score measured over the baseline period and the mean BCSS total score in the final 4 weeks of the treatment period. Secondary measures included assessment of lung function, rescue medication use, exacerbations, health-related quality of life, opinion of efficacy and safety. Although an initial reduction in BCSS total score (indicating symptom improvement) was seen with sibenadet therapy, this effect was not maintained for the study duration. Salmeterol therapy, however, resulted in a sustained reduction in BCSS total score. No notable benefit over placebo was seen in lung function, exacerbations or health-related quality of life with either active treatment. While the results of this study failed to demonstrate sustained efficacy with sibenadet therapy, they do indicate the value of symptom assessment in the clinical evaluation of new drugs for the treatment of COPD.

BACKGROUND: the importance of psychosocial variables in asthma is increasingly recognised, although attempts to relate these to asthma outcomes often produce only weak relationships. This study aimed to identify whether such relationships might be obscured by the effects of recent asthma experience on psychological status. METHODS: an adult community sample of 37 patients who had suffered a recent attack of asthma and 37 with stable asthma were given measures of panic fear and control confidence. The relationship with subsequent emergency service use was examined using two way ANOVA and correlational analyses. Covariate influences (psychiatric morbidity, age, sex, treatment level, asthma duration, social status) were considered. RESULTS: Control confidence predicted emergency service use in different ways for recent attack and stable asthma patients. This interaction was highly significant (F(1,69) = 10.32, p

Background: Pulmonary rehabilitation programmes run in secondary care have proved to be one of the most effective interventions for patients with chronic obstructive pulmonary disease (COPD). Aim: to assess whether a pulmonary rehabilitation programme, similar to that run in secondary care, could be established in a primary care-run community hospital and whether it could achieve similar benefits in patients with moderately severe COPD. Design of study: Uncontrolled prospective intervention study. Setting: a primary care-run community hospital. Method: Thirty-four patients with COPD aged between 53 and 80 years of age (mean = 70 years) with a forced expiratory volume (FEV1) of 30 to 50% (mean = 40%) predicted were enrolled in a programme established in the activities room at Honiton Community Hospital. Patients were assessed at the start, on completion of the programme, and six months after completion, using spirometry, shuttle-walking distance, and short form-36 (SF-36) and chronic respiratory questionnaire (CRQ) scores. Results: all but one patient completed the programme. There were significant improvements in the walking distance (by a mean of 100 m), in the SF-36, and in all domains of the CRQ. There was no significant change in the FEV1 or forced vital capacity. Conclusion: Pulmonary rehabilitation programmes can be run in community hospitals. They appear to be as effective as those run in secondary care and patients may find them easier to access.

Despite an increase in the provision of services to patients with asthma, morbidity from the disease remains high. Recent research (outside asthma) has raised the possibility that patients may develop a conceptualisation of illnesses which is not entirely compatible with the prevailing biomedical view. This paper compares the way in which health care professionals and patients with asthma described various aspects of the illness, using an approach which considered the type of knowledge which might be used to construct the respective conceptualisations of asthma. A qualitative method is empliyed, using focus groups. Eight focus groups were convened, four of professionals and four of patients with asthma. Following the initial data analysis, the results were reviewed linguistically, with particular attention to the use of metaphor. The health care professionals and patients participating in this study agreed broadly in their explanations of the aetiology and drug treatment of asthma. The data suggest lack of congruence in the development of treatment strategies and locus of control. Health care professionals and patients in this study used linguistically different metaphors to represent the disease: the former more frequently used metaphors evoking on-going processes, the latter visualising the chest (in their use of metaphor) as a static container, emptying and filling throughout the course of the disease. Two commentaries from philosophical and anthropological literature are considered in order to offer theoretical accounts relevant to this interpretation. The data suggest an emerging duality in the approach to treatment plans, in the roles played by professionals and patients with asthma, and in the different types of knowledge used by professionals and patients to construct their respective working models of asthma.

Aims: to compare the effectiveness of opportunistic spirometric screening of patients attending a general practice surgery with screening on randomly selected home visits. Method: 100 patients aged 45+ attending the Honiton Surgery (surgery group) and 100 randomly selected patients visited at their homes (home group) were invited to perform spirometry and complete a symptom and medication questionnaire. Main outcome measures were successful completion of spirometry and questionnaire and ah estimate of COPD prevalence. Results: Surgery assessments were successful in 94/100 (95% C.I. 89% to 99%) cases. Eighteen percent of those visited at home refused the invitation to attend for spirometry; 33% (95% C.I. 24% to 42%) resulted in a successful assessment; there was no. reply when visiting 46% of cases and 3% of he visits were refused or terminated on the day. The mean age of the surgery group and home group was 63.7 years and 64.5 years respectively. The mean time per patient was 17 minutes in the surgery group and 1 hour 26 minutes in the home group. Twenty five (27%, 95% C.I. 18% to 36%) of those assessed in the surgery group and 10 (30%, 95% C.I. 14% to 46%) of the home group had an FEV1 < 80% predicted. Ofthese, 14/25 (56%) and 4/10 (40%) were current or ex-smokers. of these, eight and three respectively had cough, wheeze or breathlessness, giving ah overall COPD prevalence of 11/127 (9%, 95% C.I. 0% to 19%). Three of these eleven (27%) had mild disease, 7/11 (64%) moderate and 1/11 (9%) severe. The mean age of the patients with COPD was 70.8 years. Four of the eleven (36%) patients with COPD already had a diagnosis recorded in their records (3 COPD, 1 asthma). Analysis of surgery attendance (any health care professional) of all patients aged 45 and above, indicated that over a one year period 79.1% (95% C.I. 78.2% to 80.0%) and over a two year period 89% (95% c.i. 88.3% to 89.7%) of the total practice population attended on at least one occasion. Conclusion: Opportunistic spirometric assessment of patients routinely attending surgery results in a high uptake; over a period of two years around 84% of the target population could be assessed. Home visiting may be used for reaching those not routinely attending the surgery.

Objective: British Thoracic Society guidelines advocate the use of oral steroid therapy as a means of controlling symptoms in patients with severe asthma. However, it is well established that there are a number of undesirable adverse effects associated with this form of treatment. The aim of this study was to determine whether the addition of nebulised budesonide reduced oral steroid usage in oral steroid-dependent patients. Design: a 21- to 35-day run-in period allowed asthma stability to be assessed before patients were randomised in a double-blind manner to receive nebulised budesonide or placebo. At the end of the 15-week treatment period, all patients were given nebulised budesonide and followed for a further 4 weeks. Oral steroid reduction was also studied throughout the treatment period. Participants: 118 patients (aged 16 to 65 years) with severe oral steroid- dependent asthma (5 mg/day oral prednisolone and ≥800 μg/day inhaled steroid) were enrolled into the study. of these, 76 were randomised to receive nebulised budesonide or placebo. Interventions: Eligible patients were randomised to receive either nebulised budesonide 2mg twice daily or nebulised placebo in addition to their existing oral steroid medication. Results: the addition of nebulised budesonide to existing oral steroid therapy provided a significant reduction in the number of asthma exacerbations experienced over the 15-week treatment period compared with placebo (1.1 vs 0.35; p < 0.05). Moreover, this seemed to be coupled with a marked decrease in the severity of asthma symptoms such as cough (nebulised budesonide group: mean change -0.16; nebulised placebo group: +0.23; p < 0.05) breathlessness (-0.34 vs +0.06; p < 0.05) and sleep disturbance (-0.05 nights per week vs +0.93 nights per week; p < 0.01). Notably, these benefits were achieved without any deterioration in lung function and in conjunction with patients attempting to reduce their dosage of oral steroid. 68% of patients in the nebulised budesonide group were able to achieve a reduction in oral steroid dosage, compared with 53% in the placebo group, although this was not a significant difference. Conclusions: the addition of nebulised budesonide to regular oral steroid treatment can help to improve symptoms in patients with severe asthma. Moreover, this is achieved without an increase in steroid-related adverse effects. However, the percentage reduction in oral steroid usage between the nebulised budesonide group and the placebo group was not found to be significant (68 versus 53%).

We have used data from the CompuFile DIN-LINK database to assess current approaches to the management of COPD and whether the publication of the BTS COPD guidelines has had any noticeable effect on the number of patients diagnosed with COPD, the use of spirometery, the use of medication and the offer of smoking cessation advice. The DIN-LINK database contains data from anonymised, Read-coded records on approximately 1 million patients contributed by 360 GPs in 100 nationally distributed practices. Records containing a diagnosis of COPD or asthma were identified and form the basis of this analysis. The numbers of patients with each of these diagnoses, with diagnostic transfer from asthma to COPD (A to COPD) and the number of newly diagnosed patients with COPD in each 12 month period from April 95 to May 2000 were calculated. The numbers of patents with COPD who had ever had spirometry (S) performed, who had ever had spirometry performed prior to the diagnosis of COPD being made (S prior) and who had had spirometry performed in the 3 months prior to the diagnosis of COPD being made (S in 3/12) were also calculated. There were no significant trends in the use of short acting (β2 agonists and inhaled steroids over the 5 years but there appeared to be a steady increase in the use of long acting beta agonists over the 5 years & anticholinergics during the last 3 years. There was also an increase in the proportion of patients offered smoking cessation advice over the 5 years but there was no change in the trend over the last 3 years. Many patients are still diagnosed and managed without spirometry, but in the years following the publication of the COPD Guidelines there appears to have been an increase in the use of spirometry. We cannot prove causality from these data but will continue to monitor trends. Year Asthma COPD a to COPD S ever S prior S in 3/12 1996 40127 4331 864 518 81 48 1997 40582 4476 936 604 92 49 1998 41776 4701 1033 794 175 111 1999 41938 4717 1109 950 279 186 2000 42218 5067 1004 1065 377 249.

Early detection of mild or moderate COPD in patients who have minimal or no symptoms offers the best hope of modifying disease progression either through pharmacotherapy or smoking cessation. As part of a larger study of COPD in general practice, we compared the effectiveness of screening patients attending a general practice surgery with home visits. We aimed to get 100 patients aged 45+ to perform spirometry and complete a symptom & medication questionnaire when attending the surgery for whatever reason and we also wrote to 100 patients informing them that we intended to call at their homes and inviting them to take part. 6 of the surgery and 67 of the home patients (22 declined invitation, 45 were not in) were unable or unwilling to be screened. Spirometry was not possible in 4 patients seen at the surgery because of inadequate technique but all home patients performed satisfactorily. The mean ages of the surgery and home groups were 63.7 yrs and 64.5 yrs respectively. The mean time per patient was 0.5h in the surgery group and 1.5h in the home group. 25 (28%) of the surgery group and 10 (30%) of the home group had an FEV1 < 80% predicted. of these 14 (56%) and 4 (40%) respectively were current or ex-smokers. of these 8 and 3 respectively had cough, wheeze or breathlessness, giving an overall prevalence of COPD of 8.9%. 3 (27%) of these had mild disease, 7 (64%) moderate and 1 (9%) severe. The mean age of the patients with COPD was 70.8 yrs. 4 (36) of the patients with COPD already had a diagnosis recorded in their records and 1 was recorded as having asthma. 4 (36%) stated they were receiving inhaled bronchodilators and 4 (36%) inhaled corticosteroids. Opportunistic assessment of patients routinely attending surgery results in a high uptake. 78.4% of our patients attend the surgery in 1 year and 88.9% in 2 years. Thus, over a year around 75% of the target population could be assessed and home visiting used for reaching those not routinely attending the surgery.

The neurohypophysial hormone vasopressin contributes to control of urine output and, while urine flow shows a clear daily rhythm, there has been debate as to whether this is true of neurohypophysial hormones. A study was performed on fifteen adult males, with a mean age of 25 years, over a 24 h period, nine blood samples being taken at regular intervals for the determination of neurohypophysial hormones and indices of fluid balance. Samples were taken via an indwelling cannula so that sleep was undisturbed. A daily variation in the plasma concentrations of oxytocin and vasopressin was demonstrated with concentrations reaching a nadir in the late afternoon. Concentrations of both hormones peaked at 02.00 h. Vasopressin concentrations were inversely correlated with packed cell volume, indicating that the altered hormone release was affecting fluid retention. Consistent with this was the observation that the relationship of plasma osmolality to vasopressin depended on the time of day. To determine the effect of ageing, a similar study was performed on nine healthy elderly subjects with a mean age of 70 years. The nocturnal peak of vasopressin was markedly attenuated, while oxytocin release was similar to that in the younger group. These observations confirm the existence of a daily rhythm in the plasma concentrations of neurohypophysial hormones and indicate that the amplitude of the vasopressin change decreases with age.

Home treatment of patients with cystic fibrosis has many attractions and is becoming increasingly popular the investigators have studied the use, results and costs of the first year of operation of a home‐care intravenous antibiotic service using the‘Intermate’infusion device in a prospective study using questionnaires, spirometric and weight measurements Ninety‐three patients received 166 courses of intravenous antibiotics in full or in part at home during 1991 the average length of treatment was 12 5 days and on average 70% of the treatment was given at home the mean percentage predicted FEVt and FVC improved after treatment and the mean improvement was not significantly different to that produced by hospital treatment Breathlessness, sputum volume, appetite, ability to sleep, mood, energy and overall well‐being, as assessed by questionnaire, showed significant improvements after home treatment the median time spent mixing and administering drugs was 10–19 hours and visiting the hospital was 7–12 hours the median number of days of lost income to patients or their carers was 0 days the majority of the patients were extremely satisfied with the treatment and supervision that they received Using the home care service, 1442 in patient days were saved the investigators conclude that home care using‘Intermates’improves a patient's lung function and quality of life Copyright © 1995, Wiley Blackwell. All rights reserved

A 34 year old sawmill maintenance engineer developed a dry cough that was associated with widespread wheezes and crackles in his lungs. His symptoms worsened, with work related lethargy, fever, and breathlessness, and the loss of a stone in weight. At that time, while still at work, he had a neutrophil leucocytosis and increased concentration of γ globulins. When seen subsequently some two months after stopping work, his chest radiograph and lung function tests were normal, but the cells recovered at bronchoalveolar lavage showed an increase in lymphocytes and mast cells, a pattern consistent with extrinsic allergic alveolitis. Serum precipitins were identified to extracts of sawdust, wood chips, and bark from the sawmill, and to eight species of mould grown from these samples. Specific IgG binding inhibition studies suggested that a common epitope present on Trichoderma koningii might be responsible for the cross reactivity of the patient's serum with the wood and fungal extracts. A diagnosis of wood associated extrinsic allergic alveolitis was made and since changing his job the patient has remained well. Wood associated allergic alveolitis has not previously been described in British sawmill workers, but has been reported in Sweden, with a prevalence of 5%-10% in exposed workers. A review of published data suggests extrinsic allergic alveolitis in wood workers is primarily caused by inhalation of the spores of contaminating fungi, but inhaled wood dust may exert a synergistic effect.

After identification of a case of extrinsic allergic alveolitis due to exposure to wood dust at a sawmill, all employees at the sawmill where he worked were studied with an occupational, environmental, and symptom questionnaire, spirometry, skin prick tests, and serum specific IgG measurements. Ninety five of current and 14 of 17 ex-sawmill workers were studied. As a basis for comparison, a group of 58 workers from a nearby light engineering factory were also studied. Few women (6) were employed and they were excluded from the analysis. Workers at the sawmill were stratified into high and low exposure groups depending on their place of work. This division was supported both by their subjective assessment of the dustiness of their environment and the results of personal dust samples. There were no significant differences between the three groups in age, height, smoking habits, exposure to other causes of extrinsic allergic alveolitis, forced expiratory volume in one second, forced vital capacity, atopic state, or cutaneous reactivity to moulds. In the high exposure group the prevalence of work related cough and nasal and eye symptoms was higher than in the low exposure and comparison groups. The prevalence of work related wheeze was similar in both the high exposure and comparison groups, but was lower in the low exposure group. The prevalences of chronic bronchitis and symptomatic bronchial hyper-reactivity were similar in the high and low exposure groups but were lower in the comparison group. Serum concentrations of specific IgG against extracts of sawdust and Trichoderma koningii were significantly higher in the high exposure group than in the other two groups. The prevalence of symptoms suggestive of extrinsic allergic alveolitis was 4-4% in the high exposure group, greater than in the low exposure group (0%), and the comparison group (1-9%). In conclusion extrinsic allergic alveolitis probably occurs in British sawmills, and among the exposed population its prevalence may be as high as that reported in Sweden. The allergen responsible is likely to be from mould growing on the wood and may be from Trichoderma koningii.

Serum testosterone was measured pre- and post-operatively in 31 women who obtained remission of Cushing's disease following treatment by interstitial irradiation of the pituitary gland. The mean serum testosterone was initially elevated at 3.35 nmol/l, with values ranging from 0.7 to 14.4 (.)nmol-L. Following treatment the mean serum testosterone fell to 1.42 nmol/l (i.e. normal) and all but one of the 15 patients with initially elevated pre-treatment values obtained normal levels. The pre-treatment testosterone concentrations correlated significantly (r = 0.47; p = 0.019) with the midnight ACTH concentration. The likely determinant of the raised serum testosterone would appear to be the intensity of the ACTH drive, although an individual's inherent sensitivity to ACTH may also be a factor.

Twice daily injections of purified ovine and human FSH were used to investigate the control of ovarian follicle development in hypogonadotrophic hypogonadal (hpg) mice. Treatment for 5 days with doses greater than 3 μg resulted in a significant increase in the total number of growing follicles and the development of antral follicles. This was associated with increases in uterine weights and vaginal opening, indicating that steroidogenesis had also been stimulated. Further studies of the effects of combined injections of FSH and LH, linked with morphological analysis of ovarian interstitial cells, suggested that any contribution of background or contaminating LH to the effects of the FSH injections was minimal. It therefore appears that, in mice, FSH alone is capable of stimulating an increase in the initiation of follicle growth, of triggering the development of antral follicles, and supporting ovarian steroidogenesis.

Macrophages of endocrine organs have been identified by immunohistochemical localization of the macrophage-specific antigen F4/80. F4/80+ cells line vascular sinuses and capillaries in anterior and posterior pituitary, adrenal cortex, corpus luteum, parathyroid, pineal gland, and islets of Langerhans. In testis approximately 20% of interstitial cells are F4/80+. F4/80+ cells infiltrate corpus luteum in increased numbers during luteolysis.

Plasma and pituitary PRL levels are significantly greater in adult female than in male rats. This difference is thought to be brought about by ovarian steroids. We found a similar sex difference in pituitary PRL content in normal mice from 30 days of age. Ovariectomy reduced pituitary PRL content and this reduction was prevented by sc implants of estradiol-17β(E2). Implants of E2 also increased the pituitary PRL content in normal male mice to a level approaching thatin normal females. The hypogonadal (hpg) mice did not show a sex difference in pituitary PRL content. Implantation of E2 into mutants of bothsexes raised the pituitary content of PRL to the level in normalfemales. Treatment of intact but not ovariectomized hpg females with two injections/day of 6 μg FSH (NIH-FSH-S15) produced uterine growth and an increase in pituitary PRL content. Estrogen implants significantly increased plasma PRL concentrations in ovariectomized normal female and normal male mice but not in adult hpg male or female animals. These results show that elevation of the plasma E2 concen-tration increased significantly the synthesis of PRL in both normal and hpg mice of both sexes, and in the normal, but not the hpg mice, also increased the plasma concentration of PRL. © 1983 by the Endocrine Society.

Hypogonadal (hpg) mice have a deficiency of hypothalamic GnRH with an associated reduction in pituitary and plasma gonadotropins and a failure of postnatal gonadal development. GnRH is naturally delivered to the pituitary in a pulsatile manner. Our main aim was to investigate the effect of daily single compared with daily multiple GnRH injections on pituitary and gonadal function of the hpg mouse. In male hpg mice, single daily sc injections of GnRH at dosages from 50 ng to 20 μg for 20 days increased the pituitary FSH content from about 500 ng to 17, 800-32, 200 ng/pituitary, the content in normal mice being about 20, 000 ng/pituitary. The injections only slightly increased pituitary LH content. The weight of the testes was increased to about a third of those in normal adult mice and, by 60 days of injection, all stages of spermatogenesis were present in the seminiferous tubules. However, in none of the animals was there any growth of the seminal vesicles. By contrast, GnRH given as 12 injections each day for 15 days produced an increase in pituitary LH (although not to normal adult levels) as well as pituitary FSH content, and stimulated a significant increase in the weights of the seminal vesicles as well as the testes. Injection of 60 ng GnRH 12 times daily for 15 days produced increases in pituitary LH content, plasma FSH concentration, and seminal vesicle weights which were much greater than those produced by 1 μg GnRH given once daily; pituitary FSH contents were similar in the 2 groups of animals. Castration, castration plus adrenalectomy, or theimplantation of silastic capsules that contained testosterone propionate did not inhibit the increase in pituitary FSH content produced by GnRH injections. In female hpg mice single daily sc injections of GnRH for 10-15 days increased pituitary FSH content to a level 4 times that i n normal adult female mice, but there was no increase in uterine weight. Multiple injections of GnRH, either 4 or 12 each day for 10-15 days, increased pituitary FSH content to the level in normal adult female mice and also increased significantly the uterine weights. Pituitary LH content was increased to nearly normal values by 12 injections of 60 ng GnRH/day but remained low in animals given single daily injections of GnRH even at doses as high as 1 μg. Treatment with estrogen significantly reduced, whereas ovariectomy significantly enhanced, the increase in pituitary FSH content produced by multiple GnRH injections. These data show that 1) compared with the effects of single daily injections of GnRH, multiple daily injections of GnRH produce a more normal function of the pituitary-gonadal-accessory sex organ system in hpg mice of either sex; 2) a major site of negative feedback of estrogen appears to be at the pituitary i n the female, whereas in the male testosterone appears to exert its inhibitory effect at the hypothalamus or above; and 3) with every injection regimen used, GnRH is considerably more potent at stimulating FSH compared with LH synthesis in the hpg mouse. © 1983 by the Endocrine Society.

Hypogonadal mice are deficient in LH releasing hormone (LH-RH), the releasing factor for LH and FSH, with a consequent failure of postnatal ovarian and testicular development. After intravenous injection of hypogonadal females with 125I-labelled human chorionic gonadotrophin (hCG), followed by autoradiography of semi-thin (1 μm) slices of the ovary, labelled hCG was found to be associated with interstitial cells and thecal cells with little or no labelling of granulosa cells. Labelled human FSH was associated solely with granulosa cells. Hypogonadal females, implanted for 5 days with a silicone elastomer capsule of oestrogen, showed a similar response to that of normal females with hCG labelling of the granulosa cells of the larger follicles as well as of the thecal cell layer. Furthermore, subcutaneous injection of hypogonadal females with LH-RH (50 ng), 12 times daily for 5 days, increased uterine weight and stimulated ovarian development with some large follicles binding hCG to both thecal and granulosa cells. Therefore stimulation of follicular development may possibly be associated with increased oestradiol concentrations. In the male, after injection of 125I-labelled hCG, silver grains were associated with the interstitial cells alone in both hypogonadal and normal mice. Labelled human FSH was undetectable in semi-thin testicular sections, but the mode of injection (intravenous) may not have allowed enough labelled hormone to reach the testis in order to resolve the question as to whether the hypogonadal or normal testis can bind FSH.