Inhaled glucocorticoid-induced metabolome changes in asthma.

Objective: The aim of this study was toidentify dose-related systemic effects of inhaled glucocorticoids (GCs) on the global metabolome. Design and methods: Metabolomics/lipidomic analysis from plasma was obtained from 54 subjects receiving weekly escalating doses (µg/day) of fluticasone furoate (FF; 25, 100, 200, 400 and 800), fluticasone propionate (FP; 50, 200, 500, 1000 and 2000), budesonide (BUD; 100, 400, 800, 1600 and 3200) or placebo. Samples (pre- and post-dose) were analysed using ultrahigh-performance liquid chromatography-tandem mass spectroscopy and liquid chromatography-mass spectrometry. Ions were matched to library standards for identification and quantification. Statistical analysis involved repeated measures ANOVA, cross-over model, random forest and principal component analysis using log-transformed data. Results: Quantifiable metabolites (1971) had few significant changes (% increases/decreases; P < 0.05) vs placebo: FF 1.34 (0.42/0.92), FP 1.95 (0.41/1.54) and BUD 2.05 (0.60/1.45). Therapeutic doses had fewer changes: FF 0.96 (0.36/0.61), FP 1.66 (0.44/1.22) and BUD 1.45 (0.56/0.90). At highest/supratherapeutic doses, changes were qualitatively similar: reduced adrenal steroids, particularly glucuronide metabolites of cortisol and cortisone and pregnenolone metabolite DHEA-S; increased amino acids and glycolytic intermediates; decreased fatty acid ß-oxidation and branched-chain amino acids. Notable qualitative differences were lowered dopamine metabolites (BUD) and secondary bile acid profiles (BUD/FF), suggesting CNS and gut microbiome effects. Conclusions: Dose-dependent metabolomic changes occurred with inhaled GCs but were seen predominately at highest/supratherapeutic doses, supporting the safety of low and mid therapeutic doses. At comparable therapeutic doses (FF 100, FP 500 and BUD 800 µg/day), FF had the least effect on the most sensitive markers (adrenal steroids) vs BUD and FP.

Blood eosinophil counts in the general population and airways disease: a comprehensive review and meta-analysis.

BACKGROUND: The clinical context for using blood eosinophil (EOS) counts as treatment-response biomarkers in asthma and COPD requires better understanding of EOS distributions and ranges. We describe EOS distributions and ranges published in asthma, COPD, control (non-asthma/COPD) and general populations. METHODS: We conducted a comprehensive literature review and meta-analysis of observational studies (January 2008 to November 2018) that included EOS counts in asthma, severe asthma, COPD, control and general populations. Excluded studies had total sample sizes <200, EOS as inclusion criterion, hospitalised population only and exclusively paediatric participants. RESULTS: Overall, 91 eligible studies were identified, most had total-population-level data available: asthma (39 studies), severe asthma (12 studies), COPD (23 studies), control (seven studies) and general populations (14 studies); some articles reported data for multiple populations. Reported EOS distributions were right-skewed (seven studies). Reported median EOS counts ranged from 157-280 cells·µL-1 (asthma, 22 studies); 200-400 cells·µL-1 (severe asthma, eight studies); 150-183 cells·µL-1 (COPD, six studies); and 100-160 cells·µL-1 (controls, three studies); and 100-200 cells·µL-1 (general populations, six studies). The meta-analysis showed that observed variability was mostly between studies rather than within studies. Factors reportedly associated with higher blood EOS counts included current smoking, positive skin-prick test, elevated total IgE, comorbid allergic rhinitis, age ≤18 years, male sex, spirometric asthma/COPD diagnosis, metabolic syndrome and adiposity. CONCLUSION: EOS distribution and range varied by study population, and were affected by clinical factors including age, smoking history and comorbidities, which, regardless of severity, should be considered during treatment decision-making.

Moving towards a Treatable Traits model of care for the management of obstructive airways diseases.

Asthma and chronic obstructive pulmonary disease (COPD) are two prevalent chronic airways diseases. Both are complex and heterogeneous. Traditionally, clinical guidelines have advocated a stepwise approach to pharmacotherapy of asthma and COPD, but there is increasing realization that both require a more personalized and precise management approach. To this end, a management strategy based on the so-called Treatable Traits has been proposed. Emerging evidence suggests that this model improves relevant outcomes in patients with chronic airway diseases but further research is needed to guide implementation. This review discusses the challenges, opportunities, and hurdles that its implementation will have to face.

Future concepts in bronchodilation for COPD: dual- versus monotherapy.

Most patients with COPD are recommended to initiate maintenance therapy with a single long-acting bronchodilator, such as a long-acting muscarinic antagonist or long-acting ß2-agonist. However, many patients receiving mono-bronchodilation continue to experience high symptom burden, suggesting that patients are frequently not receiving optimal treatment. Treatment goals for COPD are often broad and not individually tailored, making initial treatment response assessments difficult. A personalised approach to initial maintenance therapy, based upon an individual's symptom burden and exacerbation risk, may be more appropriate.An alternative approach would be to maximise bronchodilation early in the disease course of all patients with COPD. Evidence suggests that dual bronchodilation has greater and consistent efficacy for lung function and symptoms than mono-bronchodilation, whilst potentially reducing the risk of exacerbations and disease deterioration, with a similar safety profile to mono-bronchodilators. Improvements in lung function and symptoms between dual- and mono-bronchodilation have also been demonstrated in maintenance-naïve patients, who are most likely to resemble those at first presentation in a clinical setting. Despite promising results, there are several evidence gaps that need to be addressed to allow decision makers to evaluate the merits of a widespread earlier introduction of dual bronchodilation.

A Prospective Cohort Study to Assess Obstructive Respiratory Disease Phenotypes and Endotypes in Japan: The TRAIT Study Design.

Background: Asthma, chronic obstructive pulmonary disease (COPD), and asthma-COPD overlap (ACO) are complex and heterogeneous diseases that share clinical characteristics (phenotypes) and molecular mechanisms (endotypes). Whilst physicians make clinical decisions on diagnostic groups, for some such as ACO there is no commonly accepted criteria. An alternative approach is to evaluate phenotypes and endotypes that are considered to respond well to a specific type of treatment ("treatable traits") rather than diagnostic labels. Purpose: The prospective, longitudinal, and observational TRAIT study will evaluate disease characteristics, including both phenotypes and endotypes, in relation to the presentation of obstructive respiratory disease characteristics in patients diagnosed with asthma, COPD, or ACO in Japan, with the aim of further understanding the clinical benefit of a treatable traits-based approach. Patients and Methods: A total of 1500 participants will be enrolled into three cohorts according to their treating physician's diagnosis of asthma, COPD, or ACO at screening. Part 1 of the study will involve cross-sectional phenotyping and endotyping at study enrollment. Part 2 of the study will evaluate the progression of clinical characteristics, biomarker profiles, and treatment over a 3-year follow-up period. The follow-up will involve three annual study visits and three telephone calls scheduled at 6-month intervals. A substudy involving 50 participants from the asthma cohort (in which the ratio will be approximately 1:1 including 25 participants with a smoking history of ≥10 pack-years and 25 participants with no smoking history), 100 participants from the ACO cohort, and 100 participants from the COPD cohort will evaluate disease phenotypes using inspiratory and expiratory computed tomography scans. Conclusion: TRAIT will describe clinical characteristics of patients with obstructive respiratory diseases to better understand potential differences and similarities between clinical diagnoses, which will support the improvement of personalized treatment strategies.

Benefit/Risk Profile of Single-Inhaler Triple Therapy in COPD.

Chronic obstructive pulmonary disease (COPD) is associated with major healthcare and socioeconomic burdens. International consortia recommend a personalized approach to treatment and management that aims to reduce both symptom burden and the risk of exacerbations. Recent clinical trials have investigated single-inhaler triple therapy (SITT) with a long-acting muscarinic antagonist (LAMA), long-acting ß2-agonist (LABA), and inhaled corticosteroid (ICS) for patients with symptomatic COPD. Here, we review evidence from randomized controlled trials showing the benefits of SITT and weigh these against the reported risk of pneumonia with ICS use. We highlight the challenges associated with cross-trial comparisons of benefit/risk, discuss blood eosinophils as a marker of ICS responsiveness, and summarize current treatment recommendations and the position of SITT in the management of COPD, including potential advantages in terms of improving patient adherence. Evidence from trials of SITT versus dual therapies in symptomatic patients with moderate to very severe airflow limitation and increased risk of exacerbations shows benefits in lung function and patient-reported outcomes. Moreover, the key benefits reported with SITT are significant reductions in exacerbations and hospitalizations, with data also suggesting reduced all-cause mortality. These benefits outweigh the ICS-class effect of higher incidence of study-reported pneumonia compared with LAMA/LABA. Important differences in trial design, baseline population characteristics, such as exacerbation history, and assessment of outcomes, have significant implications for interpreting data from cross-trial comparisons. Current understanding interprets the blood eosinophil count as a continuum that can help predict response to ICS and has utility alongside other clinical factors to aid treatment decision-making. We conclude that treatment decisions in COPD should be guided by an approach that considers benefit versus risk, with early optimization of treatment essential for maximizing long-term benefits and patient outcomes.

Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a double-blind, randomised, phase 3A trial.

BACKGROUND: Despite inhaled corticosteroid plus long-acting ß2-agonist (ICS/LABA) therapy, 30-50% of patients with moderate or severe asthma remain inadequately controlled. We investigated the safety and efficacy of single-inhaler fluticasone furoate plus umeclidinium plus vilanterol (FF/UMEC/VI) compared with FF/VI. METHODS: In this double-blind, randomised, parallel-group, phase 3A study (Clinical Study in Asthma Patients Receiving Triple Therapy in a Single Inhaler [CAPTAIN]), participants were recruited from 416 hospitals and primary care centres across 15 countries. Participants were eligible if they were aged 18 years or older, with inadequately controlled asthma (Asthma Control Questionnaire [ACQ]-6 score of ≥1·5) despite ICS/LABA, a documented health-care contact or a documented temporary change in asthma therapy for treatment of acute asthma symptoms in the year before screening, pre-bronchodilator FEV1 between 30% and less than 85% of predicted normal value, and reversibility (defined as an increase in FEV1 of ≥12% and ≥200 mL in the 20-60 min after four inhalations of albuterol or salbutamol) at screening. Participants were randomly assigned (1:1:1:1:1:1), via central based randomisation stratified by pre-study ICS dose at study entry, to once-daily FF/VI (100/25 µg or 200/25 µg) or FF/UMEC/VI (100/31·25/25 µg, 100/62·5/25 µg, 200/31·25/25 µg, or 200/62·5/25 µg) administered via Ellipta dry powder inhaler (Glaxo Operations UK, Hertfordshire, UK). Patients, investigators, and the funder were masked to treatment allocation. Endpoints assessed in the intention-to-treat population were change from baseline in clinic trough FEV1 at week 24 (primary) and annualised moderate and/or severe asthma exacerbation rate (key secondary). Other secondary endpoints were change from baseline in clinic FEV1 at 3 h post-dose, St George's Respiratory Questionnaire (SGRQ) total score, and ACQ-7 total score, all at week 24. Change from baseline in Evaluating Respiratory Symptoms in Asthma total score at weeks 21-24 was also a secondary endpoint but is not reported here. Exploratory analyses of biomarkers of type 2 airway inflammation on treatment response were also done. This study is registered with ClinicalTrials.gov, NCT02924688, and is now complete. FINDINGS: Between Dec 16, 2016, and Aug 31, 2018, 5185 patients were screened and 2439 were recruited and randomly assigned to FF/VI (100/25 µg n=407; 200/25 µg n=406) or FF/UMEC/VI (100/31·25/25 µg n=405; 100/62·5/25 µg n=406; 200/31·25/25 µg n=404; 200/62·5/25 µg n=408), with three patients randomly assigned in error and not included in analyses. In the intention-to-treat population, 922 (38%) patients were men, the mean age was 53·2 years (SD 13·1) and body-mass index was 29·4 (6·6). Baseline demographics were generally similar across all treatment groups. The least squares mean improvement in FEV1 change from baseline for FF/UMEC/VI 100/62·5/25 µg versus FF/VI 100/25 µg was 110 mL (95% CI 66-153; p<0·0001) and for 200/62·5/25 µg versus 200/25 µg was 92 mL (49-135; p<0·0001). Adding UMEC 31·25 µg to FF/VI produced similar improvements (FF/UMEC/VI 100/31·25/25 µg vs FF/VI 100/25 µg: 96 mL [52-139; p<0·0001]; and 200/31·25/25 µg vs 200/25 µg: 82 mL [39-125; p=0·0002]). These results were supported by the analysis of clinic FEV1 at 3 h post-dose. Non-significant reductions in moderate and/or severe exacerbation rates were observed for FF/UMEC 62·5 µg/VI versus FF/VI (pooled analysis), with rates lower in FF 200 µg-containing versus FF 100 µg-containing treatment groups. All pooled treatment groups demonstrated mean improvements (decreases) in SGRQ total score at week 24 compared with baseline in excess of the minimal clinically important difference of 4 points; however, there were no differences between treatment groups. For mean change from baseline to week 24 in asthma control questionnaire-7 score, improvements (decreases) exceeding the minimal clinically important difference of 0·5 points were observed in all pooled treatment groups. Adding UMEC to FF/VI resulted in small, dose-related improvements compared with FF/VI (pooled analysis: FF/UMEC 31·25 µg/VI versus FF/VI, -0·06 (95% CI -0·12 to 0·01; p=0·094) FF/UMEC 62·5 µg/VI versus FF/VI, -0·09 (-0·16 to -0·02, p=0·0084). By contrast with adding UMEC, the effects of higher dose FF on clinic trough FEV1 and annualised moderate and/or severe exacerbation rate were increased in patients with higher baseline blood eosinophil count and exhaled nitric oxide. Occurrence of adverse events was similar across treatment groups (patients with at least one event ranged from 210 [52%] to 258 [63%]), with the most commonly reported adverse events being nasopharyngitis (51 [13%]-63 [15%]), headache (19 [5%]-36 [9%]), and upper respiratory tract infection (13 [3%]-24 [6%]). The incidence of serious adverse events was similar across all groups (range 18 [4%]-25 [6%)). Three deaths occurred, of which one was considered to be related to study drug (pulmonary embolism in a patient in the FF/UMEC/VI 100/31·25/25 µg group). INTERPRETATION: In patients with uncontrolled moderate or severe asthma on ICS/LABA, adding UMEC improved lung function but did not lead to a significant reduction in moderate and/or severe exacerbations. For such patients, single-inhaler FF/UMEC/VI is an effective treatment option with a favourable risk-benefit profile. Higher dose FF primarily reduced the rate of exacerbations, particularly in patients with raised biomarkers of type 2 airway inflammation. Further confirmatory studies into the differentiating effect of type 2 inflammatory biomarkers on treatment outcomes in asthma are required to build on these exploratory findings and further guide clinical practice. FUNDING: GSK.

Therapeutic index of inhaled corticosteroids in asthma: A dose-response comparison on airway hyperresponsiveness and adrenal axis suppression.

AIMS: To compare the airway potency, systemic activity and therapeutic index of three inhaled corticosteroids that differ in glucocorticoid receptor binding affinity, physicochemical and pharmacokinetic properties. METHODS: This escalating-dose, placebo-controlled, cross-over study randomised adults with asthma to 1 or 2 treatment periods with ≥25 days washout in-between. Each treatment period comprised five 7-day dose escalations (µg/d): fluticasone furoate (FF; 25 → 100 → 200 → 400 → 800), fluticasone propionate (FP; 50 → 200 → 500 → 1000 → 2000), budesonide (BUD; 100 → 400 → 800 → 1600 → 3200) or placebo. Airway hyperresponsiveness to adenosine-5'-monophosphate (AMP PC20 ) was assessed on day 8. Plasma cortisol was assessed on day 1 (predose baseline) and from pre-PM dose on day 6 to pre-PM dose day 7 (24-h weighted mean). RESULTS: Fifty-four subjects were randomised. FF showed greater airway potency than FP and BUD (AMP PC20 dose at which 50% of the maximum effect is achieved [ED50 ] values: 48.52, 1081.27 and 1467.36 µg/d, respectively). Systemic activity (cortisol suppression) ED50 values were 899.99, 1986.05 and 1927.42 µg/d, respectively. The therapeutic index (ED50 cortisol suppression/ED50 AMP PC20 ) was wider for FF (18.55) than FP (1.84) and BUD (1.31). FF 100 µg/d and 200 µg/d were both comparable in terms of airway potency with high doses of FP (≥1000 µg twice daily [BID]) and BUD (≥1500 µg/BID). The systemic activity of FF 100 µg/d and 200 µg/d (cortisol suppression: 7.41% and 14.28%, respectively) was comparable with low doses of FP (100 µg/BID and 250 µg/BID) and BUD (100 µg/BID and 200 µg/BID). CONCLUSION: This study provides evidence that FF can provide more protection against airway hyperresponsiveness, with less systemic activity, than FP or BUD. This suggests that all inhaled corticosteroids are not therapeutically similar and may differ in their therapeutic index. (203162; NCT02991859).

A randomised controlled trial of the effect of a connected inhaler system on medication adherence in uncontrolled asthmatic patients.

Suboptimal adherence to maintenance therapy contributes to poor asthma control and exacerbations. This study evaluated the effect of different elements of a connected inhaler system (CIS), comprising clip-on inhaler sensors, a patient-facing app and a healthcare professional (HCP) dashboard, on adherence to asthma maintenance therapy.This was an open-label, parallel-group, 6-month, randomised controlled trial in adults with uncontrolled asthma (asthma control test (ACT) score less than 20) on fixed-dose inhaled corticosteroids/long-acting ß-agonist maintenance therapy (n=437). All subjects received fluticasone furoate/vilanterol ELLIPTA dry-powder inhalers for maintenance and salbutamol/albuterol metered-dose inhalers for rescue, with a sensor attached to each inhaler. Participants were randomised to one of five CIS study arms (allocation ratio 1:1:1:1:1) reflecting the recipient of the data feedback from the sensors, as follows: 1) maintenance use to participants and HCPs (n=87); 2) maintenance use to participants (n=88); 3) maintenance and rescue use to participants and HCPs (n=88); 4) maintenance and rescue use to participants (n=88); and 5) no feedback (control) (n=86).For the primary endpoint, observed mean±sd adherence to maintenance therapy over months 4-6 was 82.2±16.58% (n=83) in the "maintenance to participants and HCPs" arm and 70.8±27.30% (n=85) in the control arm. The adjusted least squares mean±se was 80.9±3.19% and 69.0±3.19%, respectively (study arm difference: 12.0%, 95% CI 5.2-18.8%; p<0.001). Adherence was also significantly greater in the other CIS arms versus the control arm. The mean percentage of rescue medication free days (months 4-6) was significantly greater in participants receiving data on their rescue use compared with controls. ACT scores improved in all study arms with no significant differences between groups.A CIS can improve adherence to maintenance medication and reduce rescue medication use in patients with uncontrolled asthma.

High eosinophil counts predict decline in FEV1: results from the CanCOLD study.

INTRODUCTION: The aim of this study was to examine the association between blood eosinophil levels and the decline in lung function in individuals aged >40 years from the general population. METHODS: The study evaluated the eosinophil counts from thawed blood in 1120 participants (mean age 65 years) from the prospective population-based Canadian Cohort of Obstructive Lung Disease (CanCOLD) study. Participants answered interviewer-administered respiratory questionnaires and performed pre-/post-bronchodilator spirometric tests at 18-month intervals; computed tomography (CT) imaging was performed at baseline. Statistical analyses to describe the relationship between eosinophil levels and decline in forced expiratory volume in 1 s (FEV1) were performed using random mixed-effects regression models with adjustments for demographics, smoking, baseline FEV1, ever-asthma and history of exacerbations in the previous 12 months. CT measurements were compared between eosinophil subgroups using ANOVA. RESULTS: Participants who had a peripheral eosinophil count of ≥300 cells·µL-1 (n=273) had a greater decline in FEV1 compared with those with eosinophil counts of <150 cells·µL-1 (n=430; p=0.003) (reference group) and 150-<300 cells·µL-1 (n=417; p=0.003). The absolute change in FEV1 was -32.99 mL·year-1 for participants with eosinophil counts <150 cells·µL-1; -38.78 mL·year-1 for those with 150-<300 cells·µL-1 and -67.30 mL·year-1 for participants with ≥300 cells·µL-1. In COPD, higher eosinophil count was associated with quantitative CT measurements reflecting both small and large airway abnormalities. CONCLUSION: A blood eosinophil count of ≥300 cells·µL-1 is an independent risk factor for accelerated lung function decline in older adults and is related to undetected structural airway abnormalities.

Impact of baseline COPD symptom severity on the benefit from dual versus mono-bronchodilators: an analysis of the EMAX randomised controlled trial.

RATIONALE: Symptom relief is a key treatment goal in patients with chronic obstructive pulmonary disease (COPD). However, there are limited data available on the response to bronchodilator therapy in patients at low risk of exacerbations with different levels of symptom severity. This study compared treatment responses in patients with a range of symptom severities as indicated by baseline COPD assessment test (CAT) scores. METHODS: The 24-week EMAX trial evaluated the benefits of umeclidinium/vilanterol versus umeclidinium or salmeterol in symptomatic patients at low exacerbation risk who were not receiving inhaled corticosteroids. This analysis assessed lung function, symptoms, health status, and short-term deterioration outcomes in subgroups defined by a baseline CAT score [<20 (post hoc) and ⩾20 (pre-specified)]. Outcomes were also assessed using post hoc fractional polynomial modelling with continuous transformations of baseline CAT score covariates. RESULTS: Of the intent-to-treat population (n = 2425), 56% and 44% had baseline CAT scores of <20 and ⩾20, respectively. Umeclidinium/vilanterol demonstrated favourable improvements compared with umeclidinium and salmeterol for the majority of outcomes irrespective of the baseline CAT score, with the greatest improvements generally observed in patients with CAT scores <20. Fractional polynomial analyses revealed consistent improvements in lung function, symptoms and reduction in rescue medication use with umeclidinium/vilanterol versus umeclidinium and salmeterol across a range of CAT scores, with the largest benefits seen in patients with CAT scores of approximately 10-21. CONCLUSIONS: Patients with symptomatic COPD benefit similarly from dual bronchodilator treatment with umeclidinium/vilanterol. Fractional polynomial analyses demonstrated the greatest treatment differences favouring dual therapy in patients with a CAT score <20, although benefits were seen up to scores of 30. This suggests that dual bronchodilation may be considered as initial therapy for patients across a broad range of symptom severities, not only those with severe symptoms (CAT ⩾20).Trial registration: NCT03034915, 2016-002513-22 (EudraCT number).The reviews of this paper are available via the supplemental material section.

Critical Error Frequency and the Impact of Training with Inhalers Commonly used for Maintenance Treatment in Chronic Obstructive Pulmonary Disease.

Introduction: Training in correct inhaler use, ideally in person or by video demonstration, can minimize errors but is rarely provided in clinics. This open-label, low-intervention study evaluated critical error rates with dry-powder inhalers (DPIs), before and after training, in patients with chronic obstructive pulmonary disease. Methods: Patients prescribed an inhaled corticosteroid (ICS)/long-acting ß2-agonist (LABA) (ELLIPTA, Turbuhaler, or DISKUS), long-acting muscarinic antagonist (LAMA)/LABA (ELLIPTA or Breezhaler), or LAMA-only DPI (ELLIPTA, HandiHaler, or Breezhaler) were enrolled. Critical errors were assessed before training (Visit 1 [V1]; primary endpoint) and 6 weeks thereafter (Visit 2 [V2]; secondary endpoint). Logistic regression models were used to calculate odds ratios (ORs) for between-group comparisons. Results: The intent-to-treat population comprised 450 patients. At V1, fewer patients made ≥1 critical error with ELLIPTA (10%) versus other ICS/LABA DPIs (Turbuhaler: 40%, OR 4.66, P=0.005; DISKUS: 26%, OR 2.48, P=0.114) and other LAMA or LAMA/LABA DPIs (HandiHaler: 34%, OR 3.50, P=0.026; Breezhaler: 33%, OR 3.94, P=0.012). Critical error rates with the primary ICS/LABA DPI were not significantly different between ELLIPTA ICS/LABA (10%) and ICS/LABA plus LAMA groups (12-25%). Critical errors with the primary ICS/LABA DPI occurred less frequently with ELLIPTA ICS/LABA with or without LAMA (11%) versus Turbuhaler ICS/LABA with or without LAMA (39%, OR 3.99, P<0.001) and DISKUS ICS/LABA with or without LAMA (26%, OR 2.18, P=0.069). Simulating single-inhaler versus multiple-inhaler triple therapy, critical error rates were lower with ELLIPTA fluticasone furoate/vilanterol (FF/VI; 10%) versus ELLIPTA FF/VI plus LAMA (22%), considering errors with either DPI (OR 2.50, P=0.108). At V2, critical error rates decreased for all DPIs/groups, reaching zero only for ELLIPTA. Between-group comparisons were similar to V1. Conclusion: Fewer patients made critical errors with ELLIPTA versus other ICS/LABA, and LAMA or LAMA/LABA DPIs. The effect of "verbal" training highlights its importance for reducing critical errors with common DPIs.

Factors that affect blood eosinophil counts in a non-asthmatic population: Post hoc analysis of data from Brazil.

BACKGROUND: Improved understanding of the normal range of blood eosinophil counts (BEC) and conditions that influence them in non-asthmatic individuals should allow more accurate estimation of the threshold at which eosinophilic disease should be considered, diagnosed, and treated. This analysis investigated the impact of atopy, smoking, and parasitic infection on BEC. METHODS: This was a post hoc analysis of non-asthmatic subjects from a case-control study (CONEP 450/10) conducted at the Program for Control of Asthma in Bahia (ProAR). Participant BECs were measured at baseline; correlations between predefined risk factors and BEC were assessed via univariate and stratified analysis. RESULTS: Of the 454 participants included, 3% were helminth parasite-positive, 18% were non-helminth parasite-positive; and 450 had BEC data. The median (interquartile range [IQR]) BEC was 152 (96, 252) cells/µL. Any positive skin prick test, elevated total immunoglobulin E, allergic rhinitis, and being a current smoker were all individually associated with higher BEC (p < 0.05) compared with BEC in participants without these factors, but having a non-helminthic parasitic infection was not. Participants with all 4 risk factors that were associated with higher BEC had a median (IQR) BEC of 192 cells/µL (94, 416) versus 106 cells/µL (70, 164) for those with no risk factors. CONCLUSIONS: In non-asthmatic subjects, atopy, allergic rhinitis, and current smoking status were associated with higher BEC compared with subjects without these factors, but BEC values were well below the threshold commonly accepted as normal. Therefore, BEC should be interpreted in the context of an individual's medical conditions and other BEC-influencing factors.

Risk factors for exacerbations and pneumonia in patients with chronic obstructive pulmonary disease: a pooled analysis.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) are at risk of exacerbations and pneumonia; how the risk factors interact is unclear. METHODS: This post-hoc, pooled analysis included studies of COPD patients treated with inhaled corticosteroid (ICS)/long-acting ß2 agonist (LABA) combinations and comparator arms of ICS, LABA, and/or placebo. Backward elimination via Cox's proportional hazards regression modelling evaluated which combination of risk factors best predicts time to first (a) pneumonia, and (b) moderate/severe COPD exacerbation. RESULTS: Five studies contributed: NCT01009463, NCT01017952, NCT00144911, NCT00115492, and NCT00268216. Low body mass index (BMI), exacerbation history, worsening lung function (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage), and ICS treatment were identified as factors increasing pneumonia risk. BMI was the only pneumonia risk factor influenced by ICS treatment, with ICS further increasing risk for those with BMI <25 kg/m2. The modelled probability of pneumonia varied between 3 and 12% during the first year. Higher exacerbation risk was associated with a history of exacerbations, poorer lung function (GOLD stage), female sex and absence of ICS treatment. The influence of the other exacerbation risk factors was not modified by ICS treatment. Modelled probabilities of an exacerbation varied between 31 and 82% during the first year. CONCLUSIONS: The probability of an exacerbation was considerably higher than for pneumonia. ICS reduced exacerbations but did not influence the effect of risks associated with prior exacerbation history, GOLD stage, or female sex. The only identified risk factor for ICS-induced pneumonia was BMI <25 kg/m2. Analyses of this type may help the development of COPD risk equations.

Chronic Obstructive Pulmonary Disease as a Predictor of Cardiovascular Risk: A Case-Control Study.

Chronic obstructive pulmonary disease (COPD) is a complex multi-morbid disorder with significant cardiac mortality. Current cardiovascular risk prediction models do not include COPD. We investigated whether COPD modifies future cardiovascular risk to determine if it should be considered in risk prediction models.Case-control study using baseline data from two randomized controlled trials performed between 2012 and 2015. Of the 90 eligible subjects, 26 COPD patients with lung hyperinflation were propensity matched for 10-year global cardiovascular risk score (QRISK2) with 26 controls having normal lung function. Patients underwent cardiac magnetic resonance imaging, arterial stiffness and lung function measurements. Differences in pulse wave velocity (PWV), total arterial compliance (TAC) and aortic distensibility were main outcome measures.PWV (mean difference 1.0 m/s, 95% CI 0.02-1.92; p = 0.033) and TAC (mean difference -0.27 mL/m2/mmHg, 95% CI 0.39-0.15; p < 0.001) were adversely affected in COPD compared to the control group. The PWV difference equates to an age, sex and risk-factor adjusted increase in relative risk of cardiovascular events and mortality of 14% and 15%, respectively.There were no differences in aortic distensibility. In the whole cohort (n = 90) QRISK2 (ß = 0.045, p = 0.005) was associated with PWV in multivariate analysis. The relationship between QRISK2 and PWV were modified by COPD, where the interaction term reached significance (p = 0.014). FEV1 (ß = 0.055 (0.027), p = 0.041) and pulse (B = -0.006 (0.002), p = 0.003) were associated with TAC in multivariate analysis.Markers of cardiovascular outcomes are adversely affected in COPD patients with lung hyperinflation compared to controls matched for global cardiovascular risk. Cardiovascular risk algorithms may benefit from the addition of a COPD variable to improve risk prediction and guide management.HAPPY London ClinicalTrials.gov: NCT01911910 and HZC116601; ClinicalTrials.gov: NCT01691885.

Circulating neutrophils levels are a predictor of pneumonia risk in chronic obstructive pulmonary disease.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have excess risk of developing pneumonia; however, no definitive biomarkers of risk have been established. We hypothesized that blood neutrophils would help predict pneumonia risk in COPD. METHODS: A meta-analysis of randomized, double-blind clinical trials of COPD patients meeting the following criteria were selected from the GlaxoSmithKline trial registry: ≥1 inhaled corticosteroid-containing (ICS) arm (fluticasone propionate/salmeterol or fluticasone furoate/vilanterol), a control arm (non-ICS), pre-randomization blood neutrophil counts, ≥24-week duration. The number of patients with pneumonia events and time to first event (Kaplan-Meier analysis) were evaluated (post-hoc), stratified by baseline blood neutrophil count and ICS use. A Cox proportional hazards model was used to calculate hazard ratios (HR), split by median baseline blood neutrophils. RESULTS: Ten studies (1998 to 2011) with 11,131 patients were identified. The ICS (n = 6735) and non-ICS (n = 4396) cohorts were well matched in neutrophil distributions and demographics. Increasing neutrophil count was associated with an increased proportion of patients with pneumonia events; patients below the median neutrophil count were at less risk of a pneumonia event (HR, 0.75 [95% confidence interval 0.61-0.92]), and had longer time to a first event, compared with those at/above the median. The increase in pneumonia risk by neutrophil count was similar between the two cohorts. CONCLUSIONS: Increased blood neutrophils in COPD were associated with increased pneumonia risk, independent of ICS use. These data suggest blood neutrophils may be a useful marker in defining treatment pathways in COPD.