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.

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.

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).

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.

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.

Blood eosinophils and treatment response with triple and dual combination therapy in chronic obstructive pulmonary disease: analysis of the IMPACT trial.

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.

Comparative Efficacy of Once-Daily Umeclidinium/Vilanterol and Tiotropium/Olodaterol Therapy in Symptomatic Chronic Obstructive Pulmonary Disease: A Randomized Study.

INTRODUCTION: We report the results of the first direct comparison of the once-daily fixed-dose long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) combinations umeclidinium/vilanterol (UMEC/VI) and tiotropium/olodaterol (TIO/OLO) in patients with COPD. METHODS: This was a randomized, two-period crossover open-label study in symptomatic patients with COPD [age 40 years or older, postbronchodilator forced expiratory volume in 1 s (FEV1) of 70% or less and 50% or more of predicted normal values, and modified Medical Research Council Dyspnoea Scale score of 2 or greater] not receiving inhaled corticosteroid therapy. Patients were randomized to receive UMEC/VI (62.5/25 µg once daily) via a multidose dry powder inhaler (ELLIPTA) followed by TIO/OLO (5/5 µg once daily) via a soft mist inhaler (Respimat), each for 8 weeks with an interim 3-week washout or vice versa. The primary end point was the change from baseline in trough FEV1 at week 8 with a noninferiority margin of - 50 mL in the per-protocol (PP) population. The incidence of adverse events was also assessed. RESULTS: In total, 236 patients (mean age 64.4 years, 60% male) were included in the intent-to-treat population and 227 were included in the PP population. UMEC/VI treatment was noninferior in the PP population and superior in the intent-to-treat population to TIO/OLO treatment with regard to trough FEV1 at week 8 [FEV1 change from baseline 180 mL vs 128 mL; difference 52 mL (95% confidence interval 28-77 mL); p < 0.001]. Patients receiving UMEC/VI had twofold increased odds of experiencing a clinically meaningful increase (100 mL or more) from baseline in trough FEV1 at week 8 compared with patients receiving TIO/OLO (odds ratio 2.05; 95% confidence interval 1.34-3.14). Adverse events occurred in 25% of patients in the UMEC/VI group and in 31% of patients in the TIO/OLO group. CONCLUSION: In this first direct comparison of two once-daily fixed-dose LAMA/LABA combinations, superiority was observed for the primary end point of trough FEV1 at week 8 with UMEC/VI compared with TIO/OLO in patients with symptomatic COPD. Both treatments had similar safety profiles. These findings confirm the results of previous indirect LAMA/LABA comparisons, and show that an efficacy gradient exists within the LAMA/LABA class. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02799784. FUNDING: GlaxoSmithKline.

Blood eosinophils as a marker of response to inhaled corticosteroids in COPD.

Identification of a biomarker that predicts response to inhaled corticosteroids (ICS) would help evaluate the risk/benefit profile of ICS in chronic obstructive pulmonary disease (COPD) and guide treatment.The ISOLDE study randomised 751 patients (mean post-bronchodilator forced expiratory volume in 1 s (FEV1) 1.4 L: 50% predicted normal) to fluticasone propionate 500 µg twice daily or placebo for 3 years, finding no difference in FEV1 rate of decline between treatments (p=0.16) and a significant reduction in median exacerbation rate with fluticasone propionate versus placebo (p=0.026). We re-analysed ISOLDE results by baseline blood eosinophil count to investigate whether eosinophil level predicts ICS benefit.Patients with eosinophils <2% (n=456) had a similar rate of post-bronchodilator FEV1 decline with fluticasone propionate as placebo (-2.9 mL·year(-1); p=0.688). With eosinophils ≥2% (n=214), the rate of decline decreased by 33.9 mL·year(-1) with fluticasone propionate versus placebo (p=0.003). Exacerbation rate reduction on ICS for fluticasone propionate versus placebo was higher in the eosinophil <2% group compared with the ≥2% group; time-to-first moderate/severe exacerbation was not different between treatments in either group.A baseline blood eosinophil count of ≥2% identifies a group of COPD patients with slower rates of decline in FEV1 when treated with ICS: prospective testing of this hypothesis is now warranted.

Understanding asthma-chronic obstructive pulmonary disease overlap syndrome.

Asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) is a loosely-defined clinical entity referring to patients who exhibit characteristics of both asthma and chronic obstructive pulmonary disease (COPD). Clinical definitions and classifications for ACOS vary widely, which impacts our understanding of prevalence, diagnosis and treatment of the condition. This literature review was therefore conducted to characterize the prevalence of ACOS and the effect of different disease definitions on these estimates, as this has not previously been explored. From an analysis of English language literature published from 2000 to 2014, the estimated prevalence of ACOS ranges from 12.1% to 55.2% among patients with COPD and 13.3%-61.0% among patients with asthma alone. This variability is linked to differences in COPD and asthma diagnostic criteria, disease ascertainment methods (spirometry-based versus clinical or symptom-based diagnoses and claims data), and population characteristics including age, gender and smoking. Understanding the reasons for differences in prevalence estimates of ACOS across the literature may help guide decision making on the most appropriate criteria for defining ACOS and aid investigators in designing future ACOS clinical studies aimed at effective treatment.

Implementing lessons learned from previous bronchial biopsy trials in a new randomized controlled COPD biopsy trial with roflumilast.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease mediated by an array of inflammatory cells and mediators, but above all, CD8+ T-lymphocytes, macrophages and neutrophils are important players in disease pathogenesis. Roflumilast, a first-in-class, potent and selective phosphodiesterase 4 (PDE4) inhibitor, reduces the rate of exacerbations in patients with a high risk of future exacerbations and has been shown to reduce inflammatory cells and mediators in induced sputum, a surrogate of airway inflammation. However, these anti-inflammatory effects are yet to be confirmed in another robust study directly assessing inflammatory markers in bronchial sub-mucosa. METHODS/DESIGN: An international, 16-week, randomized, double-blind, placebo-controlled, parallel-group study investigating the effects of roflumilast 500 µg once-daily versus placebo on inflammatory parameters in bronchial biopsy tissue specimens, sputum and blood serum. One hundred and fifty patients with COPD and chronic bronchitis for at least 12 months will be recruited into the study and randomized in a 1:1 ratio to receive either roflumilast or placebo. The primary endpoint will be the number of CD8+ cells (cell counts per mm2) in bronchial biopsy tissue specimens (sub-mucosa) and the key secondary endpoint will be the number of CD68+ cells (cell counts per mm2), assessed by indirect immunohistochemistry. DISCUSSION: It is hypothesized that treatment with roflumilast reduces the characteristic inflammation found in the airways of patients with moderate-to-severe COPD, compared with placebo. The design of the present study has built on the work of previous bronchial biopsy studies available in the literature. It is hoped that it will reveal the cellular mechanisms underlying the anti-inflammatory effects of roflumilast and identify potentially important biomarkers and other surrogate endpoints in patients with COPD. The design and rationale for this trial are described herein.

Moving from the Oslerian paradigm to the post-genomic era: are asthma and COPD outdated terms?

In the majority of cases, asthma and chronic obstructive pulmonary disease (COPD) are two clearly distinct disease entities. However, in some patients there may be significant overlap between the two conditions. This constitutes an important area of concern because these patients are generally excluded from randomised controlled trials (mostly because of smoking history in the case of asthma or because of significant bronchodilator reversibility in the case of COPD). As a result, their pathobiology, prognosis and response to therapy are largely unknown. This may lead to suboptimal management and can limit the development of more personalised therapeutic options. Emerging genetic and molecular information coupled with new bioinformatics capabilities provide novel information that can pave the way towards a new taxonomy of airway diseases. In this paper we question the current value of the terms 'asthma' and 'COPD' as still useful diagnostic labels; discuss the scientific and clinical progress made over the past few years towards unravelling the complexity of airway diseases, from the definition of clinical phenotypes and endotypes to a better understanding of cellular and molecular networks as key pathogenic elements of human diseases (so-called systems medicine); and summarise a number of ongoing studies with the potential to move the field towards a new taxonomy of airways diseases and, hopefully, a more personalised approach to medicine, in which the focus will shift from the current goal of treating diseases as best as possible to the so-called P4 medicine, a new type of medicine that is predictive, preventive, personalised and participatory.

A comparison of the efficacy and safety of once-daily fluticasone furoate/vilanterol with twice-daily fluticasone propionate/salmeterol in moderate to very severe COPD.

Fluticasone furoate/vilanterol trifenatate (FF/VI) is a once-daily inhaled corticosteroid/long-acting ß2-agonist combination in development for chronic obstructive pulmonary disease (COPD) treatment. We compared the efficacy and safety of FF/VI versus fluticasone propionate/salmeterol (FP/SAL) twice daily over 12 weeks. Moderate to very severe COPD patients received FF/VI 100/25 µg once daily in the morning (n=266) or FP/SAL 500/50 µg twice daily (n=262). The primary end-point was a change from baseline in 0-24 h weighted mean forced expiratory volume in 1 s (wmFEV1) at 12 weeks. Additional end-points included time to 100 mL improvement from baseline on day 1 and a change from baseline in St George's Respiratory Questionnaire (SGRQ). Safety was also assessed. wmFEV1 (mean 130 mL) was greater and time to 100 mL improvement shorter (median 16 min) with FF/VI than FP/SAL (weighted mean 108 mL, median 28 min). Health status (SGRQ total score) improved in both groups (FF/VI -4.3 units, FP/SAL -3.0 units). Differences between treatments were not statistically significant. Six patients in the FF/VI (2%) and three in the FP/SAL (1%) arm experienced serious adverse events, none of which were considered to be drug related. Improvements in lung function and health status were not significantly different between FF/VI 100/25 µg once daily and FP/SAL 500/50 µg twice daily; there was no apparent difference between the safety profiles of either therapy.

A randomised trial of fluticasone furoate/vilanterol (50/25 µg; 100/25 µg) on lung function in COPD.

BACKGROUND: Fluticasone furoate (FF)/vilanterol (VI) is a novel once-daily inhaled corticosteroid/long-acting ß2-agonist combination therapy for COPD. We aimed to assess the efficacy and safety of two strengths of FF/VI (100/25 µg; 50/25 µg) vs. individual components (FF 100 µg, VI 25 µg) and placebo over 24 weeks. METHODS: Multicentre, randomised, placebo-controlled, double-blind, parallel-group study of patients (N = 1030) with moderate-to-severe COPD. All medication was administered once daily in the morning. Co-primary efficacy endpoints were: (1) weighted mean (wm) FEV1 (0-4 h post-dose on day 168) to assess acute lung function effects; and (2) trough FEV1 (23-24 h post-dose on day 169) to assess long-lasting effects. Symptom-related outcomes were analysed and adverse events (AEs) assessed. RESULTS: Main findings were: (1) the combination of FF/VI at a strength of 100/25 µg significantly (p < 0.001) improved wm FEV1 (173 ml) and trough FEV1 (115 ml) vs. placebo. Similar effects were observed with FF/VI 50/25 µg; (2) no significant difference was seen between FF/VI 100/25 µg and VI 25 µg for trough FEV1 (48 ml, p = 0.082), while an effect was observed between FF/VI 100/25 µg and FF 100 µg for wm FEV1 (120 ml, p < 0.001); (3) VI 25 µg over 24 weeks improved lung function vs. placebo significantly for wm FEV1 (103 ml, p < 0.001) and trough FEV1 (67 ml, p = 0.017); and (4) no safety signal was observed. CONCLUSIONS: In subjects with moderate-to-severe COPD, FF/VI 100/25 µg provides rapid and significant sustained bronchodilation at 24 weeks. Lung function is improved to a similar extent with FF/VI 50/25 µg and to a somewhat lesser extent with VI 25 µg. All treatments were well tolerated. GSK study number: HZC112206. ClinicalTrials.gov: NCT01053988.

Cysteinyl leukotriene 1 receptor expression associated with bronchial inflammation in severe exacerbations of COPD.

BACKGROUND: Cysteinyl leukotriene 1 (CysLT1) receptor expression is known to be increased in the airway mucosa of patients with asthma, especially during exacerbations; however, nothing is known of its expression in COPD. METHODS: We applied immunohistochemistry and in situ hybridization to endobronchial biopsies to determine inflammatory cell CysLT1 receptor protein and mRNA expression in the following: (1) 15 nonsmoker control subjects (NSC), (2) 16 smokers with moderate to severe COPD in its stable phase (S-COPD), and (3) 15 smokers with COPD hospitalized for a severe exacerbation (SE-COPD). RESULTS: The total number of bronchial mucosal inflammatory cells (CD45+) and those expressing CysLT1 receptor protein were significantly greater in SE-COPD (CysLT1 receptor protein: median [range] = 139 [31-634]) as compared with S-COPD (32 [6-114]) or NSC (16 [4-66]) (P < .001 for both). CysLT1 receptor gene expression showed similar differences. A greater proportion of CD451 cells expressed CysLT1 receptor protein in SE-COPD (median [range] = 22% [8-81]) compared with S-COPD (10% [4-32]) (P < .03) or NSC (7% [1-19]) (P < .002). In SE-COPD, the relative frequencies of CysLT1 receptor-expressing cells were as follows: tryptase1 mast cells > CD681 monocytes/macrophage > neutrophils > CD201 B lymphocytes = EG21 eosinophils. Moreover, there were positive correlations between the numbers of cells expressing CysLT1 receptor protein and the numbers of CD451 cells (r = 0.78; P < .003) and tryptase1 mast cells (r = 0.62; P < .02). CONCLUSIONS: Bronchial mucosal CysLT1 receptor-positive inflammatory cells are present in the bronchial mucosa in COPD in greatest number in those experiencing a severe exacerbation.

Chronic obstructive pulmonary disease: a modifiable risk factor for cardiovascular disease?

Significant cardiac morbidity and mortality exists in patients with COPD. Shared risk factors include age, smoking history and exposure to air pollution and passive smoke. Although the inappropriate under-prescribing of ß-blockers contributes, it is now appreciated that the observed cardiac risk is not only due to smoking and conventional cardiovascular risk factors, but also other independent factors. A number of hypotheses exist for the increased cardiovascular morbidity and mortality seen in COPD including inflammation, pulmonary hypertension, lung hyperinflation and shared genetics models. Mounting evidence from large randomised controlled trials suggests that COPD treatment may be cardio-protective. We review the current evidence supporting the aforementioned hypotheses and how their modulation may prevent cardiovascular morbidity and mortality in COPD. The persisting underdiagnosis of COPD may have significant consequences. Further mechanistic studies identifying the onset and impact of individual interventions will develop our understanding of this emerging and highly relevant clinical field.

COPD uncovered: an international survey on the impact of chronic obstructive pulmonary disease [COPD] on a working age population.

BACKGROUND: Approximately 210 million people are estimated to have chronic obstructive pulmonary disease [COPD] worldwide. The burden of disease is known to be high, though less is known about those of a younger age. The aim of this study was to investigate the wider personal, economic and societal burden of COPD on a cross country working-age cohort. METHODS: A cross-country [Brazil, China, Germany, Turkey, US, UK] cross-sectional survey methodology was utilised to answer the research questions. 2426 participants aged 45-67 recruited via a number of recruitment methods specific to each country completed the full survey. Inclusion criteria were a recalled physician diagnosis of COPD, a smoking history of > 10 pack years and the use of COPD medications in the previous 3 months prior to questioning. The survey included items from the validated Work Productivity and Activity Impairment [WPAI] scale and the EuroQoL 5 Dimension [EQ-5D] scale. Disease severity was measured using the 5-point MRC [Medical Research Council] dyspnoea scale as a surrogate measure. RESULTS: 64% had either moderate [n = 1012] or severe [n = 521] COPD, although this varied by country. 75% of the cohort reported at least one comorbid condition. Quality of life declined with severity of illness [mild, mean EQ-5D score = 0.84; moderate 0.58; severe 0.41]. The annual cost of healthcare utilisation [excluding treatment costs and diagnostic tests] per individual was estimated to be $2,364 [£1,500]. For those remaining in active employment [n: 677]: lost time from work cost the individual an average of $880 [£556] per annum and lifetime losses of $7,365 [£4,661] amounting to $596,000 [£377,000] for the cohort. 447 [~40%] of the working population had retired prematurely because of COPD incurring individual estimated lifetime income losses of $316,000 [£200,000] or a combined total of $141 m [£89.6 m]. As the mean age of retirees was 58.3 and average time since retirement was 4 years, this suggests the average age of retirement is around 54. This would mean a high societal and economic impact in all study countries, particularly where typical state retirement ages are higher, for example in Brazil, Germany and the UK [65] and the US [65,66,67], compared to Turkey [58 for women, 60 for men] and China [60]. CONCLUSIONS: Although generalisation across a broader COPD population is limited due to the varied participant recruitment methods, these data nevertheless suggest that COPD has significant personal, economic and societal burden on working age people. Further efforts to improve COPD diagnosis and management are required.

Single maintenance and reliever therapy (SMART) of asthma: a critical appraisal.

The use of a combination inhaler containing budesonide and formoterol as both maintenance and quick relief therapy (SMART) has been recommended as an improved method of using inhaled corticosteroid/long-acting beta agonist (ICS/LABA) therapy. Published double-blind trials show that budesonide/formoterol therapy delivered in SMART fashion achieves better asthma outcomes than budesonide monotherapy or lower doses of budesonide/formoterol therapy delivered in constant dosage. Attempts to compare budesonide/formoterol SMART therapy with regular combination ICS/LABA dosing using other compounds have been confounded by a lack of blinding and unspecified dose adjustment strategies. The asthma control outcomes in SMART-treated patients are poor; it has been reported that only 17.1% of SMART-treated patients are controlled. In seven trials of 6-12 months duration, patients using SMART have used quick reliever daily (weighted average 0.92 inhalations/day), have awakened with asthma symptoms once every 7-10 days (weighted average 11.5% of nights), have suffered asthma symptoms more than half of days (weighted average 54.0% of days) and have had a severe exacerbation rate of one in five patients per year (weighted average 0.22 severe exacerbations/patient/year). These poor outcomes may reflect the recruitment of a skewed patient population. Although improvement from baseline has been attributed to these patients receiving additional ICS therapy at pivotal times, electronic monitoring has not been used to test this hypothesis nor the equally plausible hypothesis that patients who are non-compliant with maintenance medication have used budesonide/formoterol as needed for self-treatment of exacerbations. Although the long-term consequences of SMART therapy have not been studied, its use over 1 year has been associated with significant increases in sputum and biopsy eosinophilia. At present, there is no evidence that better asthma treatment outcomes can be obtained by moment-to-moment symptom-driven use of ICS/LABA therapy than conventional physician-monitored and adjusted ICS/LABA therapy.

Airway inflammation in patients with asthma with high-fixed or low-fixed plus as-needed budesonide/formoterol.

BACKGROUND: Budesonide/formoterol maintenance and reliever therapy maintains asthma control and reduces exacerbation frequency compared with higher fixed-dose combination regimens. Its effects on eosinophilic airway inflammation and structure are unknown. OBJECTIVE: We sought to compare the effects of budesonide/formoterol 200/6 microg twice daily plus as-needed with budesonide/formoterol 800/12 microg twice daily on airway eosinophils and remodeling. METHODS: This 52-week, parallel-group, randomized, double-blind study of 127 asthma patients who were symptomatic despite therapy compared (1) the change between induced sputum percent eosinophils at baseline and the geometric mean of 4 on-treatment values and (2) the change in endobronchial biopsy eosinophil counts pre- and post-treatment. RESULTS: Mean daily doses of budesonide/formoterol were 604/18 microg in the maintenance and reliever therapy group and 1,600/24 microg in the high fixed-dose group. In the former, the geometric mean percent sputum eosinophils remained unchanged (1.6% to 1.9%), whereas biopsy specimen subepithelial eosinophils increased (6.2 to 12.3 cells/mm(2)). Sputum and biopsy eosinophil counts decreased with high fixed-dose treatment (2.2% to 1.2% and 7.7 to 4.8 cells/mm(2), respectively), resulting in significant treatment differences of 0.7% (ratio, 1.8; 95% CI, 1.2-2.8; P = .0038) and 7.5 cells/mm(2) (ratio, 2.9; 95% CI, 1.6-5.3; P < .001), respectively. There were no between-treatment differences in reticular basement membrane thickness, exhaled nitric oxide, exacerbation frequency, or FEV(1). CONCLUSION: Compared with fixed-dose combination treatment containing a 4-fold higher maintenance dose of budesonide, budesonide/formoterol maintenance and reliever therapy is associated with higher eosinophil counts, but these remain within the range associated with stable clinical control.

Cigarette smoking alters bronchial mucosal immunity in asthma.

RATIONALE: Cigarette smoking worsens asthma and is associated with reduced response to corticosteroid therapy. As cigarette smoke is known to have immunomodulatory effects, we hypothesized that one mechanism by which smoking mediates its adverse effect is by reduction of the numbers of bronchial mucosal dendritic cells (DCs), which control B-cell growth and T-cell responses. OBJECTIVES: We set out to sample the bronchial mucosa in smoking and never-smoking patients with asthma and to count DCs, B cells, and cells expressing genes for two key T-lymphocyte regulatory cytokines. METHODS: Twenty-one never-smoker patients with asthma (6 steroid naive), 24 smoker patients with asthma (9 steroid naive), and 10 healthy never-smokers (control subjects) were recruited and their endobronchial biopsy samples were immunostained for detection of mature DCs (CD83(+)), Langerhans cells (CD1a(+)), B lymphocytes (CD20(+)), and helper T-cell type 1 (IFN-gamma) and helper T-cell type 2 (IL-4) cytokine-expressing cells. MEASUREMENTS AND MAIN RESULTS: The number (per square millimeter) of CD83(+) mature DCs was significantly lower in smoker patients with asthma (median [range]: 37 [0, 131]) in comparison with never-smoker steroid-naive and steroid-treated patients with asthma (76 [24, 464]; p = 0.006) or control subjects (85 [40, 294]; p = 0.004). Moreover, B cells were fewer in smoker (26 [4, 234]) versus never-smoker steroid-naive and steroid-treated patients with asthma (45 [10, 447]; p = 0.01) and in smoker steroid-naive patients with asthma (23 [4, 111]) versus control subjects (34 [10, 130]; p = 0.05). The number of cells expressing IFN-gamma showed a trend toward fewer in smoker (70 [6, 24]) versus never-smoker steroid-naive patients with asthma (144 [44, 323]; p = 0.10). CONCLUSIONS: There are important and statistically significant differences in the number of CD83(+) mature DCs and B cells in the large airways of smokers with asthma. We speculate that their reductions may render patients with asthma less responsive to corticosteroids and more susceptible to infection.

Antiinflammatory effects of salmeterol/fluticasone propionate in chronic obstructive lung disease.

RATIONALE: No currently available treatment is reported to reduce the exaggerated airway wall inflammation of chronic obstructive pulmonary disease. OBJECTIVES: We tested the hypothesis that inhaled combined long-acting beta2-agonist (salmeterol) and corticosteroid (fluticasone propionate) will reduce inflammation. METHODS: Bronchial biopsies and induced sputum were taken from 140 current and former smokers (mean age, 64 yr) with moderate to severe disease, randomized in a 13-wk double-blind study to placebo (n = 73) or salmeterol/fluticasone propionate 50/500 microg (n = 67) twice daily. Biopsies were repeated at 12 wk and sputa at 8 and 13 wk. After adjustment for multiplicity, comparisons between active and placebo were made for median change from baseline in the numbers of biopsy CD8+ and CD68+ cells/mm2 and sputum neutrophils. MEASUREMENTS AND MAIN RESULTS: Combination therapy was associated with a reduction in biopsy CD8+ cells of -118 cells/mm2 (95% confidence interval [CI], -209 to -42; p = 0.02), a reduction of 36% over placebo (p = 0.001). CD68+ cells were unaffected by combination treatment. Sputum differential (but not total) neutrophils reduced progressively and, at Week 13, significantly with combination treatment (median treatment difference, 8.5%; 95% CI, 1.75%-15.25%; p = 0.04). The combination also significantly reduced biopsy CD45+ and CD4+ cells and cells expressing genes for tumor necrosis factor-alpha and IFN-gamma and sputum total eosinophils (all p < or = 0.03). These antiinflammatory effects were accompanied by a 173-ml (95% CI, 104-242; p < 0.001) improvement in prebronchodilator FEV1. CONCLUSIONS: The combination of salmeterol and fluticasone propionate has a broad spectrum of antiinflammatory effects in both current and former smokers with chronic obstructive pulmonary disease, which may contribute to clinical efficacy.