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Background There is conflicting evidence from previous studies as to whether eosinophil counts predict the risk of future exacerbations in COPD. Aims In this post hoc analysis, we investigated the link between baseline eosinophil count and moderate/severe exacerbation rates during the DYNAGITO trial. Methods DYNAGITO was a 52-week, double-blind, randomised trial in patients with COPD with FEV1 Results At baseline, 81% of patients had an eosinophil count ≤300 cells/µL and 49% had an eosinophil count ≤150 cells/µL. 65–76% of patients were receiving ICS across eosinophil subgroups. Similar rates of moderate/severe exacerbations were observed across eosinophil subgroups (figure). Rates were similar across eosinophil counts in patient subgroups with low or high exacerbation history. Conclusions Relatively few patients had an eosinophil count >300 cells/µL, and there was no increase in exacerbation rates with increasing baseline eosinophil count in the total population, or in patients with low or high exacerbation history. In this population, many of whom were receiving ICS, exacerbation history, but not blood eosinophil count, was an important determinant of exacerbation risk.

Rationale The DYNAGITO trial investigated the effect of bronchodilation on exacerbation rate in patients with COPD. The observed rates were 0.90 per patient-year with tiotropium/olodaterol (T/O) and 0.97 per patient-year with tiotropium alone (Tio) (rate ratio 0.93; 99% confidence interval 0.85–1.02; P=0.0498). We investigated whether the effect on exacerbation rate was the same across patients with varying degrees of baseline airflow limitation. Methods DYNAGITO was a 52-week, double-blind trial in which patients with COPD were randomized (1:1) to receive T/O 5/5µg or Tio 5µg once daily, delivered via Respimat® (NCT02296138). Patients continued to take inhaled corticosteroids (ICS) if receiving them at baseline. Inclusion criteria included post-bronchodilator FEV1 Results Overall, there were 2,784 patients classed as GOLD 2, 4,039 GOLD 3 and 992 GOLD 4. Baseline COPD treatment differed by GOLD stage. More patients were receiving a long-acting muscarinic antagonist (LAMA) only or LAMA/long-acting β2-agonist (LABA) in GOLD 2 (12.6% and 13.4%) than GOLD 3 (7.5% and 12.0%) or 4 (5.6% and 8.4%), while fewer patients were receiving LAMA/LABA/ICS in GOLD 2 (32.6%) than in GOLD 3 (42.8%) or 4 (47.7%). T/O reduced the exacerbation rate compared with Tio in GOLD 2 and 3 patients, but not in GOLD 4 patients (figure 1). Conclusion The results demonstrate that improving bronchodilation with T/O reduced the exacerbation rate compared with Tio in patients with GOLD 2 and 3 COPD. The lack of effect of bronchodilators in the most severely limited patients has been reported previously (Wedzicha et al. N Engl J Med 2016;374:2222–34) and may reflect the complex contributors to airflow obstruction in very severe COPD.

Introduction Blood eosinophils level in Chronic Obstructive Pulmonary Disease (COPD) is a candidate biomarker for Regulatory qualification as a drug development tool identifying individuals who may benefit from targeted therapies. Current evidence focused on association with exacerbations and response to therapy, however the association of eosinophilia with cardiorespiratory physiology has not been determined. Methods The ERICA (Evaluating the Role of Inflammation in Chronic Airway Disease) study is a large multicentre study of patients with COPD.1 Aortic pulse wave velocity (PWV), carotid intimal thickness (CIMT) and spirometry were measured. Health Status (CAT) was recorded. From the full blood count, both absolute and percentage eosinophil counts were considered. We used previously validated cut offs2 of 0.3 × 109 cells/L and 2% to compare aortic PWV, CIMT and spirometry variables using a Student’s t-test. A multivariate model was then built to examine the effect after adjusting for confounding factors. Results 519 subjects were included in this analysis. Of these, 58% were men, mean (SD) age of 66.9 (7.6) years with a median smoking history of 42 pack years. Mean (SD) resting heart rate was 75 (13)bpm, mean arterial pressure 104 (12) mmHg and percentage predicted FEV152.5 (16.1)%. When comparing high and low eosinophil groups at both 0.3 × 109 cells/L and 2% cut-offs there was no difference in smoking status or pack years, spirometry variables or CAT score. There was no difference in prevalence of ischaemic heart disease, stroke or diabetes. Aortic PWV or CIMT were not different between groups. Multiple regression confirmed this (Table). Conclusions A phenotype defined by blood eosinophilia does not relate to cardiorespiratory physiological variables in subjects with COPD. References Mohan Det al. Journal of COPD2015. Negewo Net al. Respirology2017.

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

Various statistical methods have been used to measure the impact of treatment on chronic obstructive pulmonary disease (COPD) exacerbations. Poisson regression has recently been recommended as the appropriate method but the model does not satisfactorily account for variability between patients. In contrast, use of a negative binomial model, which corresponds to assuming a separate Poisson parameter for each patient, offers a more appealing approach. The present paper reviews analysis methods, with particular focus on the negative binomial model. To illustrate the differences that arise from using different analysis methods, we have reanalysed data from two large studies which, among other objectives, investigated the effectiveness of inhaled corticosteroids in reducing COPD exacerbation rates. Using the negative binomial model to reanalyse data from the TRISTAN and ISOLDE studies, the overall estimates of exacerbation rates on each treatment arm are higher and the confidence intervals for comparisons between treatments are wider, but the overall conclusions of TRISTAN and ISOLDE regarding reduction of exacerbations remain unchanged. The negative binomial approach appears to provide a better fit to the distribution of the data than earlier methods and is currently the method of choice. Research needs to continue on further methods to improve the analysis of exacerbation data.

Resumo: ADoença Pulmonar Obstrutiva Crónica é uma doença complexa caracterizada por uma obstrução parcialmente reversível das vias aéreas, redução progressiva da função pulmonar, exacerbações recorrentes e compromisso de qualidade de vida. A relação entre o estado de saúde e as exacerbações está bem estabelecida: um mau estado de saúde está associado a uma maior frequência de exacerbações, de hospitalizações e mortalidade. Estudos recentes demonstraram que os corticosteródes inalados não têm efeito, ou este é diminuto, no declínio do FEV1, mas reduzem o número e gravidade das exacerbações e, desta forma, a deterioração do estado de saúde. Embora pareça haver uma associação entre as exacerbações e o estado de saúde, o seu mecanismo não está ainda esclarecido. Por outro lado, não há uma evidência directa que a diminuição do número de intercorrências melhore o estado de saúde.O objectivo do presente estudo foi reavaliar os dados obtidos pelo ISOLDE â Inhaled Steroids in Obstrutive Pulmonary Lung Disease in Europe, utilizando modelos estatísticos para avaliar a existência de uma relação directa entre a frequência das exacerbações e a deterioração do estado de saúde e se a influência do propionato de fluticasona neste resulta do seu efeito sobre o número de exacerbações.Trata-se de um estudo randomizado, multicêntrico, duplamente cego, controlado com placebo, envolvendo fumadores e ex-fumadores com idade compreendidas entre os 40 e os 75 anos com o diagnóstico de DPOC.O St. Georgeâs Respiratory Questionaire (SGRQ) é um questionário supervisionado, utilizado especificamente nos doentes com patologia das vias aéreas. à constituído por 50 itens com uma pontuação total de 0-100, correspondendo o zero a um estado de saúde óptimo e cem a mau, podendo uma diferença de 4 pontos ser clinicamente significativo. Trata-se de uma medida válida da deterioração clínica do doente com obstrução crónica das vias aéreas e da resposta à s alterações terapêuticas, bem como um factor preditivo de mortalidade na DPOC.Os doentes foram randomizados, administrando 500 mg de propionato de fluticasona 2 vezes por dia ou placebo utilizando um inalador pressurizado doseável e um spacer. Foi permitido o uso de salbutamol e brometo de ipatrópio, quando necessário.O questionário SGRQ foi preenchido individualmente após o período de run-in, com uma periodicidade semestral durante 3 anos na presença ou não de exacerbações. Exacerbação foi definida como uma intercorrência respiratória requerendo tratamento com antibióticos ou corticosteróides orais. Foram avaliados 613 doentes com DPOC moderadamente grave ao longo de 3 anos. A taxa de exacerbações foi calculada como o número de agudizações por ano. Os doentes foram divididos em três grupos, de acordo com o número de exacerbações: nenhuma; pouco frequente (< 1,65 exac/ano); frequente (> 1,65 exac./ano).A gravidade da DPOC foi classificada de acordo com os critérios da American Thoracic Society: ligeira (FEV1 pós-broncodilatadorâ¥50% do previsto) e moderada a grave (FEV1 pós-broncodilatador

Background: Combined treatment with inhaled corticosteroids and long acting s2 agonists is approved for the treatment of chronic obstructive pulmonary disease (COPD), but little is known about the onset of effect of the combination. Methods: Data were used from 1465 patients with COPD entered into a large 1 year double blind trial with daily measurements of peak expiratory flow (PEF) and symptom scores. Results: PEF was significantly higher after 1 day in patients treated with salmeterol 50 µg twice daily or the salmeterol/fluticasone propionate combination 50/500 µg twice daily than placebo. In patients treated with fluticasone propionate 500 µg twice daily alone, PEF differed from placebo after 2 days. The differences after 2 weeks compared with placebo were 16 l/min (95% confidence interval (CI) 11 to 21), 11 l/min (95% CI 6 to 16), and 27 l/min (95% CI 22 to 33) for salmeterol, fluticasone propionate, and the salmeterol/fluticasone propionate combination, respectively. For all treatments the effect on PEF after 2 weeks was comparable to that seen at the end of the study. The difference between the salmeterol/fluticasone propionate combination and placebo after 2 weeks as a percentage of baseline was similar for PEF and clinic forced expiratory volume in 1 second (FEV1). Differences in breathlessness scores were statistically significant after 1 day for the group treated with salmeterol alone and after 2 days for the combination group. The 2 week change in FEV1 was only partly indicative of a long term response in individual patients. Conclusions: The effects of salmeterol and fluticasone propionate, alone or in combination, on PEF and breathlessness are seen within days and most of the obtainable effect on these parameters is reached within 2 weeks.

Fashions in ideas, like clothes, come and go. From approximately 1950-1980, physiological research was seen as the key discipline in understanding lung disease and was at the cutting edge of pulmonary science. Subsequently, its importance has been down played amid a widely accepted but unfounded assumption that we now have a perfect working understanding of the physiological behaviour of the respiratory system in health and disease. Although it seems improbable that completely new disciplines within respiratory physiology will emerge with fundamentally different ways of describing the mechanical or gas exchanging function of the lung, advances in computing and new observations in disease have highlighted previously unsuspected physiological abnormalities that have changed the way we view lung disease and the interface between disordered lung mechanics, symptomatology and disability. This is especially true for the two related physiological concepts of expiratory flow limitation and dynamic hyperinflation, which are now being taken from the physiological laboratory to the bedside with dramatic effect. Each arises from well-established theoretical and practical observations first made 40 yrs ago and now adapted to a range of settings, particularly in the field of obstructive lung disease. This review focuses on how these conditions are defined and assessed and what evidence there is that they might be important in lung disease.

Introduction Les β2 agonistes de longue duree d’action (LABA), les corticoides inhales (CSI) et leur association diminuent les exacerbations dans la BPCO (EBPCO) chez les patients ayant une obstruction chronique severe des voies aeriennes (OCVA). Leur efficacite dans la reduction d’EBPCO chez les patients avec une OCVA moderee demeure incertaine ( Fig. 1 ). Methodes Summit (Study to Understand Mortality and Morbidity) etude multicentrique randomisee controlee en double-aveugle chez 16 485 patients (40–80 ans) avec une BPCO moderee qui etaient a risque eleve de maladie cardiovasculaire. Les traitements inhales quotidiens etaient : placebo (n = 4 111), vilanterol [VI] 25 μg ; n = 4 118, furoate de fluticasone [FF] 100 μg ; n = 4 135 et l’association (FF 100 μg + VI 25 μg [FF/VI]) ; n = 4 121. L’impact sur les EBPCO moderees/severes etait un autre objectif predefini. Resultats Les participants etaient principalement des hommes (75 %) d’âge moyen 65 ± 8 ans avec 47 % de fumeurs actifs et une moyenne de VEMS de 60 % de la valeur predite (54–65 %). Dans l’annee precedant l’inclusion, 39 % des patients ont eu une EBPCO et 15 % deux ou plus. La mortalite toute cause (critere principal) n’a pas ete affectee par l’un des traitements. Versus placebo, le risque d’une premiere EBPCO a diminue avec FF/VI (HR 0,80, IC 95 % 0,73 ; 0,86) et VI (HR 0,91, IC 95 % 0,84 ; 0,99), mais pas avec FF (HR 0,97, IC 95 % 0,90 ; 1,05) ( Fig. 1 ). Tous les traitements ont conduit a une diminution du taux d’EBPCO moderees/severes (FF/VI 29 % [22 ; 35], VI 10 % [2 ; 10], et FF 12 % [4 ; 19]). Des resultats similaires ont ete rapportes sur le delai d’apparition de la 1re EBPCO necessitant des hospitalisations et le taux. Dans une analyse post hoc, FF/VI a augmente le delai d’apparition de la 1re EBPCO moderee ou severe vs placebo dans une mesure similaire chez des patients avec un VEMS Conclusion Chez les patients avec une OCVA moderee, FF/VI conduit a une diminution du risque d’EBPCO moderee/severe et de son taux. Un effet similaire a ete rapporte pour les EBPCO necessitant une hospitalisation. Les effets etaient similaires chez les patients avec un VEMS Financements Finance par GSK 113782 ( NCT01313676 ).

Introduction La mesure du nombre d’eosinophiles circulant a ete associee a la survenue d’exacerbations plus frequentes au cours de l’histoire naturelle de la BPCO. Objectif Au cours de l’etude Wisdom, on a apprecie si les patients avec un nombre d’eosinophiles different presentaient plus ou moins d’exacerbation de BPCO a l’arret de la corticotherapie inhalee. Methodes L’etude Wisdom ( NCT00975195 ) a permis, sur un an, de randomiser, en groupes paralleles, 2488 patients BPCO severe a tres severe ayant un passe d’exacerbations. Ils ont tous recu 18 μg de tiotropium, 100 ug salmeterol et 1000 μg de propionate de fluticasone par jour pendant 6 semaines puis ont continue ou reduit CSI au cours des 12 semaines suivantes. Cette analyse post hoc a compare les resultats sur la survenue des exacerbations apres le retrait de CSI basee sur l’analyse des sous-groupes du nombre d’eosinophiles dans le sang. Resultats Deux mille deux cent quatre-vingt-seize patients ont ete suivis apres le retrait des CSI. Le taux de survenue d’exacerbation moderees a severes etait similaire entre les patients avec un taux d’eosinophiles circulant Conclusion Au cours de l’etude Wisdom, un taux d’eosinophiles circulant augmente (≥ 4 % ou ≥ 300 cells/μL) etait un facteur predictif d’une augmentation du risque d’exacerbation chez les patients avec une BPCO severe a tres severe sevres de CSI.

Background: In chronic obstructive pulmonary disease (COPD), the degree of circadian variation in forced expiratory volume in 1 second (FEV1) and the influence of anticholinergic blockade is not known. Tiotropium is a long acting inhaled anticholinergic bronchodilator that increases daytime FEV1 in COPD. We hypothesised that tiotropium would modify the overnight change in FEV1, and this would be unaffected by the timing of drug administration. Methods: A double blind, randomised, placebo controlled trial was conducted with tiotropium 18 mg once daily in the morning (09.00 hours), evening (21.00 hours), or an identical placebo. Patients with stable COPD (n=121, FEV1=41% predicted) underwent spirometric tests every 3 hours for 24 hours at baseline and after 6 weeks of treatment. Results: There were no significant differences at baseline between the groups. Tiotropium improved mean (SE) FEV1 (over 24 hours) in the morning (1.11 (0.03) l) and evening (1.06 (0.03) l) groups compared with placebo (0.90 (0.03) l), and nocturnal FEV1 (mean of 03.00 and 06.00 hours) in the morning (1.03 (0.03) l) and evening (1.04 (0.03) l) groups compared with placebo (0.82 (0.03) l) at the 6 week visit (p

Background: A trial of corticosteroids has been recommended for all patients with chronic obstructive pulmonary disease (COPD), with the subsequent "response" determining the treatment selected. This approach assumes that patients can be reliably divided into responder and non-responder groups. We have assessed whether such a separation is statistically valid, which factors influence the change in forced expiratory volume in 1 second (FEV1) after prednisolone, and whether the prednisolone response predicts 3 year changes in FEV1, health status, or number of exacerbations during placebo or fluticasone propionate treatment. Methods: Oral prednisolone 0.6 mg/kg was given for 14 days to 524 patients with COPD before randomised treatment for 3 years with fluticasone propionate or placebo. Factors relating to change in FEV1 after prednisolone were investigated using multiple regression. The response to prednisolone was entered into separate mixed effects models of decline in FEV1 and health status during the 3 years of the study. Results: The post-bronchodilator FEV1 increased by a mean 60 ml (CI 46 to 74) after prednisolone with a wide unimodal distribution. Current smoking was the factor most strongly associated with the change in FEV1 after prednisolone, with an increase of 35 ml in current smokers and 74 ml in confirmed ex-smokers (p

A review of the management of COPD is presented, with particular emphasis on the effect on the approach to management of new information which has become available in the 5 years since the BTS guidelines on COPD were published. A major problem is the effective implementation of what is already known, and allocation of the resources necessary to make this available to all who might benefit.

Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with worse health and increased healthcare utilisation. The Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study in COPD showed a 26% reduction in the yearly rate of exacerbations in patients treated with fluticasone propionate (FP) compared to placebo, but did not indicate which patients showed greatest benefit. In this study the patients were stratified into mild and moderate-to-severe COPD using the American Thoracic Society criterion of forced expiratory volume in one second (FEV1) 50% predicted, and the total number of exacerbations and those requiring treatment with oral corticosteroids were examined. There were 391 (195 FP) patients with mild COPD and 359 (180 FP) patients with moderate-to-severe disease. The exacerbation rate was highly skewed in mild disease, but more normally distributed in moderate-to-severe disease. FP reduced the overall exacerbation rate in moderate-to-severe disease (FP median rate 1.47 yr(-1), placebo 1.75 yr(-1)), but not in mild disease (FP 0.67 yr(-1), placebo 0.92 yr(-1)). FP use was associated with fewer patients with > or = 1 exacerbation x yr(-1) being treated with oral corticosteroids (mild: FP 8%, placebo 16%; moderate-to-severe: FP 17%, placebo 30%). Effects of fluticasone propionate on exacerbations were seen predominantly in patients with a postbronchodilator forced expiratory volume in one second

Background: Safety and efficacy of tiotropium Respimat 5 µg (R5) and 2.5 µg (R2.5) doses were compared with tiotropium HandiHaler 18 µg (HH) in two recent chronic obstructive pulmonary disease (COPD) trials. Aims and objectives: To compare bronchodilator efficacy of once-daily R5 and R2.5 and HH in TIOtropium Safety and Performance In Respimat (TIOSPIR; NCT01126437)1 and the 205.458 (NCT01222533)2 trials. Methods: TIOSPIR: Randomized, double-blind (n= 17,135; mean 2.3 years' follow up) trial assessing mortality and exacerbations. Included a spirometry substudy (n= 1370), predefined test of noninferiority of R5 and R2.5 vs HH for trough forced expiratory volume in 1 second (FEV1), average 24 - 120 weeks (noninferiority margin 50 mL). 205.458: Multicentre, placebo-controlled, randomized within Respimat (1.25, 2.5, 5 µg), five-way crossover trial with 4-week treatment periods (n= 154). Results: TIOSPIR: Adjusted mean trough FEV1 (average 24 - 120 weeks) was 1.285L for R5 and 1.295 L for HH (difference vs HH, -10 mL; 95% confidence interval [CI], -38 to 18 mL), and 1.258 L for R2.5 (difference vs HH, -37 mL; 95% CI, -65 to -9 mL). 205.458: R2.5, R5 and HH showed significant improvements in trough FEV1 versus placebo. Mean trough FEV1 for R5 was comparable to HH but was 27 and 41 mL lower than HH for R2.5 and R1.25, respectively. Conclusion: In TIOSPIR, R5 was noninferior to HH for FEV1, but R2.5 was inferior to HH. Similar results were seen in the 205.458 trial and support the use of tiotropium Respimat 5µg once daily for the maintenance treatment of COPD.

BACKGROUND—Cough is a common and troublesome symptom in cryptogenic fibrosing alveolitis (CFA) but the mechanisms responsible are not known. The cough threshold to inhaled capsaicin is increased in asthma and chronic obstructive pulmonary disease (COPD) where lung volumes are increased, but the relationship between cough response and symptom intensity has not been studied in CFA where lung volumes are reduced. METHODS—Capsaicin challenge tests were performed on 15 subjects with proven CFA and 96 healthy controls. Symptoms, as assessed by daily diary card cough score and by visual analogue scale (VAS), were related to the capsaicin sensitivity (C5) and compared with lung volumes. Volume restriction was produced in a group of 12normal healthy subjects by a plastic shell tightly strapped to the chest wall. Capsaicin challenge tests were performed in these subjects, both strapped and unstrapped, to determine whether volume restriction altered the cough reflex. RESULTS—The median C5 response in normal subjects was more than 500 µM compared with 15.6 µM in those with CFA (p

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease, which is characterised by reduced post-bronchodilator lung function in all patients 1. Although hyperresponsiveness and acute bronchodilator reversibility have been regarded as characteristics of asthma, it is now generally acknowledged that these clinical features are also present in COPD. Results as high as 39–66% for reversibility 2, dependent on the method of expression, and 60% for hyperresponsiveness, as measured with methacholine, have been reported. Patients generally show progressive lung function loss, accompanied by worsening respiratory symptoms and health status 1. These clinical features are associated with airway inflammation, i.e. bronchial infiltration of neutrophils, macrophages, lymphocytes, and mast cells 3–5. Smoking accelerates lung function loss and increases mortality in COPD, and smoking cessation has consistently been shown to improve these outcomes. Other risk factors for a worse prognosis include higher age, female sex, airway hyperresponsiveness, sputum production, underweight and frequent exacerbations 1. As well as smoking cessation, it is logical to investigate whether treatment that changes these risk factors and/or their underlying mechanisms can also change the long-term outcome of COPD. Many studies have assessed the long-term benefits of available COPD treatments, such as inhaled corticosteroids (ICS), long-acting β2-agonists (LABA) and long-acting anticholinergics. As a result, current guidelines recommend treatment with ICS for patients with severe COPD and frequent exacerbations, in addition to long-acting bronchodilators for patients with moderate-to-severe COPD 1. Below we summarise evidence advising the use of ICS or ICS+LABA in COPD from double-blind studies with intermediate (1–2 yrs) and long-term (>2 years) follow-up. It is now clear that regular anti-inflammatory treatment with ICS improves symptoms, health status and forced expiratory volume in 1 s (FEV1) while decreasing exacerbation rates 6–9. Withdrawing ICS (under protection of LABA) in …

Although recent guidelines for managing chronic obstructive pulmonary disease (COPD) recommend a trial of oral corticosteroids in the initial assessment, its prognostic value remains unclear. We prospectively studied 127 adults (64% men) with stable COPD (FEV1/FVC

Wheeze is a classic sign of airflow obstruction but relatively little is known of its mechanism of production or its relationship to the development of airflow obstruction. We studied eight asthmatic subjects age (mean +/- 5D) 42 +/- 5 yr, FEV1 2.46 +/- 0.36 L during an extended, symptom-limited methacholine challenge test. Breath sounds were detected by a microphone over the right upper anterior chest. Spectral analysis was by a fast Fourier transform algorithm. Mean FEV1 fell by 51 +/- 14% to 1.28 +/- 0.61 L during the challenge and airways resistance increased by 119 +/- 50%. There were no consistent changes in breathing pattern or tidal volume during the challenge. Wheeze occurred late in the challenge at the highest concentration of methacholine administered and only after expiratory tidal flow limitation had been reached. Five subjects developed wheeze on tidal breathing, the remaining three only wheezed on deep breathing. Wheezing sounds were reproducible between breaths, coefficient of variation of starting sound frequency was 4.2% and ending frequency 12%. Mean frequency of expiratory wheezes was 669 +/- 100 Hz and inspiratory wheezes 710 +/- 76 Hz. Expiratory wheeze fell in pitch during a breath (mean fall in sound frequency 187 +/- 43 Hz) but inspiratory wheezes were more variable. Expiratory wheezes occurred late in the respiratory cycle at a mean of 58% of the maximal tidal expiratory flow, whereas inspiratory wheezes occurred around maximal tidal inspiratory flows, suggesting that the mechanisms of production of inspiratory and expiratory wheezes may be different. In this model, the presence of wheeze during tidal breathing was a sign of severe airflow limitation.

Introduction Les patients atteints de BPCO sont a risque accru de pneumonie. Des etudes precedentes ont montre que le risque de pneumonie dans la BPCO est en partie lie au degre de severite de l’obstruction des voies aeriennes. De maniere importante, pour les patients recevant des traitements avec CSI, le risque est augmente chez ceux ayant une obstruction des voies aeriennes severe (30 % ≤ VEMS

Introduction Dans l’etude TORCH, l’association d’un β2 agoniste de longue duree d’action (LABA) (salmeterol) et d’un corticosteroide inhale (CSI) (propionate de fluticasone) n’a pas reduit significativement la mortalite, mais a ete associee dans une analyse post-hoc a une reduction du taux de declin du VEMS et a moins d’evenements cardiovasculaires (CV) chez des patients BPCO. L’analyse factorielle post-hoc a suggere que ces benefices etaient dus au salmeterol. Ici, nous reexaminons l’effet de ces composants dans une analyse factorielle predefinie de l’etude Summit (study to understand mortality and morbidity) dans laquelle le LABA etait le vilanterol (VI) et le CSI etaient le furoate de fluticasone (FF) ( Fig. 1 ). Methodes Summit etait une etude multicentrique randomisee controlee menee chez 16 485 patients (40–80 ans) atteints d’une BPCO moderee et d’un risque CV eleve qui ont recu un des quatre traitements inhales en une prise par jour : placebo (n = 4 111), CSI (FF ; n = 4 135), LABA (VI ; n = 4 118) et la therapie associee (FF/VI ; n = 4121). Le critere principal etait la mortalite toute cause confondue, le changement du taux de declin du VEMS et le critere CV compose etaient des criteres secondaires cles. Une analyse factorielle a ete realisee avec les facteurs FF et VI et leur interaction a egalement ete testee. Resultats Les participants etaient principalement des hommes (75 %) d’âge moyen (65 ± 8 ans) avec 47 % de fumeurs actifs et une moyenne de VEMS de 60 % de la valeur predite (54–65 %). Il n’y avait pas d’interaction statistiquement significative entre FF et VI sur les criteres principal ou secondaires (p ≥ = 0,693). La mortalite toute cause confondue n’a pas ete affectee par FF ou VI. Le taux de declin du VEMS a ete reduit de 9 mL/an avec FF, soit seul, soit en association avec VI. En revanche, VI n’a pas d’effet sur le taux de declin du VEMS. La probabilite d’un evenement CV compose etait inchangee selon le traitement. Conclusion Chez les patients BPCO avec une obstruction moderee des voies aeriennes et une maladie CV le traitement avec VI seul ou en association n’a pas d’effet sur le risque de deces ou sur le taux de declin de la fonction pulmonaire. L’utilisation de FF n’a pas d’impact sur le risque de deces, mais etait associee a une reduction du declin du VEMS. L’analyse factorielle a montre que les effets de FF ou VI etaient coherents, independamment du fait qu’ils aient ete utilises seuls ou en association. Financements Finance par GSK 113782 ( NCT01313676 ).

RESUMO: Foram estudados 20 doentes com DPOC em estado estável, idade média de 68 anos, FEV1 médio de 43,6%, TLC â 128,7%, FRC â 174,2%. Os estudos funcionais foram efectuados após 4 h e 12 h de suspensão de broncodilatadores de curta e longa acção.Foram determinados os parâmetros funcionais basais por pletismografia e efectuado um teste de exercício cárdio-pulmonar limitado por sintomas. Em 8 doentes foram determinadas as pressões esofágicas, gástricas e transdiafragmáticas.Em todos os doentes foi efectuada pletismografia optoelectrónica (OEP) basal e no exercício. Esta técnica, altamente complexa, consiste na análise do movimento de 89 pontos da caixa torácica, onde são colocados reflectores sobre os quais incidem flashes de infra-vermelhos que são filmados por 4 câmaras de TV operando a 100 imagens por segundo e sincronizadas com os flashes de infra-vermelhos.Os volumes medidos por pneumotacografia e OEP foram praticamente idênticos, com uma diferença de 5 ml em repouso e de menos 100 ml em exercício, com uma linha de regressão de 1,12.Todos os doentes analisados em conjunto hiperinsuflaram no exercício (e com resultados semelhantes aos dos estudos de O´Donnell), mas os autores encontraram dois subgrupos de doentes que designaram por hiperinsufladores â H (12 doentes) e euvolúmicos â E (8 doentes) consoante a modificação encontrada no início do teste de exercício, sem carga, dos volumes torácicos no final da expiração: mais 494 ml em H e mais 46 ml em E.As diferenças basais destes dois grupos (E e H, respectivamente) foram significativas no índice de massa corporal (IMC) â 27,5 vs 24,2, FEV1% â 50,1 vs 39,2, FEV1/FVC% -51,4 vs 42.5 e no FEF25 e 50%, isto é, os E eram doentes com menor grau de obstrução e de limitação dos débitos expiratórios mas de igual insuflação de H (TLC e FRC sem diferença significativa).Durante o exercício nos H, o Vab permaneceu constante e os Vrc e Vcw aumentaram gradualmente até ao final (isto é, o aumento do volume corrente fez-se à custa do aumento da parte superior do tórax), enquanto nos E houve um abaixamento do volume de Vab que permaneceu constante até final do exercício, com estabilidade do Vrc (isto é, o aumento do volume corrente foi deslocado para a parte inferior do tórax).No entanto, os dois grupos não apresentaram diferenças na CI, na dessaturação no exercício ou no grau de dispneia e esforço dos membros inferiores no final do exercício.Mas, nos E, tanto a carga máxima -20 W, como a duração -8,8 min, foi muito inferior à dos H: 35 W de carga e 13,7 min de duração.Todos estes fenómenos se acompanharam de aumentos nas pressões pleurais, diafragmáticas e no trabalho respiratório, muito mais elevadas em E do que em H, isto é, os E responderam ao exercício com maior trabalho muscular respiratório e menor hiperinsuflação do que os H, que hiperinsuflaram acima do volume corrente e tiveram pressões pleurais e gástricas muito inferiores. COMENTÃRIOS: Estes resultados são de facto surpreendentes, até para os próprios autores.A OEP permitiu discriminar dois subgrupos de doentes que habitualmente são estudados em conjunto e que com os métodos clássicos não foi possível identificar (embora nos vários estudos de OâDonnell exista uma grande variação no tempo de endurance dos vários doentes).Não parece existirem diferenças significativas nos resultados obtidos pela OEP e pelos métodos convencionais que justifiquem que as diferenças encontradas nos dois grupos sejam dependentes desta técnica inovadora.Como explicar então o diferente comportamento respiratório destes dois grupos de doentes com DPOC, com obstrução grave e insuflação significativa e que apenas apresentam diferenças no grau de limitação dos débitos expiratórios â FEV1, FEV1/FVC, FEFs (e também no IMC).Várias hipóteses de explicação são possíveis.A maior limitação expiratória dos H condiciona nestes maior insuflação dinâmica acima do volume corrente, enquanto nos E (menos graves) o aumento de volume no final da expiração é contrariado por pressões abdominais mais altas. Será que este fenómeno depende da gravidade, isto é, será que âquandoâ os E apresentarem maior gravidade na limitação expiratória, como nos H, adoptarão um padrão respiratório diferente?O padrão de recrutamento dos músculos respiratórios é controlado pelo comando central respiratório e adaptado à s condições mecânicas torácicas. Será que os E ainda possuem condições musculares mais preservadas para contrariar a insuflação dinâmica e os H já têm os seus músculos enfraquecidos e o padrão respiratório mais adequado será o de insuflarem?Ou será que à partida existem dois tipos de controlo ventilatório diferentes nestes doentes, como já foi encontrado em indivíduos normais a quem foi aplicada uma resistência externa respiratória?Os autores inclinam-se mais para que a explicação mais provável seja a maior limitação expiratória nos H do que nos E. No entanto, a estratégia respiratória diferente dos E é desfavorável, uma vez que o trabalho respiratório é muito maior nestes do que nos H. E também ajuda a explicar porque em doentes com menor obstrução se encontre significativa limitação de exercício independente da insuflação dinâmica.Este estudo é de facto um grande avanço na compreensão da limitação funcional na DPOC, mas mais estudos são necessários para confirmar estes dados.

Introduction Hospital readmission following treatment for a life-threatening exacerbation of COPD with acute NIV is frequent and associated with an adverse impact in terms of lung function and health related quality of life. They have been identified as a priority area in the NHS with financial penalties for any patient readmitted within 28 days following discharge. Method A multicentre open labelled randomised controlled trial recruited patients with persistent hypercapnia (PaCO 2 > 7 kPa) 2–4 weeks following resolution of acute acidosis. Patients were randomised to either home oxygen therapy (HOT) or HOT and home mechanical ventilation (HOT-HMV). HMV was titrated overnight to control nocturnal hypercapnia. Follow up was for 12 months. The primary outcome, 12-month admission free survival, has been reported previously demonstrating a significant treatment effect (ERS 2016). Secondary outcome analysis included 28-day all-cause hospital readmission and 12 month exacerbation rate. Results 116 patients were randomised (HOT = 59, HOT-HMV = 57), age 67 ± 10 years, FEV1 0.6 ± 0.2 L, PaCO 2 7.9 ± 0.9 kPa. 28-day readmission was 22 (37%) in the HOT and 7 (12%) in the HOT-HMV arm (unadjusted HR 0.27, 0.12 to 0.63, p = 0.003; adjusted HR 0.26, 0.11 to 0.61, p = 0.002) (Figure 1). 12 month exacerbation rate was reduced from median 5 (1 to 9) per year in the HOT arm to 4 (2to 6) in the HOT-HMV arm (unadjusted HR 0.64 (0.44 to 0.94); p = 0.022; adjusted HR 0.66, 0.46 to 0.95, p = 0.026). Conclusion The addition of HMV to HOT in patients with persistent hypercapnia following an acute life-threatening exacerbation of COPD reduces both 28-day readmission and 12 month exacerbation frequency. These data strongly support a change in clinical practice in the management of patients with severe COPD and persistent hypercapnia.

RESUMO: As exacerbações da DPOC são frequentes e associam-se, usualmente, a um agravamento da situação clínica de base.O objectivo do presente trabalho foi identificar a diferente probabilidade de um indivíduo sofrer uma exacerbação da sua doença, bem como se o efeito do corticosteróide inalado na agudização é influenciado pelo grau de gravidade da DPOC.Foi efectuado em estudo randomizado, duplamente cego, com um grupo de controlo placebo, com a duração de 3 anos, envolvendo 18 hospitais do Reino Unido.Os doentes foram divididos em dois grupos segundo os critérios de gravidade da American Thoracic Society para a DPOC: Ligeira, (FEV1 pós-broncodilatadorâ¥50%do previsto); Moderada/Grave (FEV1 pós-broncodilatador10%após inalação de 400 μg de salbutamol; FEV1 pós-broncodilatador

The clinical characterisation and description of the obstructive sleep apnoea–hypopnoea syndrome (OSAHS) and related syndromes were mainly revealed by several epidemiological studies conducted over the past fifty years. These highly prevalent syndromes affect about 9% of middle-aged men and 4% of women. These syndromes have serious medical and social consequences, such as cardiovascular or metabolic diseases, and even premature death. Consequently, respiratory sleep medicine (RSM) evolved and has progressed rapidly within the sleep medicine field over recent decades. New diagnostic and therapeutic techniques have appeared in response to an increasing number of patients and clinical interventions. The research progressed to focus not only on the clinical and pathophysiological but also the genetic and molecular aspects of these syndromes [1–6]. Nevertheless, the literature in the field does not provide any clear consensus on diagnostic classification and assessment. No harmonised standards of training exist across Europe for respiratory sleep medicine. The European Respiratory Society (ERS) provided external and postgraduate courses but the requirements and expectations in the field were not being fulfilled. There was a need for a project supporting both the teaching and certification. For this reason, ERS supported an application for a Sleep Harmonised Education in Respiratory Medicine for European Specialists (HERMES) Task Force project which aimed at establishing common standards in respiratory sleep training and education, in an adaptable framework which can be extended across Europe. HERMES was a project established in 2005 to provide documentation for the training and certification of adult respiratory specialists. Since 2005, the HERMES framework has been adapted for projects including paediatric respiratory medicine, critical care medicine and the development of the European Spirometry Driving Licence (spirometry). Within the HERMES model, a process of establishing consensus standards for training largely follows four key phases (fig. 1). In line with this …

We investigated the impact of season relative to other determinants of chronic obstructive pulmonary disease (COPD) exacerbation frequency in a long-term international study of patients with forced expiratory volume in 1 s (FEV(1))

1. The physiological basis of inspiratory effort sensation remains uncertain. Previous studies have suggested that pleural pressure, rather than inspiratory muscle fatigue, is the principal determinant of inspiratory effort sensation. However, only a limited range of inspiratory flows and breathing patterns have been examined. We suspected that inspiratory effort sensation was related to the inspiratory muscle tension-time index developed whatever the breathing pattern or load, and that this might explain the additional rise in sensation seen with hypercapnia. 2. To investigate this we measured hypercapnic re-breathing responses in seven normal subjects (six males, age range 21–38 years) with and without an inspiratory resistive load of 10 cm H2O. Pleural and transdiaphragmatic pressures, mouth occlusion pressure and breathing pattern were measured. Diaphragmatic and ribcage tension-time indices were calculated from these data. Inspiratory effort sensation was recorded using a Borg scale at 30s intervals during each rebreathing run. 3. Breathing pattern and inspiratory pressure partitioning were unrelated to changes in inspiratory effort sensation during hypercapnia. Tension-time indices reached pre-fatiguing levels during both free breathing and inspiratory resistive loading. 4. Stepwise multiple regression analysis using pooled mechanical, chemical and breathing pattern variables showed that pleural pressure was more closely related to inspiratory effort sensation than was transdiaphragmatic pressure. When converted to tension-time indices, ribcage tension-time index was the major determinant of inspiratory effort sensation during loaded rebreathing, but partial pressure of CO2 was an important independent variable, whereas during unloaded rebreathing partial pressure of CO2 was the most important determinant of inspiratory effort sensation. 5. These results suggest that the pattern of inspiratory pressure partitioning and inspiratory flow rate have little influence on inspiratory effort sensation during CO2 stimulated breathing. The close association between inspiratory effort sensation and ribcage tension-time index, an index of inspiratory muscle work, suggests that inspiratory effort sensation may forewarn of potential inspiratory muscle fatigue. Changes in PaCO2 have a small independent effect on respiratory perception.

In the last 8 years the FEV1 (forced expiratory volume in 1 s) of a ‘typical’ patient with chronic obstructive pulmonary disease (COPD) has fallen by ∼400 ml. However, the knowledge of those caring for this hypothetical patient has grown rapidly in this same period and Thorax has played a vital role in this change of fortune. In 2003 there were 1698 citations to COPD articles in PubMed, compared with 1494 in the first 6 months of 2010 alone, a remarkable growth in the interest in and perhaps quality of research in this field. Many themes have been considered in this last 8 years, not least how to diagnose the disease. Swanney et al 1 defined population norms for the lower limit of normal of the FEV1/forced vital capacity (FVC) ratio to avoid overdiagnosis of airflow obstruction in the elderly. However, not all were convinced, especially when there appeared to be no difference in mortality when the definition was varied in this way.2 The absence of bronchodilator reversibility proved to be an unreliable defining feature in COPD,3 and the treatment guidelines changed to reflect this new research.4 Classifying patients with GOLD (global initiative for chronic obstructive lung disease) stage 1 disease (reduced FEV1/FVC but FEV1 >80% predicted) proved difficult as some patients were not reproducibly obstructed. However, those with symptoms did show more rapid decline in lung function,5 were more likely to have previous bronchitic symptoms6 and responded physiologically to inhaled bronchodilators.7 So, contrary to earlier views, GOLD stage 1 may be a clinically relevant entity after all. COPD is …

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

Respiratory physiology, the study of the function of the respiratory system in health and disease, was one of the core disciplines in respiratory medicine throughout the second half of the 20th Century. Moreover, clinical and basic physiologists were central to the creation of the European Respiratory Society (ERS) 20 yrs ago. Despite concerns that all the “interesting” questions in physiology had been answered, the last 20 yrs have shown that applying physiological principles to respiratory disease not only leads to new insights into how the lungs work when stressed, but has also identified new areas where the diagnosis and treatment of previously intractable or unrecognised physiological disorders has transformed the lives of large numbers of people. This editorial reflects this diversity of interest, but is only a snapshot of some of the exciting possibilities that a physiological approach to respiratory disease has made possible. By the late 1980s the key principles underpinning lung mechanics and gas exchange within the lung had been established and applied to most, but not all, problems. One orphan area was the understanding of the mechanisms controlling lung extravascular water volume. Although the lungs are functionally exposed to conditions causing an increase in microvascular filtration, such as capillary recruitment, increase in cardiac output and hypoxia, a common condition in cardiopulmonary disorders, the extracellular matrix normally limits extravascular water volume to

Short-term trials of bronchodilator drugs are widely used to assess patients with stable chronic obstructive pulmonary disease (COPD), but there is an uncertainty about the equivalence of the FEV1 response to beta-agonists and anticholinergic drugs, their relative ability to identify patients likely to improve with corticosteroids, the most appropriate way to express the results of these tests, and whether age or allergic status affects the beta-agonist and anticholinergic response differently. We studied 100 consecutive patients with stable COPD (mean FEV1, 0.96 +/- 0.48 L; mean age, 62 +/- 8 yr). Spirometry was measured before and after either 5 mg of nebulized salbutamol or 500 micrograms of nebulized ipratropium bromide and repeated after 2 wk of 30 mg of oral prednisolone daily. Total IgE, specific RAST, and skin prick testing values were recorded. Using modified American Thoracic Society response criteria, 33 patients failed to bronchodilate after the acute trials, 16 responded only to nebulized salbutamol, 17 to nebulized ipratropium, and 34 to both drugs. Twenty-two patients improved after corticosteroids. This was usually detected by a positive acute trial response (salbutamol 90% specific; ipratropium 84% specific). Baseline FEV1 differed between days, and in those who responded on only 1 day, this variation correlating with the response to ipratropium (r = 0.66). Expressing the response criterion as a percentage change in the available bronchodilatation increased the numbers responding with a high baseline FEV1, and vice versa. Neither age nor allergic status was related to the change in FEV1 after either drug in these patients. In COPD patients, testing with high-dose nebulized bronchodilators identifies a substantial number of partially reversible patients whatever age it is employed.(ABSTRACT TRUNCATED AT 250 WORDS)

Although inspiratory resistive loading (IRL) reduces the ventilatory response to CO2 (VE/PCO2) and increases the sensation of inspiratory effort (IES), there are few data about the converse situation: whether CO2 responsiveness influences sustained load compensation and whether awareness of respiratory effort modifies this behavior. We studied 12 normal men during CO2 rebreathing while free breathing and with a 10-cmH2O.l-1.s IRL and compared these data with 5 min of resting breathing with and without the IRL. Breathing pattern, end-tidal PCO2, IES, and mouth occlusion pressure (P0.1) were recorded. Free-breathing VE/PCO2 was inversely related to an index of effort perception (IES/VE; r = -0.63, P less than 0.05), and the reduction in VE/PCO2 produced by IRL was related to the initial free-breathing VE/PCO2 (r = 0.87, P less than 0.01). IRL produced variable increases in inspiratory duration (TI), IES, and P0.1 at rest, and the change in tidal volume correlated with both VE/PCO2 (r = 0.63, P less than 0.05) and IES/VE (r = -0.69, P less than 0.05), this latter index also predicting the changes in TI with loading (r = -0.83, P less than 0.01). These data suggest that in normal subjects perception of inspiratory effort can modify free-breathing CO2 responsiveness and is as important as CO2 sensitivity in determining the response to short-term resistive loading. Individuals with good perception choose a small-tidal volume and short-TI breathing pattern during loading, possibly to minimize the discomfort of breathing.

BACKGROUND: The relation between pulmonary disease and physiological abnormality in patients with hypoxic cor pulmonale is controversial and the association between arterial hypoxaemia and right ventricular hypertrophy has been challenged. To address these problems matched patients treated with and without domiciliary oxygen were studied. METHODS: Necropsy data were obtained on 19 patients (14 male), 10 of whom had been treated with domiciliary oxygen. Pulmonary artery pressure and total pulmonary vascular resistance as well as blood gas tensions during the breathing of air and oxygen were available for the six months before death. Formalin fixed lung slices were assessed for panacinar and centriacinar emphysema. Right and left ventricular weights were measured and their ratio (LV&S/RV) was used as an index of right ventricular hypertrophy. Carotid body weights were available in 14 cases. RESULTS: Fourteen patients died of respiratory failure and antemortem thrombus was found in the pulmonary arteries of eight cases. Physiological measurements were unrelated to the degree of macroscopic emphysema, pulmonary hypertension, or daytime blood gas tensions. When allowance was made for the higher "ambient" arterial oxygen tension (PaO2) of those who had oxygen, PaO2 was correlated with LV&S/RV (r = 0.79), absolute right ventricular weight (r = -0.53), and carotid body weight (r = 0.68). CONCLUSIONS: These data show that in hypoxic cor pulmonale in vivo physiological disturbances are poor indicators of the underlying disease process. The relation of "ambient" PaO2 to right ventricular hypertrophy and carotid body weight suggests that domiciliary oxygen therapy might lead to regression of such established disease.

BACKGROUND: Heat and moisture loss from the respiratory tract during exercise are important triggers of exercise induced asthma. METHODS: A new heat and moisture exchange mask has been developed which both recovers exhaled heat and water and has a sufficiently low resistance for use during exercise. The effect of the mask on inspired air temperature was studied in four normal subjects. Eight asthmatic subjects performed identical exercise protocols on three separate days, breathing room air through a conventional mouthpiece, a dummy mask, and the new heat and moisture exchange mask. Seven different asthmatic subjects exercised while breathing cold air at -13 degrees C through a dummy or active mask. RESULTS: All subjects found the new mask comfortable to wear. The mean inspired temperature when the mask was used rose to 32.5 (1.4) degrees C when normal subjects breathed room air at 24 degrees C and to 19.1 (2.7) degrees C when they inhaled subfreezing air at -13 degrees C. The heat and moisture exchange mask significantly reduced the median fall in forced expiratory volume in one second (FEV1) after exercise to 13% (range 0-49%) when asthmatic subjects breathed room air compared with 33% (10-65%) with the dummy mask and 28% (21-70%) with the mouthpiece. The fall in FEV1 when the asthmatic subjects breathed cold air was 10% (0-26%) with the heat and moisture exchange mask compared with 22% (13-51%) with the dummy mask. CONCLUSION: Use of a heat and moisture exchange mask can raise the inspired temperature and humidity and ameliorate the severity of exercise induced asthma. The mask may be of practical value in non-contact sport or for people working in subzero temperatures.

To the Editors: In his recent editorial, Suissa 1 has again expressed criticism of the TORCH (Toward a Revolution in Chronic Obstructive Pulmonary Disease (COPD) Health) trial 2. The focus this time is the analysis of rate of decline in lung function 3, and in particular he questions whether the reduction in rate of decline in forced expiratory volume in one second (FEV1) observed with the active treatments (salmeterol, fluticasone or the combination of both treatments) compared with placebo is due to “regression to the mean” caused by missing data. Missing data for lung function and exacerbations are unfortunately inevitable in any long-term trial in COPD. Suissa 1 states that “… measurements were missing so that the pure intent-to-treat analysis was not possible”. Such a “pure intent-to-treat” analysis of lung function or exacerbation data is not possible for any long-term COPD trial, as this would require complete data. In fact, the quantity of missing data for lung function in TORCH is similar to the UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) 4 and OPTIMAL 5 trials quoted in the article by Suissa 1. In TORCH, 4,857 (79%) patients provided lung function data at 48 weeks, OPTIMAL had complete 1-yr lung function data for 322 (72%) patients and, …

Bronchodilator drugs produce variable improvements in forced expiratory volume in 1 s (FEV(1)), but larger changes in end-expiratory lung volume (EELV) in chronic obstructive pulmonary disease (COPD), which were suggested to be related to the presence of expiratory flow limitation (EFL) at rest. We tested this concept in 42 COPD patients (FEV(1) 42.3+/-13.8% predicted) during spontaneous breathing before and after 5 mg nebulised salbutamol. EFL was detected by within-breath changes in respiratory system reactance measured by a multifrequency forced oscillation method, while changes in EELV were assessed by inspiratory capacity (IC). Bronchodilation (BD) increased IC (from 1.8+/-0.5 to 2.1+/-0.6 L, p

Introduction Les antecedents d’exacerbation (AE) sont des donnees importantes dans la classification GOLD. Toutefois, la relation entre les (AE) et la mortalite est moins claire. Nous avons etudie les relations entre les (AE) et la mortalite dans les donnees de l’etude (TIOSPIR™). Objectif Determiner si AE (≥ 1 exacerbation l’annee precedant l’inclusion), et l’utilisation de CSI a l’inclusion influence la mortalite des patients atteints de BPCO. Methodes Cette analyse post-hoc a compare la mortalite toutes causes et les exacerbations entre quatre sous-groupes de patients caracterises par l’utilisation de CSI a l’inclusion et AE, avec un ajustement pour le VEMS post-BD, le tabagisme et l’utilisation concomitante de β2-agoniste longue duree d’action (LABA) a l’inclusion. Resultats Les caracteristiques a l’inclusion telles que l’âge, indice de masse corporelle, le sexe, le tabagisme, et les antecedents de maladie cardiaque etaient comparables entre les sous-groupes. Les patients avec un AE avaient un risque plus eleve de deces (delai jusqu’a l’evenement fatal) par rapport aux patients sans AE. Les augmentations observees dans les sous-groupes avec l’utilisation de CSI (risque relatif [RR] : 1,31) et sans CSI (HR : 1,26) etaient comparables. Le risque d’exacerbation (delai de premiere exacerbation) etait augmente chez les patients avec AE (avec et sans utilisation de CSI). Conclusion Chez les patients atteints de BPCO dans l’etude TIOSPIR™, un antecedent d’exacerbation l’annee precedant l’inclusion augmentait le risque de deces et le risque d’exacerbation independamment de l’utilisation de CSI.

The within-breath change in reactance (Delta(rs)) measured by forced oscillation technique (FOT) at 5 Hz reliably detects expiratory flow limitation in chronic obstructive pulmonary disease (COPD). The present study compared this approach to the standard negative expiratory pressure (NEP) method. In total, 21 COPD patients were studied by applying both techniques to the same breath and in 15 patients the measurements were repeated after bronchodilator. For each patient and condition five NEP tests were performed and independently scored by three operators unaware of the FOT results. In 180 tests, FOT classified 53.3% as flow limited. On average, the operators scored 27.6% of tests flow limited and 47.6% non-flow limited, but could not score 24.8%. The methods disagreed in 7.9% of cases; in 78% of these the NEP scores differed between operators. Bronchodilation reduced NEP and DeltaX(rs) scores, with only the latter achieving significance. Averaging the operators' NEP scores, a threshold between 24.6-30.8% of tidal volume being flow limited by NEP produced 94% agreement between methods. In conclusion, when negative expiratory pressure and forced oscillation technique were both available they showed good agreement. As forced oscillation technique is automatic and can measure multiple breaths over long periods, it is suitable for monitoring expiratory flow limitation continuously and identifying patients' breathing close to the onset of expiratory flow limitation, where intermittent sampling may be unrepresentative.