Search

Rationale Given the known effectiveness of tiotropium in chronic obstructive pulmonary disease (COPD) and the significant benefit observed in COPD patients with concomitant features of asthma, it is relevant to investigate whether patients included in the recent large trials of tiotropium in asthma can be confidently considered to have asthma alone. Methods Baseline characteristics were analysed for patients enrolled in two replicate Phase III, randomised, double-blind, placebo-controlled, parallel-group studies of tiotropium in asthma patients symptomatic despite treatment with inhaled corticosteroids plus long-acting beta agonists (Kerstjens et al . NEJM 2012). The entry criteria were: age 18–75 years; asthma diagnosed before the age of 40 years; =5-year history of asthma; score of =1.5 in the Asthma Control Questionnaire (ACQ) 7; and life-long non-smokers or ex-smokers ( Results 912 patients were enrolled: 456 received add-on treatment with tiotropium and 456 received placebo. Mean age of the study population was 53.0 years; 37.6% of patients were aged =50 years. Mean age at diagnosis of asthma was 22.7 (range 0–44) years. Median duration of asthma was 28.0 (range 5–72) years, with 76.5% of patients having asthma for =20 years before enrolment. The majority of patients (75.9%) were life-long non-smokers; 24.1% were ex-smokers with a median number of pack-years of only 5.0. Mean ACQ score was 2.6 (range 1–5). Mean immunoglobulin E was 1210 µmol/L. The mean ( ± SD) bronchodilator response to salbutamol was 217 ± 217 mL. Conclusions The age of onset, duration of symptoms, lack of smoking, allergic status and bronchodilator response provide reasonable certainty that the patients enrolled in these studies had asthma and not COPD. Features compatible with COPD were thus more likely to reflect the effects of long-standing severe persistent asthma than the alternative diagnosis, and the efficacy demonstrated by tiotropium to represent improvement of asthma.

Rationale The addition of tiotropium provides bronchodilation and reduces exacerbations in patients with severe asthma (Kerstjens et al . NEJM 2012). Subgroup analyses were performed to determine whether this positive effect was limited to definable subgroups. Methods Eligible patients: were aged 18–75 years; had a =5-year history of asthma; were diagnosed before the age of 40; scored =1.5 on Asthma Control Questionnaire 7; and were life-long non-smokers or ex-smokers ( Results 912 patients were randomised: 456 received 5 µg tiotropium via Respimat ® Soft Mist™ Inhaler and 456 received placebo once daily for 48 weeks. In the total study group, the time to first severe exacerbation was increased by the addition of tiotropium (risk reduction 21%; hazard ratio 0.79; p = 0.03). The time to first episode of asthma worsening was increased in the tiotropium group compared with placebo (risk reduction 31%; hazard ratio 0.69; p Conclusions The increase in time to first severe exacerbation and first episode of asthma worsening found with the addition of tiotropium was not limited to specific subgroups of patients, including some characteristics that are usually found in patients with chronic obstructive pulmonary disease, such as former smoking, non-allergic status or minimal reversibility. Tiotropium seems effective across a broad spectrum of patients with severe persistent asthma who remain symptomatic and experience exacerbations despite the combination use of moderate- to high-dose inhaled corticosteroids plus long-acting beta agonists.

The interpretation of studies of decline of FEV1 in patients with established COPD is complicated by many methodologic problems, such as retrospective analyses, small patient groups, different patient selection, and differences in the mathematical models used. Nevertheless, it is clear that the rate of loss of lung function is above all determined by the smoking status and history. A more abnormal bronchoconstrictor response is predictive of a steeper decline of lung function. Other prognostic factors have not been consistently found in patients with established disease. The decline can be influenced favorably by smoking cessation, and probably by oxygen administration in hypoxemic patients. Long-term oral steroid use seems to be associated with a more favorable course of FEV1, but the value of inhaled corticosteroids has not yet been established. Maintenance therapy with bronchodilators only does not appear to improve the decline of FEV1.

The objective of this study was to determine the costs and effects of combined bronchodilator and anti-inflammatory therapy. In a 2.5-yr randomized controlled study, combined beta 2-agonist/corticosteroid therapy (BA + CS) and combined beta 2-agonist/anticholinergic therapy (BA + AC) were compared with beta 2-agonist/placebo therapy (BA + PL). Included in the study were 274 patients 18 to 60 yr of age with moderately severe obstructive airways disease. The main clinical endpoints were lung function, hyperresponsiveness, restricted activity days, and symptom-free days. The economic endpoints were the costs of health care utilization. Compared with BA + PL, BA + CS led to significant improvements in FEV1, PC20, and symptom-free days. BA + AC did not differ from BA + PL in this respect. The respective annual acquisition costs of BA + CS, BA + AC, and BA + PL were 532 US$, 277 US$, and 156 US$. Thus, BA + CS costs 376 US$ more than BA + PL. However, compared with BA + PL therapy, BA + CS led to statistically significant savings in other health care costs of about 175 US$ (95% CI from 46 to 303 US$). Thus, more than half of the additional costs of adding the inhaled corticosteroid are compensated for by a reduction in the costs of other health care services. Overall, inhaled corticosteroids lead to a small but net increase in health care costs of 201 US$ per patient per year.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND--Despite effective treatments, the morbidity and mortality of obstructive airways disease (asthma and COPD) remains high. Home monitoring of peak expiratory flow (PEF) is increasingly being advocated as an aid to better management of obstructive airways disease. The few available studies describing effects of treatment on the level and variation of PEF have involved relatively small numbers of subjects and did not use control groups. METHODS--Patients aged 18-60 years were selected with PC20 < or = 8 mg/ml and FEV1 < 95% confidence interval of predicted normal. They were randomised to receive, in addition to a beta 2 agonist, either an inhaled corticosteroid (BA+CS), an anticholinergic (BA+AC), or a placebo (BA+PL). One hundred and forty one of these subjects with moderately severe obstructive airways disease completed seven periods of two weeks of morning and afternoon PEF measurements at home during 18 months of blind follow up. RESULTS--Improvements in PEF occurred within the first three months of treatment with BA+CS and was subsequently maintained: the mean (SE) increase in morning PEF was 51 (8) l/min in the BA+CS group compared with no change in the other two groups. Similarly, afternoon PEF increased by 22 (7) l/min. Diurnal variation in PEF (amplitude %mean) decreased from 18.0% to 10.2% in the first three months of treatment with BA+CS. Within-subject relations between changes in diurnal variation in PEF and changes in PC20 were found to be predominantly negative (median rho-0.40) but with a large scatter. Relations between diurnal variation in PEF and changes in symptom scores, FEV1, and bronchodilator response were even weaker. CONCLUSIONS--In patients with moderately severe obstructive airways disease, PEF rates and variation are greatly improved by inhaled corticosteroids. Since the relation of diurnal PEF variation with PC20, symptoms, FEV1, and bronchodilator response were all weak, these markers of disease severity may all provide different information on the actual disease state. PEF measurements should be used in addition to the other markers but not instead of them.

BACKGROUND--Recent reports have suggested short-term changes in serum parameters of bone metabolism with inhaled corticosteroids. The relevance of these findings to the balance between bone formation and resorption during years of corticosteroid treatment remains uncertain. METHODS--Two novel markers of bone turnover were first compared with conventional markers in a pilot study and subsequently measured in a long-term double blind study of inhaled corticosteroids. In study I 15 patients were newly started on at least 800 micrograms inhaled corticosteroids daily. At entry and after four weeks serum levels of alkaline phosphatase, osteocalcin, and PICP (procollagen type I carboxy terminal propeptide; a procollagen splice product) were measured as markers of bone formation, as well as the urinary hydroxyproline/creatinine ratio and serum levels of ICTP (type I collagen carboxy terminal telopeptide; a collagen degradation product) as markers of bone resorption. In study II 70 patients with airways obstruction received 800 micrograms beclomethasone daily in addition to terbutaline and 85 received bronchodilators only in a double blind fashion. Serum levels of PICP and ICTP were measured before and after 2.5 years of treatment. RESULTS--In study I a decrease in osteocalcin levels was accompanied by an increase in levels of PICP and a small and non-significant rise in alkaline phosphatase. There were no changes in hydroxyproline or ICTP. In study II no differences were found in serum levels of PICP between the treatment groups; an increase in serum ICTP was found in the group treated without inhaled corticosteroids compared with the group treated with inhaled corticosteroids. CONCLUSIONS--No detrimental long-term effect of inhaled corticosteroids was found with three conventional and two novel parameters of bone metabolism. The results indicate that long-term changes in bone turnover during treatment with inhaled corticosteroids should not be deduced from short-term studies with single serum parameters of bone metabolism, but well designed long-term studies of, for example, bone densitometry should be awaited before quoting detrimental effects of inhaled corticosteroids on bone metabolism.

Objectives The aim of the present study was to determine associations between respiratory health and exposure to smoke of fires. Methods The studies comprised 3 subsequent stages. First, all active firefighters of the municipal fire brigades of 3 provinces in the Netherlands were invited to fill in a web-based questionnaire. Second, a randomly chosen subset of 402 firefighters underwent spirometry and methacholine provocation, and blood samples were taken to assess atopy and serum pneumoproteins. Third, 51 exposed subjects of the second stage were enrolled in the third stage of the study when they were exposed to fire smoke and a blood sample could be obtained within 24 h post-exposure. Sputum was induced within 5 days following exposure, and after at least 24 h more spirometry and bronchial responsiveness testing was carried out and a second blood sample was taken. After 3 months a third blood sample was taken. In serum pneumoproteins and cytokines were assessed. Results Significant positive associations were found between exposure to fire smoke and respiratory health parameters (respiratory symptoms, bronchial hyper responsiveness, serum pneumoproteins and cytokines) with and without adjustments for smoking, sex, atopy, age and main job exposure. Conclusions The results suggest that the risk of health consequences of exposure to fire smoke is underestimated in public and occupational health. From a practical point of view, reduction of exposure to fire smoke could be achieved relatively easy when first responders are instructed about these health consequences and how to reduce fire smoke exposure.

Background-In the day to day care of obstructive airways diseases (asthma and chronic obstructive pulmonary disease) important decisions such as disease classification and choice of therapy are based on assessment of the bronchodilator response. However, surprisingly little is known of the long term course of the bronchodilator response in patients with obstructive airways disease.Methods-Data from a multicentre trial were used in which 274 patients aged 18-60 years with airways obstruction were selected with PC20 Results-There was a significant reduction in BDR of 117 ml after three months of treatment with a beta2 agonist plus a corticosteroid (BA + CS), but not after bronchodilators only. Significant reductions with BA + CS were also found in BDR as a percentage of initial FEV1, and in BDR as a percentage of predicted FEV1. Bronchodilator tests were quite variable (SD 186 nil or 11% of initial value) and less than half of the patients could consistently be classified as ''irreversible'' with recommended cutoff levels. The bronchodilator response at the start of the study proved to be a poor predictor of improvement in FEV1 under BA + CS treatment (correct prediction 60%).Conclusions-Bronchodilator responses decrease substantially with inhaled corticosteroid therapy, and within subject variability is considerable both in asthma and chronic obstructive pulmonary disease. Dichotomous decisions on whether patients are ''irreversible'' according to any single bronchodilator measurement should therefore be made with great caution. The bronchodilator response cannot, be used accurately as a predictor of response to inhaled corticosteroids in obstructive airways disease.

Background There is a growing interest to use health status or disease control questionnaires in routine clinical practice. However, the validity of most questionnaires is established using techniques developed for group level validation. This study examines a new method, using patient interviews, to validate a short health status questionnaire, the Clinical COPD Questionnaire (CCQ), at the individual patient level. Methods Patients with COPD who visited an outpatient clinic completed the CCQ before the consultation, and the specialist physician completed it after the consultation. After the consultation all patients had a semi-structured in-depth interview. The patients' CCQ scores were compared with those of the treating clinician, and with mean scores from 5 clinicians from a pool of 20 who scored the CCQ after reading the transcript of the in-depth interviews only. Agreement was assessed using Lin's concordance correlation coefficient (CCC), and Blant and Altman plots. Interviews with patients with low agreement were reviewed for possible explanations. Results A total of 44 COPD patients (32 male, mean age 66 years, FEV1 45% of predicted) participated. Agreement between the patients' CCQ scores and those of the treating clinicians (CCC = 0.87) and the mean score of the reviewing clinicians (CCC = 0.86) was very high. No systematic error was detected. No explanation for individuals with low agreement was found. Conclusion The validity of the CCQ on the individual patient level, as assessed by these methods, is good. Individual health status assessment with the CCQ is therefore sufficiently accurate to be used in routine clinical practice.

BACKGROUND: There is no agreement on how a bronchodilator response should be expressed. Ideally, the index used should be able to distinguish asthma from chronic obstructive lung disease and be independent of initial FEV1. METHODS: Two hundred and seventy four adults (aged 18-60 years) outpatients with obstructive airways disease were studied. Patients were divided into syndrome groups on the basis of a standardised history: asthma (n = 99), asthmatic bronchitis (n = 88), and chronic obstructive lung disease (n = 51); 36 subjects could not be attributed to any subgroup. FEV1 was measured before and 20 minutes after inhalation of 1000 micrograms terbutaline. Different expressions of bronchodilator response (delta FEV1) were compared with respect to their dependence on initial FEV1 and their efficacy in separating subjects with asthma from those with chronic obstructive lung disease. delta FEV1 was expressed as a percentage of initial FEV1 (delta FEV1%init), absolute value (delta FEV1[1]), percentage of predicted FEV1 (delta FEV1%pred), standardised residual (delta SR-FEV1), and percentage of maximal possible increase (delta FEV1%[pred-init]). RESULTS: delta FEV1%init was more dependent on initial FEV1 (p = -0.405) than delta FEV1[1] (r = -0.145), delta FEV1%pred (r = -0.166), and delta SR-FEV1 (r = -0.127). delta FEV1%[pred-init] reached infinity when initial FEV1 approached predicted levels. delta FEV1%pred had a higher likelihood ratio (1.71) for separating patients with asthma from those with chronic obstructive lung disease than other expressions of bronchodilator response. Asthmatic patients had larger mean bronchodilator responses than patients in other subgroups; this difference was largest for delta SR-FEV1 (F = 9.19) and delta FEV1%pred (F = 9.03); it was much smaller for delta FEV1%init (F = 5.89). Despite significant differences in mean response, there was a large overlap of individual responses between diagnostic subgroups. The bronchodilator response was continuously and unimodally distributed for all expressions. CONCLUSIONS: delta FEV1%pred appears to be the most useful method of expressing bronchodilator response, both for clinical and for research purposes. Reversibility of airways obstruction in response to a bronchodilator is a continuous variable and not a dichotomous triat. Any cut off level of a "positive" bronchodilator response is therefore arbitrary.

In the past 10 years many intervention studies have triedto define the optimal dose of inhaled corticosteroids in thetreatment of patients with mild or moderate asthma. In allbut the largest studies it has been very difficult to show adose related effect on common outcome parameters suchas symptoms and lung function. Relevant differences notonly in end-parameters but also in study designs, andpatient selections have made it difficult to compare indi-vidual study results. Despite the confusions, guidelinecommittees and leading scientists have tried to adviseclinicians about the dosage of inhaled corticosteroids thatthey should prescribe to their patients. It is not surprisingthat these advices still differ or are rather vague [1–3]. Forthe clinician many important questions remain: 1) whento start with an inhaled corticosteroid in patients withasthmatic symptoms; 2) is starting high and then steppingdown with inhaled corticosteroids more efficacious thanthe step up method; 3) is there a real requirement for themonitoring of symptoms, lung function, or inflammationin order the maintain the best results in the treatment ofpatients?; and 4) once therapy is started, how long shouldit continue?In this issue of the European Respiratory Journal (ERJ)two of these questions come closer to an answer: is aninitial high dose (step down treatment) of an inhaledcorticosteroid beneficial for patients with mild or moderateasthma; and, do clinicians have to start earlier with inhaledcorticosteroids, i.e. at the moment that bronchial inflam-mation causes airway responsiveness without asthma likesymptoms.G

Background: Adenosine receptor activation is suggested to play a role in asthmatic airway inflammation. Inhibition of adenosine receptors may have an effect on the late asthmatic response (LAR) after allergen inhalation and this mechanism could offer a potential new treatment in asthma.Methods: We evaluated the effect of an inhaled adenosine-(2A) (A(2A))-receptor agonist (GW328267X), 25 mu g, in 15 nonsmoking atopic asthmatics who underwent an inhaled allergen challenge following twice daily treatment for 1 week in a double-blind, placebo- and fluticasone propionate (250 mu g) controlled study.Results: In contrast to fluticasone, treatment with the A(2A)-receptor agonist neither significantly protect against the allergen-induced early and late asthmatic reaction, nor the accompanying inflammatory response as measured by sputum total cell counts, number of EG2+ cells, and the concentration of interleukin-8 and eosinophil cationic protein.Conclusion: The inhaled A(2A)-receptor agonist, GW328267X, 25 mu g does not affect the allergen-induced LAR or the associated inflammatory response in asthma.

Concerns about suppression of the hypothalamic pituitary adrenal (HPA) axis by systemic steroids as well as by inhaled corticosteroids have been widely held since their introduction. Several studies have suggested that inhaled corticosteroids can replace oral corticosteroids during exacerbations of asthma1 and in severe asthma.2 We have recently published a study in which treatment of unstable asthmatic patients for 2 weeks with high doses of inhaled fluticasone resulted in a greater improvement in airway hyperresponsiveness than oral prednisolone.3 Additionally—and to our surprise—we found a comparable decrease in serum cortisol levels with fluticasone 1000 μg twice daily and oral prednisolone 30 mg/day. A radioimmunoassay (RIA) method was used to determine serum cortisol suppression in blood with corticosteroid treatment, as in most …

Aims: Guidelines advocate that improvement in functional status should be a major goal in COPD treatment. Many tools are available to assess aspects of functional status. This review aims to categorise systematically the available tools based on their construct (i.e. what the tool intends to measure) and to rate the tools for use in the primary care setting. Methods: PubMed was searched with the keywords 'functional status' or 'physical capacity' or 'functional capacity' and 'COPD'. All tools were categorised and rated on their measurement properties, feasibility, and usage in primary care COPD patients. The tools were divided into four constructs functional capacity, functional performance, functional reserve, and capacity utilisation and used the following modes of measurement: laboratory tests; semi-laboratory tests; field tests; and patient-reported outcomes. Results: The PubMed search resulted in 364 articles. Thirty-two tools were identified and rated. Conclusions: In primary care, the 6-minute walking distance test is the most reliable semi-laboratory functional capacity test, but is not very practical. The pedometer is the best functional performance field test. The Medical Research Council (MRC) dyspnoea questionnaire and the functional status domain of the Clinical COPD Questionnaire (CCQ) are the best patient-reported outcome tools to assess functional performance. (C) 2011 Primary Care Respiratory Society UK. All rights reserved. JWH Kocks, et al. Prim Care Respir J 2011; 20(3): 269-275 http://dx.doi.org/10.4104/pcrj.2011.00031

Background: Many patients with asthma remain symptomatic despite treatment with inhaled corticosteroids (ICS) with or without long-acting beta(2)-agonists (LABAs). Tiotropium add-on to ICS plus a LABA has been shown to improve lung function and reduce exacerbation risk in patients with symptomatic asthma.Objective: To determine whether the efficacy of tiotropium add-on therapy is dependent on patients' baseline characteristics.Methods: Two randomized, double-blind, parallel-group, twin trials (NCT00772538 and NCT00776984) of once-daily tiotropium Respimat (R) mu g mg add-on to ICS plus a LABA were performed in parallel in patients with severe symptomatic asthma. Exploratory subgroup analyses of peak forced expiratory volume in 1 s (FEV1), trough FEV1, time to first severe exacerbation, time to first episode of asthma worsening, and seven-question Asthma Control Questionnaire responder rate were performed to determine whether results were influenced by baseline characteristics.Results: 912 patients were randomized: 456 received tiotropium and 456 received placebo. Tiotropium improved lung function, reduced the risk of asthma exacerbations and asthma worsening, and improved asthma symptom control, compared with placebo, independent of baseline characteristics including gender, age, bodymass index, disease duration, age at asthma onset, and FEV1% predicted at screening and reversibility.Conclusion: Once-daily tiotropium 5 mu g compared with placebo improved lung function, reduced the risk of asthma exacerbations and asthma worsening, and improved asthma symptom control, independent of a broad range of baseline characteristics, as add-on to ICS plus LABAs in patients with severe symptomatic asthma. Trial registry: ClinicalTrials.gov; numbers NCT00772538 and NCT00776984 URL: www.clinicaltrials.gov. (C) 2016 The Authors. Published by Elsevier Ltd.

SummaryIntroductionThe GOLD guidelines advocate not to institute inhaled corticosteroids (ICS) in patients with mild-to-moderate COPD. However, many patients do use ICS and in some patients, withdrawal is associated with deteriorating lung function and increased exacerbation rates. Unfortunately, physicians do not know in which patients they can stop ICS treatment safely.AimTo identify predictors of COPD exacerbations after ICS withdrawal.MethodsDuring ICS treatment, post-bronchodilator spirometry, body plethysmography, and health status assessment were performed in 68 COPD patients using ICS. Additionally, sputum cell differentials, supernatant leukotriene B4, eosinophilic cationic protein, and myeloperoxidase, serum C-reactive protein and soluble intracellular adhesion molecule, and urinary desmosine were assessed. Sputum was also analysed for mRNA levels of haemoxygenase-1, tumour necrosis factor-α, RANTES, interleukin 5(IL-5), IL-10, IL-12, IL-13, transforming growth factor-β, and interferon-γ.StatisticsCox regression analyses were performed using time to exacerbation as outcome variable to identify significant hazards for a COPD exacerbation after ICS withdrawal.ResultsHigher sputum % eosinophils, higher sputum MPO/neutrophil level, longer duration of COPD symptoms

Most patients with amyotrophic lateral sclerosis (ALS) develop respiratory insufficiency in the advanced stage of their disease. Non-invasive ventilation (NIV) is commonly regarded to be a treatment that is effective in reducing these complaints. To assess whether the effect of NIV on gas exchange and quality of life (QOL) is different in patients with ALS versus without ALS. A post hoc analysis was done with data from a previously published trial, in which all patients were instituted on NIV. Arterial blood gasses were assessed next to QOL by generic as well as disease-specific questionnaires. 77 patients started NIV: 30 with ALS and 47 without. Both groups showed significant improvements in blood gasses after 2 and 6 months. Compared to the non-ALS group, the ALS group had significantly worse scores after 6 months in MRF-28, SRI, HADS and SF-36 than the non-ALS group. This study shows that NIV improves gas exchange, both in patients with and without ALS. QOL improves markedly more in patients without ALS than in those with ALS, in whom only some domains improve. Our observation of little or no effect in ALS patients warrants a large study limited to ALS patients only.

SummaryIntroductionAccording to current GOLD strategy, patients with COPD classified as groups A and B may be treated with inhaled bronchodilators, either long-acting β2-agonist (LABA) or long-acting muscarinic antagonist (LAMA). However, there is little guidance on which class of agent is preferred and a lack of prospective data to differentiate the two.MethodsIn this study, we performed post-hoc analyses of pooled data from two prospective, controlled clinical trials comparing the LABA indacaterol and LAMA tiotropium in 1422 patients with moderate airflow limitation and no history of exacerbations in the previous year. This population fits the definitions of GOLD A and B groups and could be further stratified by symptom severity using Baseline Dyspnea Index (i.e. modeling GOLD A or B) and inhaled corticosteroid (ICS) use at baseline. Outcomes measured after 12 weeks of treatment were lung function (forced expiratory volume in 1 s; FEV1), health status (St George's Respiratory Questionnaire; SGRQ), symptoms (Transition Dyspnea Index; TDI) and rescue medication use.ResultsIn ‘GOLD A’ patients not receiving ICS, differences favored indacaterol versus tiotropium (trough FEV1 0.05 L; rescue medication use −0.41 puffs/day; TDI total score 0.94 points; SGRQ total score −3.13 units, all p

Background: Measurements of airway responsiveness are frequently used to evaluate anti-asthma drugs. Objective: This study investigated the utility of methacholine airway responsiveness measurements in evaluating anti-asthma medications, both in terms of a bronchoprotective effect and the ability to attenuate allergen-induced methacholine airway hyperresponsiveness. Methods: Methacholine airway responsiveness was measured as PC 20 on two occasions (separated by 35 ± 17 days, mean ± SD) in 40 subjects with mild, stable asthma. Additional subjects had PC 20 measurements made before and after administration of either inhaled salbutamol (200 μg) ( n = 20) or allergen inhalation challenge ( n = 31). Results: The reproducibility of the methacholine PC 20 with this method was high (intraclass correlation coefficient = 0.94). The average shift in PC 20 after salbutamol was 4.11 doubling concentrations (SD = 1.08). On the basis of these results, a sample size of 12 subjects would be required to demonstrate a 1 doubling concentration difference in the bronchoprotective effect of two drugs with a 90% power. The average shift in PC 20 after allergen was 1.29 doubling concentrations. On the basis of these results and an estimated SD of 0.96, a sample size of 24 subjects would be required to demonstrate that a drug is effective in attenuating 50% of allergen-induced airway hyperresponsiveness with a 90% power. Conclusion: These results confirm the high reproducibility of methacholine PC 20 measurements in subjects with mild, stable asthma and demonstrate its utility in evaluating the effects of anti-asthma drugs. (J Allergy Clin Immunol 1998;101:342-8.)

BACKGROUND The role of inhaled corticosteroids in the long term management of chronic obstructive pulmonary disease (COPD) is still unclear. A meta-analysis of the original data sets of the randomised controlled trials published thus far was therefore performed. The main question was: “Are inhaled corticosteroids able to slow down the decline in lung function (FEV 1 ) in COPD?” METHODS A Medline search of papers published between 1983 and 1996 was performed and three studies were selected, two of which were published in full and one in abstract form. Patients with “asthmatic features” were excluded from the original data. Ninety five of the original 140 patients treated with inhaled corticosteroids (81 with 1500 μg beclomethasone daily, six with 1600 μg budesonide daily, and eight with 800 μg beclomethasone daily) and 88 patients treated with placebo (of the initial 144 patients) were included in the analysis. The effect on FEV 1 was assessed by a multiple repeated measurement technique in which points of time in the study and treatment effects (inhaled corticosteroids compared with placebo) were investigated. RESULTS No baseline differences were observed (mean age 61 years, mean FEV 1 45% predicted). The estimated two year difference in prebronchodilator FEV 1 was +0.034 l/year (95% confidence interval (CI) 0.005 to 0.063) in the inhaled corticosteroid group compared with placebo. The postbronchodilator FEV 1 showed a difference of +0.039 l/year (95% CI –0.006 to 0.084). No beneficial effect was observed on the exacerbation rate. Worsening of the disease was the reason for drop out in four patients in the treatment group compared with nine in the placebo group. In the treatment group six of the 95 subjects dropped out because of an adverse effect which may have been related to the treatment compared with two of the 88 patients in the placebo group. CONCLUSIONS This meta-analysis in patients with clearly defined moderately severe COPD showed a beneficial course of FEV 1 during two years of treatment with relatively high daily dosages of inhaled corticosteroids.

Background Smoking is the most important cause for the development of COPD. Since not all smokers develop COPD, it is obvious that other factors must be involved in disease development. We hypothesize that heme oxygenase-1 (HO-1), a protective enzyme against oxidative stress and inflammation, is insufficiently upregulated in COPD. The effects of HO-1 modulation on cigarette smoke induced inflammation and emphysema were tested in a smoking mouse model. Methods Mice were either exposed or sham exposed to cigarette smoke exposure for 20 weeks. Cobalt protoporphyrin or tin protoporphyrin was injected during this period to induce or inhibit HO-1 activity, respectively. Afterwards, emphysema development, levels of inflammatory cells and cytokines, and the presence of B-cell infiltrates in lung tissue were analyzed. Results Smoke exposure induced emphysema and increased the numbers of inflammatory cells and numbers of B-cell infiltrates, as well as the levels of inflammatory cytokines in lung tissue. HO-1 modulation had no effects on smoke induced emphysema development, or the increases in neutrophils and macrophages and inflammatory cytokines. Interestingly, HO-1 induction prevented the development of smoke induced B-cell infiltrates and increased the levels of CD4+CD25+ T cells and Foxp3 positive cells in the lungs. Additionally, the CD4+CD25+ T cells correlated positively with the number of Foxp3 positive cells in lung tissue, indicating that these cells were regulatory T cells. Conclusion These results support the concept that HO-1 expression influences regulatory T cells and indicates that this mechanism is involved in the suppression of smoke induced B-cell infiltrates. The translation of this interaction to human COPD should now be pursued.

There is increasing evidence that a specific immune response contributes to the pathogenesis of COPD. B-cell follicles are present in lung tissue and increased anti-elastin titers have been found in plasma of COPD patients. Additionally, regulatory T cells (Tregs) have been implicated in its pathogenesis as they control immunological reactions. We hypothesize that the specific immune response in COPD is smoke induced, either by a direct effect of smoking or as a result of smoke-induced lung tissue destruction (i.e. formation of neo-epitopes or auto antigens). Furthermore, we propose that Tregs are involved in the suppression of this smoke-induced specific immune response. The presence of B cells, memory B cells and Tregs was assessed by flow cytometry in peripheral blood of 20 COPD patients and 29 healthy individuals and related to their current smoking status. COPD patients had lower (memory) B-cell percentages and higher Treg percentages in peripheral blood than healthy individuals, with a significant negative correlation between these cells. Interestingly, current smokers had higher percentages of (class-switched) memory B cells than ex-smokers and never smokers, irrespective of COPD. This increase in (class-switched) memory B cells in current smokers is intriguing and suggests that smoke-induced neo-antigens may be constantly induced in the lung. The negative correlation between B cells and Tregs in blood is in line with previously published observations that Tregs can suppress B cells. Future studies focusing on the presence of these (class switched) memory B cells in the lung, their antigen specificity and their interaction with Tregs are necessary to further elucidate the specific B-cell response in COPD.

Background A validated instrument to assess the effects of chronic cough on health status in patients with chronic obstructive pulmonary disease (COPD) is currently not available. The Leicester Cough Questionnaire (LCQ) is a cough-specific health status questionnaire which is originally validated for a population of general patients presenting with chronic cough. We examined the psychometric performance of the LCQ in patients with COPD and chronic productive cough. Methods Concurrent validity, internal consistency, reproducibility and responsiveness were determined. The St. George's Respiratory Questionnaire (SGRQ) and the Short Form-36 (SF-36) were used as external criteria. Questionnaires were completed at the start of the study. After 2 and 12 weeks the LCQ was repeated, together with a global rating of change. Results In total 54 patients were included. Concurrent validity analysis showed significant correlations between corresponding domains of the LCQ and the SGRQ (rs -0.31 to -0.60). Corresponding domains of the LCQ and the SF-36 showed weaker correlations (rs 0.04 to 0.41). Internal consistency was adequate for two of the three domains (Cronbach's α 0.74 - 0.86). Test-retest reliability in stable patients was high (intraclass correlation coefficients 0.79 - 0.93). The mean difference after two weeks was 0.73 (± 1.75). Responsiveness analysis indicated that the LCQ was able to detect changes after 12 weeks. Conclusion The LCQ is a valid, reliable, responsive instrument to measure health status in COPD patients with chronic productive cough. Trial Registration ClinicalTrials.gov: NCT01071161