Constant P. van Schayck

Slowing the Deterioration of Asthma and Chronic Obstructive Pulmonary Disease Observed during Bronchodilator Therapy by Adding Inhaled Corticosteroids: A 4-Year Prospective Study

Rates of morbidity and mortality due to asthma and chronic obstructive pulmonary disease (COPD) have increased during the last two decades [1, 2]. These increases might be related to the use of bronchodilator therapy without anti-inflammatory medication [3, 4]. Recently, two studies found that regular bronchodilator treatment had adverse effects on the control of asthma [5] and the progression of asthma and COPD [6]. In a previous study of 160 patients with asthma or COPD [6], we found that continuous treatment with a bronchodilator (ipratropium bromide, 40 g, or salbutamol, 400 g, four times daily) was associated with a much higher annual decline in the forced expiratory volume in 1 second (FEV1) compared with treatment on demand. It is unclear whether an unfavorable course of asthma or COPD during bronchodilator therapy alone can be reversed or decelerated by additional anti-inflammatory therapy with inhaled corticosteroids. We studied 56 of the 160 patients who had an unfavorable disease course during bronchodilator therapy alone (an annual decline in FEV1 of at least 80 mL/y in combination with at least two exacerbations per year). These 56 patients (28 with asthma and 28 with COPD) were also treated with an inhaled corticosteroid (beclomethasone dipropionate, 800 g daily) during years 3 and 4 of the study. We assessed whether the worsening of their disease during bronchodilator therapy alone was reversed or decelerated by additional anti-inflammatory treatment with beclomethasone. The outcome measures were dynamic lung function indices (annual decline in pre- and postbronchodilator FEV1, peak expiratory flow rate [PEFR], and forced inspiratory volume in 1 second [FIV1]), static lung function indices (residual volume [RV], ratio of residual volume to total lung capacity (RV/TLC), inspiratory vital capacity [IVC]), nonspecific bronchial responsiveness (assessed by determining the concentration of histamine that provokes a 20% decrease in FEV1 [Pc 20]), exacerbations, and respiratory symptoms. Methods Patients Patient selection has been previously described [6]. In short, 29 family physicians in the catchment area of the University of Nijmegen, Nijmegen, the Netherlands, selected all patients who were 30 years or older and had symptoms of asthma or COPD. Only patients who showed mild-to-moderate airway obstruction (FEV1 > 50% of the predicted value [7]) or bronchial hyper-responsiveness to histamine (Pc 20 8 mg/mL) were included in the study. Patients dependent on inhaled corticosteroids who had chronic heart failure, malignant disorders, or other severe life-threatening diseases were excluded from the study. Of these patients, 160 (59 with asthma and 101 with COPD) completed the bronchodilator trial. During the 2 years of bronchodilator treatment, a rapid decline in FEV1 ( 80 mL/y) and a relatively high exacerbation rate ( 1/y) were observed in a subgroup of 56 patients (35%). Because of their unfavorable disease course, these patients were selected for additional treatment with inhaled beclomethasone for 2 years. The criteria for diagnosis of asthma or COPD were based on the standards of the American Thoracic Society [8]. Asthma was defined [6, 8] by a combination of factors: bronchial hyper-responsiveness to histamine (Pc 20 8 mg/mL); reversible obstruction (an improvement in FEV1 of more than 15% of the prebronchodilator value 60 minutes after the administration of both salbutamol, 400 g, and ipratropium bromide, 80 g); dyspnea; and allergy (defined as at least one positive result on seven radioallergosorbent tests that assessed sensitivity to pollen from weeds, grasses, and trees; cats and dogs; house dust mite; and Aspergillus fumigatus) or wheezing. Chronic obstructive pulmonary disease was defined [6, 8] by the combination of chronic cough or chronic sputum production for at least 3 months during at least 2 consecutive years; and continuous bronchus obstruction (FEV1 85% of the predicted value). The separate features of asthma and COPD overlap (for instance, some asthmatic patients had chronic cough, and some COPD patients had a Pc 20 8 mg/mL), but the definitions based on feature combinations ensured that no patients with asthma also had COPD and vice versa [6]. The study was approved by the Medical Ethics Committee of the University of Nijmegen. All patients gave informed consent. Study Design and Treatment At the start of the 4-year intervention study, the patients were randomly assigned to one of two parallel treatment regimens: continuous bronchodilator therapy (four times daily) or treatment on demand (dry powder inhalations during symptomatic periods) [6]. The patients used salbutamol, 400 g, during 1 year and ipratropium bromide, 40 g, during the other year; both were administered as dry powder inhalations. The sequence of the drugs was determined by random allocation. During years 3 and 4, the 56 patients received 400 g of beclomethasone, two times daily, in combination with 400 g of salbutamol or 40 g of ipratropium bromide, four times daily (all dry powder inhalations). The bronchodilator inhaled during year 2 was also used in years 3 and 4. During the first 2 years of the study, 27 of the 56 patients received bronchodilator therapy on demand (of the 27, 15 had asthma and 12 had COPD). For patients treated on demand, the mean (SE) daily number of dry powder inhalations of salbutamol or ipratropium bromide was 1.2 0.3 in those with asthma and 0.8 0.2 in those with COPD. During years 3 and 4, 28 patients received salbutamol (15 with asthma and 13 with COPD) and 28 received ipratropium bromide (13 with asthma and 15 with COPD). Once every 3 months, inhalation technique and compliance with the prescribed medication were checked. Patients were instructed to rinse their mouths after the dry powder inhalations. During the second year of beclomethasone therapy, a single-blind prospective study was done to assess patient compliance with beclomethasone and the additional bronchodilator. Compliance was measured by counting capsules at the end of a 4-month period. Patients were unaware that their medication was counted after this period. Lung Function, Nonspecific Bronchial Responsiveness, and Reversibility All measurements were carried out by two qualified laboratory assistants during exacerbation-free periods. No bronchodilator was inhaled for at least 8 hours before the pulmonary function tests. At the start and after 24 and 48 months of the study, the inspiratory vital capacity (IVC), residual volume (RV), functional residual capacity (FRC), and total lung capacity (TLC) were assessed using the wet Gould spirometer (Sensormedics, Bilthoven, the Netherlands) according to the standards of the European Coal and Steel Community [7]. The FEV1, bronchial responsiveness to histamine, and the reversibility of airway obstruction were assessed at 6-month intervals using the Microspiro HI-298 (Chest Corporation, Tokyo, Japan) [9]. Moreover, FEV1 and reversibility were also assessed after 1 and 13 months of study [6]. The best of three forced expiratory maneuvers, with the highest sum of the forced vital capacity (FVC) and FEV1, was used for data analysis. The bronchial responsiveness to histamine was measured according to the method described by Cockcroft and colleagues [10]. Results were expressed as the concentration of histamine that provoked a 20% decrease in FEV1 (Pc 20). After the FEV1 had returned to the baseline value, the bronchodilating response (reversibility) was assessed 60 minutes after the administration of both 80 g of ipratropium bromide and 400 g of salbutamol (metered dose aerosol) [6]. The bronchodilating response was expressed as the increase in FEV1 relative to the predicted value of the FEV1. Peak Expiratory Flow Assessments Once a week (on the same day and at the same time), peak expiratory flow rate (PEFR) was measured with the Assess peak flow meter (HealthScan Products, Cedar Grove, New Jersey) [11] in the morning and in the evening. The highest value of three measurements was included in the analysis. The diurnal PEFR index (absolute difference between the evening value and the morning value divided by the highest value) was calculated. Exacerbations Our definition of exacerbation was based on that of Fletcher as modified by Boman and colleagues [12]. When an exacerbation occurred, a 10-day course of oral prednisone was administered. Patients received 25 mg for 2 days, 20 mg for 2 days, 15 mg for 2 days, and so forth. Symptoms and Adverse Effects Using a scale of 0 to 4, all patients recorded, on a weekly basis, the presence and severity of symptoms (cough, phlegm, dyspnea, fatigue, disturbed sleep at night). The adverse effects of medication (dysphonia and oropharyngeal irritation) were recorded by the patients once every 3 months. Moreover, every 6 months, the presence and severity of oral candidiasis were assessed using a questionnaire (no, light, or severe symptoms). Smoking At the start of the study, smoking history was assessed in pack-years. During the study, the average number of cigarettes smoked per day was also recorded in weekly diary entries. Power Calculations Assuming that the clinically relevant, decreased annual decline in FEV1 during beclomethasone treatment is 25 mL/y and that the residual standard deviation is 50 mL/y, the coefficient of variation is 25/50 or 0.5. Based on an of 0.05 and a of 0.20 (power:1 0.2, or 0.8), the required number of patients for the study would be 51. Based on an estimated dropout rate of 10%, the required initial number of study patients would be 56. Statistical Analysis Data on outcome variables obtained before and during beclomethasone therapy were compared. Differences were tested by repeated-measures analysis of variance, the paired Student t-test for normally distributed variables, and the Wilcoxon paired signed-rank test for non-normally distributed variables. Before the analysis, the Pc 20 values were 2log transformed. The an

Symptom-based questionnaire for identifying COPD in smokers

Background: Symptom-based questionnaires may enhance chronic obstructive pulmonary disease (COPD) screening in primary care. Objectives: We prospectively tested questions to help identify COPD among smokers without prior history of lung disease. Methods: Subjects were recruited via random mailing to primary care practices in Aberdeen, UK, and Denver, Colo., USA. Current and former smokers aged 40 or older with no prior respiratory diagnosis and no respiratory medications in the past year were enrolled. Participants answered questions covering demographics and symptoms and then underwent spirometry with reversibility testing. A study diagnosis of COPD was defined as fixed airway obstruction as measured by postbronchodilator FEV1/FVC <0.70. We examined the ability of individual questions in a multivariate framework to correctly discriminate between persons with and without COPD. Results: 818 subjects completed all investigations and proceeded to analysis. The list of 54 questions yielded 52 items for analysis, which was reduced to 17 items for entry into multivariate regression. Eight items had significant relationships with the study diagnosis of COPD, including age, pack-years, body mass index, weather-affected cough, phlegm without a cold, morning phlegm, wheeze frequency, and history of any allergies. Individual items yielded odds ratios ranging from 0.23 to 12. This questionnaire demonstrated a sensitivity of 80.4 and specificity of 72.0. Conclusions: A simple patient self-administered questionnaire can be used to identify patients with a high likelihood of having COPD, for whom spirometric testing is particularly important. Implementation of this questionnaire could enhance the efficiency and diagnostic accuracy of current screening efforts.

Effect of smoke-free legislation on perinatal and child health: a systematic review and meta-analysis

BACKGROUND Smoke-free legislation has the potential to reduce the substantive disease burden associated with second-hand smoke exposure, particularly in children. We investigated the effect of smoke-free legislation on perinatal and child health. METHODS We searched 14 online databases from January, 1975 to May, 2013, with no language restrictions, for published studies, and the WHO International Clinical Trials Registry Platform for unpublished studies. Citations and reference lists of articles of interest were screened and an international expert panel was contacted to identify additional studies. We included studies undertaken with designs approved by the Cochrane Effective Practice and Organisation of Care that reported associations between smoking bans in workplaces, public places, or both, and one or more predefined early-life health indicator. The primary outcomes were preterm birth, low birthweight, and hospital attendances for asthma. Effect estimates were pooled with random-effects meta-analysis. This study is registered with PROSPERO, number CRD42013003522. FINDINGS We identified 11 eligible studies (published 2008-13), involving more than 2·5 million births and 247,168 asthma exacerbations. All studies used interrupted time-series designs. Five North American studies described local bans and six European studies described national bans. Risk of bias was high for one study, moderate for six studies, and low for four studies. Smoke-free legislation was associated with reductions in preterm birth (four studies, 1,366,862 individuals; -10·4% [95% CI -18·8 to -2·0]; p=0·016) and hospital attendances for asthma (three studies, 225,753 events: -10·1% [95% CI -15·2 to -5·0]; p=0·0001). No significant effect on low birthweight was identified (six studies, >1·9 million individuals: -1·7% [95% CI -5·1 to 1·6]; p=0·31). INTERPRETATION Smoke-free legislation is associated with substantial reductions in preterm births and hospital attendance for asthma. Together with the health benefits in adults, this study provides strong support for WHO recommendations to create smoke-free environments. FUNDING Thrasher Fund, Lung Foundation Netherlands, International Paediatric Research Foundation, Maastricht University, Commonwealth Fund.

Symptom-Based Questionnaire for Differentiating COPD and Asthma

Background: Many patients with obstructive lung disease (OLD) carry an inaccurate diagnostic label. Symptom-based questionnaires could identify persons likely to need spirometry. Objectives: We prospectively tested questions derived from a comprehensive literature review and an international Delphi panel to help identify chronic OLD (COPD) in persons with prior evidence of OLD. Methods: Subjects were recruited via random mailing to primary-care practices in Aberdeen, Scotland, and Denver, Colorado. Persons aged 40 and older reporting any prior diagnosis of OLD or any respiratory medications in the past year were enrolled. Participants answered 54 questions covering demographics and symptoms and underwent spirometry with reversibility testing. A study diagnosis of COPD was defined by fixed airway obstruction as measured by post-bronchodilator FEV1/FVC <0.70. We examined ability of individual questions in a multivariate framework to discriminate between persons with and without the study diagnosis of COPD. Results: 597 persons completed all investigations and proceeded to analysis. The list of 54 questions yielded 52 items for analyses, which was reduced to 19 items for entry into a multivariate regression model. Nine items had significant relationships with the study diagnosis of COPD, including increased age, pack-years, worsening cough, breathing-related disability or hospitalization, worsening dyspnea, phlegm quantity, cold going to the chest, and receipt of treatment for breathing. Individual items yielded odds ratios ranging from 0.33 to 20.7. This questionnaire demonstrated a sensitivity of 72.0 and a specificity of 82.7. Conclusions: A short, symptom-based questionnaire identifies persons more likely to have COPD among persons with prior evidence of OLD.

Nicotine Vaccines to Assist with Smoking Cessation Current Status of Research

Tobacco smoking causes cardiovascular, respiratory and malignant disease, and stopping smoking is among the key medical interventions to lower the worldwide burden of these disorders. However, the addictive properties of cigarette smoking, including nicotine inhalation, render most quit attempts unsuccessful. Recommended therapies, including combinations of counselling and medication, produce long-term continuous abstinence rates of no more than 30%. Thus, more effective treatment options are needed.An intriguing novel therapeutic concept is vaccination against nicotine. The basic principle of this approach is that, after entering the systemic circulation, a substantial proportion of nicotine can be bound by antibodies. Once bound to antibodies, nicotine is no longer able to cross the blood-brain barrier. As a consequence, the rewarding effects of nicotine are diminished, and relapse to smoking is less likely to occur. Animal studies indicate that antibodies profoundly change the pharmacokinetics of the drug and can interfere with nicotine self-administration and impact on the severity of withdrawal symptoms. To date, five phase I/II clinical trials using vaccines against nicotine have been published. Results have been disappointing in that an increase in quit rates was only observed in small groups of smokers displaying particularly high antibody titres.The failure of encouraging preclinical data to completely translate to clinical studies may be partially explained by shortcomings of animal models of addiction and an incomplete understanding of the complex physiological and behavioural processes contributing to tobacco addiction. This review summarizes the current status of research and suggests some directions for the future development of vaccines against nicotine. Ideally, these vaccines could one day become part of a multifaceted approach to treating tobacco addiction that includes counselling and pharmacotherapy.

Gene-gene interaction in regulatory T-cell function in atopy and asthma development in childhood

BACKGROUND Regulatory T-cell dysfunction is associated with development of the complex genetic conditions atopy and asthma. Therefore, we hypothesized that single nucleotide polymorphisms in genes involved in the development and function of regulatory T cells are associated with atopy and asthma development. OBJECTIVE To evaluate main effects and gene-gene interactions of haplotype tagging single nucleotide polymorphisms of genes involved in regulatory T-cell function-IL6, IL6R, IL10, heme-oxygenase 1 (HMOX1), IL2, Toll-like receptor 2 (TLR2), TGFB1, TGF-beta receptor (TGFBR)-1, TGFBR2, IL2RA, and forkhead box protein 3 (FOXP3)-in relation to atopy and asthma. METHODS Single-locus and multilocus associations with total IgE (3rd vs 1st tertile); specific IgE to egg, milk, and indoor allergens; and asthma were evaluated by chi(2) tests and the multifactor dimensionality-reduction method in 3 birth cohorts (Allergenic study). RESULTS Multiple statistically significant multilocus associations existed. IL2RA rs4749926 and TLR2 rs4696480 associated with IgE in both age groups tested (1-2 and 6-8 years). TGFBR2 polymorphisms associated with total and specific IgE in both age groups and with asthma. TGFBR2 rs9831477 associated with specific IgE for milk at age 1 to 2 years and indoor allergens at age 6 to 8 years. For milk-specific IgE, interaction between TGFBR2 and FOXP3 polymorphisms was confirmed by logistic regression and consistent in 2 birth cohorts and when stratified for sex, supplying internal replications. CONCLUSION Genes involved in the development and function of regulatory T cells, specifically IL2RA, TLR2, TGFBR2, and FOXP3, associate with atopy and asthma by gene-gene interaction. Modeling of multiple gene-gene interactions is important to unravel further the genetic susceptibility to atopy and asthma.

Comparison of existing symptom‐based questionnaires for identifying COPD in the general practice setting

Objective:  Underdiagnosis of COPD is widespread, at least in part due to underuse of spirometry. Symptom‐based questionnaires may be helpful as an adjunct to spirometry. The aim of this study was to determine which types of questions might aid in identifying COPD.

Pharmacotherapy for Smoking Cessation: Current Advances and Research Topics

Promoting smoking cessation is among the key medical interventions aimed at reducing worldwide morbidity and mortality in this century. Both behavioural counselling and pharmacotherapy have been shown to significantly increase long-term abstinence rates, and combining the two treatment modalities is recommended. This article provides an update on pharmacotherapy for smoking cessation in the general population.Current first-line agents used to support quit attempts are nicotine replacement therapy (NRT), bupropion and varenicline. Research suggests that abstinence rates can be increased by combining different forms of NRT or simultaneously administering NRT and non-nicotine medications. New treatments targeting the nicotinic acetylcholine receptor as well as other pathophysiological pathways involved in nicotine addiction are being developed, with nicotine vaccines now being tested in phase III clinical trials.Among the numerous research topics currently addressed, pharmacogenetics and tailoring therapy to specific groups of smokers look most promising. However, substantial progress is unlikely to be made unless social gradients impeding effective treatment of all smokers are overcome. In addition, public smoking bans and reimbursement of medication costs are crucial in reducing the future burden of disease caused by smoking on a global level.

Organic dust toxic syndrome in swine confinement farming

BACKGROUND Pig farmers are exposed to organic dust with pro-inflammatory capacities. This makes it likely that they suffer from organic dust toxic syndrome (ODTS). No studies that included unexposed control populations are available so far. METHODS The prevalence of ODTS was established by the use of questionnaires in a group of 239 pig farmers and 311 rural controls working in nonagricultural occupations. RESULTS Pig farmers suffered more often from ODTS than controls (6.4% vs. 2.6%, P < 0.05). Organic dust toxic syndrome was associated with symptoms of atopy (prevalence odds ratio (POR) 3.1, 95% confidence interval (CI) 1.2-8.0) and with the use of wood-shavings as bedding (POR 4.3, 95% CI 1.2-15.6). An inverse association with the number of years worked as pig farmer was found (up to 5 years vs. more than 5 years; POR 5.0, 95% CI 0.8-32.9). CONCLUSIONS The prevalence of ODTS was elevated among pig farmers when compared to nonfarming, rural controls.

Feasibility of a new method to collect exhaled breath condensate in pre‐school children

Rosias PPR, Robroeks CM, van de Kant KD, Rijkers GT, Zimmermann LJ, van Schayck CP, Heynens JW, Jöbsis Q, Dompeling E. Feasibility of a new method to collect exhaled breath condensate in pre‐school children. 
Pediatr Allergy Immunol 2010: 21: e235–e244.
© 2009 John Wiley & Sons A/S