H.T.M. Folgering

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

Xanthine oxidase is involved in exercise-induced oxidative stress in chronic obstructive pulmonary disease

In the present study, we hypothesized that exhaustive exercise in patients with chronic obstructive pulmonary disease (COPD) results in glutathione oxidation and lipid peroxidation and that xanthine oxidase (XO) contributes to free radical generation during exercise. COPD patients performed incremental cycle ergometry until exhaustion with (n = 8) or without (n = 8) prior treatment with allopurinol, an XO inhibitor. Reduced (GSH) and oxidized glutathione (GSSG) and lipid peroxides [malondialdehyde (MDA)] were measured in arterial blood. In nontreated COPD patients, maximal exercise (approximately 75 W) resulted in a significant increase in the GSSG-to-GSH ratio (4. 6 +/- 0.9% at rest vs. 9.3 +/- 1.7% after exercise). In nontreated patients, MDA increased from 0.68 +/- 0.08 nmol/ml at rest up to 1. 32 +/- 0.13 nmol/ml 60 min after cessation of exercise. In contrast, in patients treated with allopurinol, GSSG-to-GSH ratio did not increase in response to exercise (5.0 +/- 1.2% preexercise vs. 4.6 +/- 1.1% after exercise). Plasma lipid peroxide formation was also inhibited by allopurinol pretreatment (0.72 +/- 0.15 nmol/ml preexercise vs. 0.64 +/- 0.09 nmol/ml 60 min after exercise). We conclude that strenuous exercise in COPD patients results in blood glutathione oxidation and lipid peroxidation. This can be inhibited by treatment with allopurinol, indicating that XO is an important source for free radical generation during exercise in COPD.In the present study, we hypothesized that exhaustive exercise in patients with chronic obstructive pulmonary disease (COPD) results in glutathione oxidation and lipid peroxidation and that xanthine oxidase (XO) contributes to free radical generation during exercise. COPD patients performed incremental cycle ergometry until exhaustion with ( n = 8) or without ( n = 8) prior treatment with allopurinol, an XO inhibitor. Reduced (GSH) and oxidized glutathione (GSSG) and lipid peroxides [malondialdehyde (MDA)] were measured in arterial blood. In nontreated COPD patients, maximal exercise (∼75 W) resulted in a significant increase in the GSSG-to-GSH ratio (4.6 ± 0.9% at rest vs. 9.3 ± 1.7% after exercise). In nontreated patients, MDA increased from 0.68 ± 0.08 nmol/ml at rest up to 1.32 ± 0.13 nmol/ml 60 min after cessation of exercise. In contrast, in patients treated with allopurinol, GSSG-to-GSH ratio did not increase in response to exercise (5.0 ± 1.2% preexercise vs. 4.6 ± 1.1% after exercise). Plasma lipid peroxide formation was also inhibited by allopurinol pretreatment (0.72 ± 0.15 nmol/ml preexercise vs. 0.64 ± 0.09 nmol/ml 60 min after exercise). We conclude that strenuous exercise in COPD patients results in blood glutathione oxidation and lipid peroxidation. This can be inhibited by treatment with allopurinol, indicating that XO is an important source for free radical generation during exercise in COPD.

Validity of spirometric testing in a general practice population of patients with chronic obstructive pulmonary disease (COPD)

Objective: To investigate the validity of spirometric tests performed in general practice. Method: A repeated within subject comparison of spirometric tests with a “gold standard” (spirometric tests performed in a pulmonary function laboratory) was performed in 388 subjects with chronic obstructive pulmonary disease (COPD) from 61 general practices and four laboratories. General practitioners and practice assistants undertook a spirometry training programme. Within subject differences in forced expiratory volume in 1 second and forced vital capacity (ΔFEV1 and ΔFVC) between laboratory and general practice tests were measured (practice minus laboratory value). The proportion of tests with FEV1 reproducibility <5% or <200 ml served as a quality marker. Results: Mean ΔFEV1 was 0.069 l (95% CI 0.054 to 0.084) and ΔFVC 0.081 l (95% CI 0.053 to 0.109) in the first year evaluation, indicating consistently higher values for general practice measurements. Second year results were similar. Laboratory and general practice FEV1 values differed by up to 0.5 l, FVC values by up to 1.0 l. The proportion of non-reproducible tests was 16% for laboratory tests and 18% for general practice tests (p=0.302) in the first year, and 18% for both in the second year evaluation (p=1.000). Conclusions: Relevant spirometric indices measured by trained general practice staff were marginally but statistically significantly higher than those measured in pulmonary function laboratories. Because of the limited agreement between laboratory and general practice values, use of these measurements interchangeably should probably be avoided. With sufficient training of practice staff the current practice of performing spirometric tests in the primary care setting seems justifiable.

Self-management of asthma in general practice, asthma control and quality of life: a randomised controlled trial

Background: A study was undertaken to determine the effectiveness of asthma self-management in general practice. Methods: Nineteen general practices were randomly allocated to usual care (UC) or self-management (SM). Asthma patients were included after confirmation of the GP diagnosis. Follow up was 2 years. Patients kept diary cards and visited the lung function laboratory every 6 months. Outcomes were number of successfully treated weeks, limited activity days, asthma specific quality of life, forced expiratory volume in 1 second (FEV1), FEV1 reversibility, concentration of histamine provoking a fall in FEV1 of 20% or more (PC20 histamine), and amount of inhaled steroids. Results: A total of 214 patients were included in the study (104 UC/110 SM; one third of the total asthma population in general practice); 62% were female. The mean percentage of successfully treated weeks per patient in the UC group was 72% (74/103 weeks) compared with 78% (81/105 weeks) in the SM group (p=0.003). The mean number of limited activity days was 1.2 (95% CI 0.5 to 1.9) in the SM group and 3.9 (95% CI 2.5 to 5.4) in the UC group. The estimated increase in asthma quality of life score was 0.10 points per visit in the UC group and 0.21 points per visit in the SM group (p=0.055). FEV1, FEV1 reversibility, and PC20 histamine did not change. There was a saving of 217 puffs of inhaled steroid per patient in favour of the SM group (p<0.05). Conclusion: Self-management lowers the burden of illness as perceived by patients with asthma and is at least as effective as the treatment usually provided in Dutch primary care. Self-management is a safe basis for intermittent treatment with inhaled corticosteroids.

Association between health-related quality of life and consultation for respiratory symptoms: results from the DIMCA programme

In general practice, diagnosis of chronic obstructive pulmonary disease (COPD) is hampered by underpresentation. A substantial proportion of subjects experiencing respiratory complaints do not consult their general practitioner (GP). In this study, the relationship between disease-specific quality of life and presentation of respiratory symptoms to a GP is investigated. A random sample from the general population (undiagnosed subjects) was screened for symptoms and objective signs of COPD (n=1,155). The lung function of subjects with symptoms of COPD was monitored for 6 months. During this period, 48 new COPD patients with a persistently reduced lung function (forced expiratory volume in one second (FEV1) less than or equal to the predicted value minus 2 SD) were detected. A disease-specific quality-of-life questionnaire (chronic respiratory questionnaire (CRQ)) was administered and clinical and GP consultation data were collected. Multivariate analysis showed that quality-of-life impairments due to dyspnoea and fatigue and variability in lung function (bronchial hyperresponsiveness, reversibility and peak expiratory flow rate variability) were related to medical consultation. Only 31% of the newly detected patients reported that they had ever visited their GP for respiratory complaints. A similarly low percentage was found in the rest of the sample (26%). It is concluded that the mere presence of respiratory symptoms or a (gradually) reduced lung function is insufficient reason for patients to seek medical help. Subjects are more likely to consult their general practitioner once their quality of everyday life is affected or they experience variability in lung function.

Relation of the perception of airway obstruction to the severity of asthma.

BACKGROUND Patients with a poor perception of their symptoms of asthma seem to have an increased risk of an asthma attack. The influence of factors such as airway calibre, bronchial hyperresponsiveness, age and sex on the “perceptiveness” of a patient are poorly understood. It is of clinical importance to identify patients who are likely to have a poor perception of their symptoms. We have studied the perception of bronchoconstriction by asthmatic patients during a histamine provocation test and analysed the influence of bronchial obstruction, hyperresponsiveness, sex, and age. We were particularly interested to establish whether there was any difference in perception between subjects with a greater or lesser severity of asthma (expressed as bronchial obstruction, hyperresponsiveness). METHODS One hundred and thirty four patients with allergic asthma underwent a histamine provocation test. The FEV1 was measured after each inhalation of histamine. Subjects were asked to rate subjective quantification of the sensation of breathlessness on a visual analogue scale (VAS). The relationship between changes in VAS values and the reduction in FEV1 as a percentage of the baseline value was analysed by determining the linear regression slope (α) between the two parameters and indicates the perception of airway obstruction. Multiple regression analysis was performed to investigate the effect of baseline FEV1, bronchial hyperresponsiveness, sex and age on the “perceptiveness” for bronchoconstriction. RESULTS The median value of the slope α (indicating the perception of airway obstruction) was 0.91 (25–75th percentile: 0.48–1.45). Age and sex had no influence on the perception of bronchoconstriction. Both initial bronchial tone (baseline FEV1) and bronchial hyperresponsiveness (PC20) showed a significant correlation with the perception of bronchoconstriction. The regression coefficients for FEV1 and 2log PC20 in the multiple regression model were 0.20 and 0.10. Patients who had a low baseline FEV1 and/or a high bronchial responsiveness to histamine were more likely to show a low perceptiveness for bronchoconstriction during the challenge test. CONCLUSIONS Low baseline FEV1 and high bronchial responsiveness are associated with a low degree of “perceptiveness” for bronchoconstriction. This suggests that patients with a more severe degree of asthma either show adaptation of “perceptiveness” for airway obstruction or that low perceptiveness leads to more severe asthma.

Effects of hypercapnia and hypocapnia on respiratory resistance in normal and asthmatic subjects.

The effects of hypercapnia and hypocapnia on respiratory resistance were studied in 15 healthy subjects and 30 asthmatic subjects. Respiratory resistance (impedance) was measured with the pseudo-random noise forced oscillation technique while the subjects rebreathed from a wet spirometer in a closed respiratory circuit in which end tidal carbon dioxide tension (PCO2) could be controlled. Hypercapnia was induced by partially short circuiting the carbon dioxide absorber, and hypocapnia by voluntary hyperventilation. The circulating air was saturated with water vapour and kept at body temperature and ambient pressure. A rise of end tidal PCO2 of 1 kPa caused a significant fall in respiratory resistance in both normal and asthmatic subjects (15% and 9% respectively). A fall of PCO2 of 1 kPa did not cause any significant change in impedance in the control group. In the asthmatic patients resistance increased by 13%, reactance fell by 45%, and the frequency dependence of resistance rose 240%. These findings confirm that hypocapnia may contribute to airway obstruction in asthmatic patients, even when water and heat loss are prevented.

Guidelines for mechanical lung function measurements in psychophysiology

Studies in psychophysiology and behavioral medicine have uncovered associations among psychological processes, behavior, and lung function. However, methodological issues specific to the measurement of mechanical lung function have rarely been discussed. This report presents an overview of the physiology, techniques, and experimental methods of mechanical lung function measurements relevant to this research context. Techniques to measure lung volumes, airflow, airway resistance, respiratory resistance, and airflow perception are introduced and discussed. Confounding factors such as ventilation, medication, environmental factors, physical activity, and instructional and experimenter effects are outlined, and issues specific to children and clinical groups are discussed. Recommendations are presented to increase the degree of standardization in the research application and publication of mechanical lung function measurements in psychophysiology.

Is physical deconditioning a perpetuating factor in chronic fatigue syndrome? A controlled study on maximal exercise performance and relations with fatigue, impairment and physical activity.

BACKGROUND Chronic fatigue syndrome (CFS) patients often complain that physical exertion produces an increase of complaints, leading to a greater need for rest and more time spent in bed. It has been suggested that this is due to a bad physical fitness and that physical deconditioning is a perpetuating factor in CFS. Until now, studies on physical deconditioning in CFS have shown inconsistent results. METHODS Twenty CFS patients and 20 matched neighbourhood controls performed a maximal exercise test with incremental load. Heart rate, blood pressure, respiratory tidal volume, O2 saturation, O2 consumption, CO2 production, and blood-gas values of arterialized capillary blood were measured. Physical fitness was quantified as the difference between the actual and predicted ratios of maximal workload versus increase of heart rate. Fatigue, impairment and physical activity were assessed to study its relationship with physical fitness. RESULTS There were no statistically significant differences in physical fitness between CFS patients and their controls. Nine CFS patients had a better fitness than their control. A negative relationship between physical fitness and fatigue was found in both groups. For CFS patients a negative correlation between fitness and impairment and a positive correlation between fitness and physical activity was found as well. Finally, it was found that more CFS patients than controls did not achieve a physiological limitation at maximal exercise. CONCLUSIONS Physical deconditioning does not seem a perpetuating factor in CFS.

Inhalation profiles in asthmatics and COPD patients: Reproducibility and effect of instruction

Turbuhaler and Salbutamol-Diskus produce therapeutic doses at peak inspiratory flow (PIF) of >30 L/min. However, the optimum flow for Fluticasone-Diskus and Turbuhaler, in terms of total emitted dose and fine particle mass, is >60 L/min. The Turbuhaler achieved a higher output at this flow, as compared to Diskus. For pMDI 25 < PIF < 90 L/min, an actuation time of 0.0-0.2 sec is optimal. The aim of this study was to examine the incidence of optimum inhalation profiles, the effect of instruction, reproducibility, and the relationship between inhalation profiles and patient characteristics in stable asthmatics and mild/moderate/severe COPD patients. For each device, triplicate inhalation profiles were recorded during 6 sessions in a 10-week period. All patients achieved PIF > 30 L/min using Diskus. After instruction, all Diskus inhalations were performed with >60 L/min, except 7% of the inhalations of the severe COPD patients. At least 95% of the Turbuhaler inhalations was also performed with the minimum flow; however, 19% of the inhalations of the severe COPD patients were not optimally performed. The hand-lung coordination was inadequate in 40% of pMDI inhalation profiles, and 80% was performed with a too high flow. The reproducibility of PIF of both dry powder inhalers (DPIs) was very high (coefficient of variation = 4-10%). The reproducibility of the pMDI variables was lower (coefficient of variation = 9-18%). The major lung function variables predictive for PIF(diskus) and PIF(turbuhaler) were maximal inspiratory mouth pressure (MIP), PIF, and inspiratory capacity. No significant predictive lung function variables for PIF(pMDI) were found. Most patients performed reproducible optimum inhalation profiles through Diskus and Turbuhaler. However, in the severe COPD group, 7-19% of the patients were not able to generate the optimum flows through the DPIs. For these patients, a flow-independent aerosol delivery system might be more suitable. The majority of patients were using the pMDI incorrectly. Instruction had no effect. So, we concluded that the pMDI should not be used in these patient groups because of the coordination problems.