Jan Kraan

Changes in bronchial hyperreactivity induced by 4 weeks of treatment with antiasthmatic drugs in patients with allergic asthma: A comparison between budesonide and terbutaline☆

We performed a double-blind crossover study to compare the effects of long-term treatment of inhaled budesonide and terbutaline on bronchial hyperreactivity in 17 patients with allergic asthma. Both drugs were administered for 4 weeks with a placebo-treatment period before and after each active-treatment period. To assess bronchial hyperreactivity, standardized inhalation provocation tests with histamine and propranolol were performed every 2 weeks. Before each inhalation provocation the drugs were withheld for at least 12 hours. Before the budesonide treatment the FEV1 value (percent predicted) was 85.3 +/- 4.1% (mean +/- SEM). After 2 and 4 weeks of treatment with this drug, the value increased significantly to 89.4 +/- 4.1% and 96.2 +/- 3.8%, respectively (p less than 0.05 and p less than 0.005). The histamine provocation concentrations causing a decrease in FEV1 of 20% (PC20) on the same days were 4.0, 7.2, and 9.5 mg/ml, respectively (both p less than 0.001). The PC20 values for propranolol, which were measured 1 hour after the histamine provocation, were 11.7, 13.3, and 14.0 mg/ml (ns). The FEV1 values before and after 2 and 4 weeks of treatment with terbutaline were 86.2 +/- 4.0%, 84.8 +/- 4.1%, and 87.0 +/- 4.6%, respectively. The histamine PC20 values on the same days were 4.7, 3.1 (p less than 0.05), and 3.8 mg/ml, respectively. The propranolol PC20 values were 14.2, 8.7, and 10.1 mg/ml (p less than 0.001 and p less than 0.05, respectively. We conclude that budesonide improves bronchial hyperreactivity, possibly by a dampening of late allergic reactions, whereas treatment with terbutaline may lead to a temporary increase of bronchial hyperreactivity, possibly as a result of beta-receptor desensitization.

QUALITY-OF-LIFE IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY-DISEASE IMPROVES AFTER REHABILITATION AT HOME

We have developed a rehabilitation programme at home and have investigated its effects on quality of life (QOL), lung function, and exercise tolerance in patients with chronic obstructive pulmonary disease (COPD). We studied 43 patients with severe airflow obstruction: forced expiratory volume in one second (FEV1) 1.3 +/- 0.4 l (mean +/- SD), FEV1/inspiratory vital capacity (IVC) 37 +/- 7.9%. After stratification, 28 patients were randomly allocated in a home rehabilitation programme for 12 weeks. Fifteen patients in a control group received no rehabilitation. The rehabilitation group received physiotherapy by the local physiotherapist, and supervision by a nurse and a general practitioner. Quality of life was assessed by the four dimensions of the Chronic Respiratory Questionnaire (CRQ). We found a highly significant improvement in the rehabilitation group compared to the control group for the dimensions dyspnoea, emotion, and mastery. Lung function showed no changes in the rehabilitation group. The exercise tolerance improved significantly in the rehabilitation group compared to the control group. The improvement in quality of life was not correlated with the improvement in exercise tolerance. Rehabilitation of COPD patients at home may improve quality of life; this improvement is not correlated with an improvement in lung function and exercise tolerance.

Relation of lung function, maximal inspiratory pressure, dyspnoea, and quality of life with exercise capacity in patients with chronic obstructive pulmonary disease.

BACKGROUND--Several studies have shown that both objective and subjective measurements are related to exercise capacity in patients with chronic obstructive pulmonary disease (COPD). In this study the relative contribution of lung function, maximal inspiratory pressure, dyspnoea, and quality of life to the performance in a walking distance test and a bicycle ergometer test was investigated. METHODS--Static lung volumes, forced expiratory volume in one second (FEV1), inspiratory slow vital capacity (IVC), transfer factor for carbon monoxide (TLCO) divided by the alveolar volume (TLCO/VA), static compliance (Cst), and maximal inspiratory peak pressure (PImaxPOES) were measured in 40 patients with COPD with severe airways obstruction (mean FEV1 44% predicted, mean FEV1/IVC 37% predicted). Quality of life was assessed by the Chronic Respiratory Questionnaire (CRQ) and dyspnoea by the Borg category scale. Exercise capacity was measured by both a six minute walking distance (test) and a maximal work load of the bicycle ergometer test (Wmax). RESULTS--Spirometric values and maximal inspiratory pressure were modestly correlated with both the six minute walking test and Wmax, r values ranging from 0.50 to 0.58. The TLCO was strongly correlated with the six minute walking test (r = 0.62) and with Wmax (r = 0.78). Quality of life showed no correlation with exercise capacity, while there was a correlation between dyspnoea and the six minute walking test (r = -0.41). Backward linear regression analysis selected TLCO and PImaxPOES as the most significant determinants for exercise performance. They explained 54% and 69% of the variance in the six minute walking test and Wmax, respectively. CONCLUSIONS--The results show that exercise capacity in patients with COPD with severe airways obstruction is more strongly related to inspiratory muscle strength and lung function than to dyspnoea and quality of life. The significant correlation between dyspnoea and the six minute walking test suggests that subjective variables are more strongly related to walking tests than to bicycle ergometer tests.

Long term benefits of rehabilitation at home on quality of life and exercise tolerance in patients with chronic obstructive pulmonary disease.

BACKGROUND--Pulmonary rehabilitation has been shown to have short term subjective and objective benefits for patients with chronic obstructive pulmonary disease (COPD). However, appropriately controlled studies have not previously been performed, nor have the benefits of different types of continuation programme for rehabilitation been investigated. Both these problems have been addressed in a single study of the long term effects of once monthly physiotherapy versus once weekly physiotherapy at home after a comprehensive home rehabilitation programme on quality of life and exercise tolerance in patients with COPD. METHODS--Thirty six patients with severe airways obstruction (mean SD) forced expiratory volume in one second (FEV1) 1.3(0.4) 1, FEV1/inspiratory vital capacity (IVC) 37.2(7.9)%) were studied. Twenty three patients followed a rehabilitation programme at home for 18 months consisting of physiotherapy and supervision by a nurse and general practitioner. During the first three months all 23 patients visited the physiotherapist twice a week for a 0.5 hour session. Thereafter, 11 patients (group A) received a session of physiotherapy once weekly while 12 patients (group B) received a session of physiotherapy once a month. The control group C (13 patients) received no rehabilitation at all. Quality of life was assessed by the Chronic Respiratory Questionnaire, exercise tolerance by the six minute walking distance, and lung function by FEV1 and IVC. Outcome measures were assessed at baseline and at three, six, 12, and 18 months. RESULTS--Long term improvements in quality of life were found in patients in groups A and B, but not in those in group C compared with baseline, but these only reached significance in group B at all time points. Patients in group B had a higher quality of life than those in group C only at three and 12 months. There was a decrease in both six minute walking distance (at 12 and 18 months) and IVC (at three, 12, and 18 months) in patients in group C compared with the baseline measurement. Between groups analysis showed no differences for six minute walking distance, FEV1, and IVC. CONCLUSIONS--This study is the first to show that rehabilitation at home for three months followed by once monthly physiotherapy sessions improves quality of life over 18 months. The change in quality of life was not associated with a change in exercise tolerance.

Reliability and validity of the chronic respiratory questionnaire (CRQ).

BACKGROUND--The Chronic Respiratory Questionnaire (CRQ) is frequently applied to assess quality of life in patients with chronic obstructive pulmonary disease (COPD). However, the reliability and validity of this questionnaire have not yet been determined. This study investigates the reliability and validity of the four separate dimensions of the CRQ. METHODS--The CRQ was administered on two consecutive days to 40 patients with COPD (mean FEV1 44% predicted, FEV1/IVC 37% predicted). Internal consistency reliability of each dimension was investigated by Cronbachs alpha reliability coefficient, test retest reliability by the Spearman-Brown reliability coefficient (p), and content validity by Pearsons correlation coefficient between the CRQ and the symptom checklist (SCL-90). RESULTS--Items of the fatigue, emotion, and mastery dimensions showed a high internal consistency reliability (alpha = 0.71-0.88) as well as a high test retest reliability (p above 0.90). These three dimensions correlated with comparable dimensions of the SCL-90. Items of the dyspnoea dimension showed a low internal consistency reliability (alpha = 0.53) and a test retest reliability of p = 0.73. CONCLUSIONS--Items of the dimensions fatigue, emotion, and mastery of the CRQ are reliable and valid and can be used to assess quality of life in patients with severe airways obstruction. Items of the dyspnoea dimension are less reliable and should not be included in the overall score of the CRQ in comparative research. However, by scoring the items of dyspnoea separately they may be useful for the evaluation of the effects of intervention in a specific patient.

Effects of home rehabilitation on physical performance in patients with chronic obstructive pulmonary disease (COPD)

We investigated whether 12 weeks of rehabilitation at home in patients with chronic obstructive pulmonary disease (COPD) had a beneficial effect on lactate production, metabolic gas exchange data, workload of the inspiratory muscles, and dyspnoea during a maximal bicycle ergometer test. A second aim was to assess whether a change in dyspnoea was related to a change of inspiratory muscle workload. Forty three COPD patients with severe airways obstruction were included in the study: mean forced expiratory volume in one second (FEV1) 1.3 +/- 0.4 L (44% predicted), mean FEV1/inspiratory vital capacity (IVC) 37 +/- 8%. Twenty eight patients started a rehabilitation programme, whilst 15 patients received no rehabilitation. Rehabilitation was carried out at home; patients were supervised by a general practitioner, a physiotherapist and a nurse. Exercise tolerance was measured by means of a 6 min walking distance test (6MWD) and maximal workload (Wmax) during an incremental symptom-limited cycle ergometer test. Inspiratory muscle workload at Wmax was assessed with the Tension Time Index (TTI), and dyspnoea at Wmax with the Borg scale. After 12 weeks, the rehabilitation group showed a significantly larger increase in 6MWD (from 438 to 447 m) and in Wmax (from 70 to 78 W) compared with the control group. A significant improvement in oxygen consumption (V1O2) (from 1.0 to 1.1 L), lactate level (from 3.7 to 3.1 mEq.L(-1)), dyspnoea (from 6.0 to 4.5) and TTI (from 0.10 to 0.08) at Wmax occurred in the rehabilitation group during the programme. The reduction in TTI was not significantly correlated with the fall in dyspnoea, as assessed by the Borg scale. We conclude that 12 weeks of rehabilitation at home in COPD patients increases symptom-limited V1O2 in combination with an increased Wmax. At this significantly higher Wmax, there was a reduction in dyspnoea, lactate level and inspiratory muscle workload. The reduction in dyspnoea was not related to a decreased inspiratory muscle workload. This study shows that rehabilitation at home can produce beneficial physiological improvements during exercise in patients with chronic obstructive pulmonary disease.

(A)Symptomatic bronchial hyper-responsiveness and asthma

Bronchial responsiveness constitutes the phenomenon of the occurrence of airways obstruction upon physical, chemical and pharmacological stimuli (l-3). The clinical presentation in asthmatic individuals includes wheeze, cough and/or dyspnoea upon exercise and inhalation of e.g. cold air, fog and perfume. The prevalence of bronchial hyper-responsiveness (BHR) in the population varies from 6 to 35% (4-14) and is strongly associated with the presence of respiratory symptoms. Even though BHR is generally accompanied by respiratory symptoms, population studies have shown that it may also occur in subjects without any respiratory symptom, so-called asymptomatic hyper-responsiveness (69,12,15). There is increasing evidence that an inflammatory process in the airway wall is one of the underlying pathophysiologic mechanisms of BHR in asthma. This inflammatory process may directly or indirectly cause smooth muscle contraction, airway wall oedema, and stimulation of the nervous system, leading to symptoms of cough, wheeze and dyspnoea. It is still unclear whether an inflammatory process is also present in asymptomatic individuals, and if so, whether it has similar cellular components. Furthermore, it is important to assess whether asymptomatic hyper-responsiveness has any prognostic importance as an early sign of disease development.

Increased peak expiratory flow variation in asthma: severe persistent increase but not nocturnal worsening of airway inflammation

Asthma at night is characterized by a nocturnal increase in airway obstruction. It has been hypothesized that nocturnal asthma results from an increase in airway wall inflammation at night. However, studies on inflammatory cells in bronchoalveolar lavage (BAL) fluid and bronchial biopsies have produced conflicting data. This study assessed inflammatory cell numbers at 16:00 h and 04:00 h in bronchial biopsies of 13 healthy controls, 15 asthmatic patients with peak expiratory flow (PEF) variation < or =15% and 10 asthmatic patients with PEF variation >15%. There was no significant increase at night in the number of CD3, CD4, CD8, CD25, AAI (tryptase) and EG2-immunopositive cells in the submucosa in both groups. Numbers of EG2-positive cells in the two asthmatic groups were significantly higher than in healthy controls, both at 16:00 h (p<0.05) and 04:00 h (p<0.01). The number of EG2, CD4 and CD25-positive cells at 04:00 and 16:00 h tended to be higher in asthmatics with a PEF variation >15% than in asthmatics with PEF variation < or =15%. At 04:00 h the median numbers of EG2-positive cells (per mm basement membrane) in subjects with PEF variation >15% and < or =15% were 6 and 3 cells, respectively, and at 16:00 h 4 and 25 cells respectively. Increased nocturnal airway obstruction is not associated with increased numbers of inflammatory cells in the bronchial submucosa at night. Apparently, asthmatic patients with a peak expiratory flow variation >15% suffer from a higher overall severity of bronchial inflammation at night and during the day.

Rheumatoid arthritis–associated autoantibodies in non–rheumatoid arthritis patients with mucosal inflammation: a case–control study

IntroductionRheumatoid arthritis–associated autoantibodies (RA-AAB) can be present in serum years before clinical onset of rheumatoid arthritis (RA). It has been hypothesized that initiation of RA-AAB generation occurs at inflamed mucosal surfaces, such as in the oral cavity or lungs. The aim of this study was to assess systemic presence of RA-AAB in patients without RA who had oral or lung mucosal inflammation.MethodsThe presence of RA-AAB (immunoglobulin A [IgA] and IgG anti-cyclic citrullinated peptide 2 antibodies (anti-CCP2), IgM and IgA rheumatoid factor (RF), IgG anti-carbamylated protein antibodies and IgG and IgA anti-citrullinated peptide antibodies against fibrinogen, vimentin and enolase) were determined in sera of non-RA patients with periodontitis (PD, n = 114), bronchiectasis (BR, n = 80) or cystic fibrosis (CF, n = 41). Serum RA-AAB levels were compared with those of periodontally healthy controls (n = 36). Patients with established RA (n = 86) served as a reference group. Association of the diseases with RA-AAB seropositivity was assessed with a logistic regression model, adjusted for age, sex and smoking.ResultsLogistic regression analysis revealed that IgG anti-CCP seropositivity was associated with BR and RA, whereas the association with PD was borderline significant. IgA anti-CCP seropositivity was associated with CF and RA. IgM RF seropositivity was associated with RA, whereas the association with BR was borderline significant. IgA RF seropositivity was associated with CF and RA. Apart from an influence of smoking on IgA RF in patients with RA, there was no influence of age, sex or smoking on the association of RA-AAB seropositivity with the diseases. Anti-CarP levels were increased only in patients with RA. The same held for IgG reactivity against all investigated citrullinated peptides.ConclusionAlthough overall levels were low, RA-AAB seropositivity was associated with lung mucosal inflammation (BR and CF) and may be associated with oral mucosal inflammation (PD). To further determine whether mucosal inflammation functions as a site for induction of RA-AAB and precedes RA, longitudinal studies are necessary in which RA-AAB of specifically the IgA isotype should be assessed in inflamed mucosal tissues and/or in their inflammatory exudates.

Characterisation of beta(2)-adrenoceptors, using the agonist [C-11]formoterol and positron emission tomography

Abstract The agonist radioligand N -[2-hydroxy-5-[1-hydroxy-2-[[2-(4- [ 11 C ] -methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide ( [ 11 C ] formoterol) was synthesised in order to test its ability to visualise pulmonary β 2 -adrenoceptors in vivo, with positron emission tomography (PET). Formoterol was labelled via reaction of a dibenzyl-protected precursor with [ 11 C ] CH 3 I. Subsequent deprotection with Pd/C and H 2 yielded [ 11 C ] formoterol in 5–15% (corrected for decay) and the specific activity ranged from 5.5–22.2 TBq mmol −1 (150–600 Ci mmol −1 ), 60–70 min after end of bombardment. Biodistribution studies with [ 11 C ] formoterol were performed in male Wistar rats which were either untreated or predosed with ( d , l )-propranolol hydrochloride (2.5 mg kg −1 , β-adrenoceptor antagonist), erythro- dl -1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol hydrochloride (ICI 118551, 0.15 mg kg −1 , β 2 -adrenoceptor antagonist), isoprenaline (15 mg kg −1 , non-subtype selective β-adrenoceptor agonist) or (±)-(2-hydroxy-5-[2-((2-hydroxy-3-(4-((1-methyl-4-trifluoromethyl)1 H -imidazol-2-yl-)phenoxy)propyl)amino)ethoxy]benzamide)monomethane sulfonate (CGP 20712A, 0.15 mg kg −1 , β 1 -adrenoceptor antagonist). Lungs, heart, liver and plasma were analysed for radioactive metabolites. The kinetics of [ 11 C ] formoterol in the lungs of male Wistar rats were investigated by means of a dynamic PET study. The biodistribution studies showed significant specific binding in tissues known to contain β 2 -adrenoceptors (lungs, spleen, and heart). Binding in these organs was blocked by ICI 118551 and isoprenaline, but not by CGP 20712A. [ 11 C ] Formoterol was rapidly metabolised in rats but lungs and heart did not substantially take up the labelled metabolites. The binding of [ 11 C ] formoterol in various tissues of rats is consistent with the β 2 -selectivity of formoterol. Whether [ 11 C ] formoterol selectively binds to the high affinity state of β 2 -adrenoceptors remains to be elucidated. [ 11 C ] Formoterol is potentially useful for studying β 2 -adrenoceptors with PET and this radioligand may provide new insights in the mechanisms underlying prolonged sympathomimetic action.