Overbeek, S.E.

Formoterol added to low-dose budesonide has no additional antiinflammatory effect in asthmatic patients. (Article)

2005-09-01T00:00:00Z

STUDY OBJECTIVE: Adding inhaled long-acting beta2-agonists to a low dose of inhaled corticosteroids (ICSs) results in better asthma control than increasing the dose of ICSs. An important, but as yet unresolved, question is whether this is due to an additional reduction of airway inflammation. DESIGN: Double-blind, parallel-group trial. PATIENTS: Forty asthma patients (FEV1, 50 to 90% predicted; provocative concentration of a substance [methacholine] causing a 20% fall in FEV1 of < 8 mg/mL; no ICSs in the last 4 weeks). INTERVENTIONS: Randomization to 8 weeks of treatment with 100 microg of budesonide bid plus placebo (BUD200) or 100 microg of budesonide bid plus 12 microg of formoterol (BUD200 + F). Then the dose of budesonide (BUD) was increased to 400 microg bid in both groups for another 8 weeks. Bronchial biopsy specimens were collected before, and after 8 and 16 weeks of treatment. Eosinophils (major basic protein [MBP]) and mast cells (tryptase) were analyzed by immunohistochemistry. RESULTS: BUD200 reduced the MBP staining (p = 0.008) and tryptase staining (p = 0.048) in the epithelium compared to baseline levels. There were no significant differences between the BUD200 and BUD200 + F groups. In both groups, increasing the dosage of BUD to 800 microg had no significant additional antiinflammatory effect. CONCLUSIONS: Our results demonstrate that BUD administered at a low dose has significant antiinflammatory effects in patients with mild asthma. No significant additional antiinflammatory effects could be demonstrated either by adding formoterol or by increasing the dose of BUD.

Dyspnoea perception during clinical remission of atopic asthma (Article)

2002-01-01T00:00:00Z

Symptoms of atopic asthma often disappear around puberty. The authors recently demonstrated that this clinical remission is accompanied with ongoing airways inflammation in most subjects. The discrepancy between lack of symptoms and persistent airway inflammation suggests that perception of the symptoms is unclear. In the present study, young adults in clinical remission of atopic asthma assigned themselves a modified Borg score during methacholine and adenosine-5'-monophosphate induced bronchoconstriction. Borg scores of subjects in clinical remission were compared with those of symptomatic asthmatic subjects. A marked variation in the Borg scores at a 20% fall in the forced expiratory volume in one second was found. Significant differences in Borg scores between remission patients and asthmatics could not be detected. It was concluded that perception of dyspnoea, induced with methacholine and adenosine challenge, is similar in young adults in clinical remission of atopic asthma compared to that of patients with symptomatic asthma. Hence, an unclear perception seems to be an unlikely explanation for the discrepancy between lack of symptoms and ongoing inflammation. Other factors, including both physical and psychological ones, may play a role in the apparent absence of symptoms, thereby potentially leading to undertreatment.

Feasibility of AsthmaCritic, a decision-support system for asthma and COPD which generates patient-specific feedback on routinely recorded data in general practice (Article)

2002-01-01T00:00:00Z

BACKGROUND: Introducing decision-support systems as a tool to stimulate the dissemination of clinical guidelines in daily practice has been disappointing. Researchers have argued that integration of such systems with clinical practice is a prerequisite for acceptance. The big question concerns the feasibility of a true integration--if only routinely recorded data are used for such a system, can patient-specific feedback be produced? OBJECTIVE: The aim of this study was to assess the feasibility of generating patient-specific feedback based on routinely recorded data in general practice by AsthmaCritic, a decision-support system for asthma and chronic obstructive pulmonary disease (COPD). METHODS: We built the decision-support system AsthmaCritic and assessed its ability to detect asthma and COPD patient records and generate patient-specific feedback by retrospective analysis of routinely recorded data in 103 713 electronic patient records from primary care practices. We grouped feedback into categories of comments by age group (<12 years and > or =12 years). The main outcome measures were the number and percentage of "triggered" (selected) asthma and COPD patient records, and the number and percentage of records on which AsthmaCritic produced at least one feedback comment during the 1-year study period, by category of comments. RESULTS: AsthmaCritic detected 8784 (8.5%) asthma and COPD patient records. During the study period, AsthmaCritic generated 255 664 feedback comments (mean 3.4 per patient visit). The most frequently generated category of comments in the case of patients aged > or =12 years was "non-compliant prescription" (23.7%), whereas the most frequent category in the case of patients <12 years was "non-compliant route" (31.1%). CONCLUSIONS: This study shows that, using routinely recorded data only, AsthmaCritic is able to detect asthma and COPD patient records for further analysis and to produce patient-specific feedback.

Segmental bronchoprovocation in allergic rhinitis patients affects mast cell and basophil numbers in nasal and bronchial mucosa (Article)

2001-01-01T00:00:00Z

Mast cells and basophils are cells that play an important role in the initiation and control of allergic inflammation in asthma and rhinitis. This study was undertaken to determine the presence and dynamics of mast cells and basophils in the nasal and bronchial mucosa of allergic rhinitis patients after segmental bronchial provocation (SBP). Eight nonasthmatic, grass pollen-allergic rhinitis patients and eight healthy controls were included. Bronchial and nasal biopsies, as well as blood samples, were taken before (T(0)) and 24 h (T(24)) after SBP. Immunohistochemical staining was performed for mast cells (tryptase and chymase; phenotypes MC(T), MC(TC), MC(C)) and basophils (BB1). In the bronchial mucosa, the number of BB1(+) cells increased significantly (p < 0.05) in allergic rhinitis patients after SBP. In the nasal mucosa, the numbers of MC(C) and MC(TC) cells decreased significantly, whereas the numbers of [BB1(+)] cells increased significantly in allergic rhinitis patients after SBP (p < 0.05). In blood, the number of basophils decreased (p < 0.05) and the level of interleukin (IL)-5 increased (p < 0.05) in atopic patients after SBP. No significant changes could be observed in healthy controls. This study shows that SBP in nonasthmatic allergic rhinitis patients reduces numbers of mast cells in the nose as a result of enhanced degranulation. At the same time, there is evidence for an influx of basophils from the blood into the nasal and bronchial mucosae.

Airway inflammation is present during clinical remission of atopic asthma (Article)

2001-01-01T00:00:00Z

Symptoms of atopic asthma often disappear at puberty. However, asthmatic subjects in clinical remission will frequently have a relapse later in life. The aim of this study was to investigate whether subjects in clinical remission of atopic asthma have persistent airway inflammation and/or airway remodeling. Bronchial biopsies were obtained from subjects in clinical remission, asthmatic subjects, and healthy control subjects. The presence and/or activation state of eosinophils, mast cells, macrophages, T lymphocytes, interleukin (IL)-5, eotaxin, and inducible nitric oxide synthase (iNOS) were analyzed. Results were compared with less invasive indicators of airway inflammation. Also aspects of airway remodeling were determined. Eosinophils, T cells, mast cells, and IL-5 were significantly elevated in the airway mucosa of subjects in remission compared with control subjects. Also, blood eosinophil cell counts were significantly higher in subjects in clinical remission. Blood eosinophil cell counts, exhaled nitric oxide (eNO) levels, and bronchial response to adenosine-5'-monophosphate correlated significantly with the quantity of tissue eosinophils. Significant airway remodeling was found in subjects in clinical remission. Our study has shown ongoing airway inflammation and airway remodeling in adolescents in clinical remission of atopic asthma. Subclinical airway inflammation may well determine the risk of an asthma relapse later in life.

Segmental bronchial provocation induces nasal inflammation in allergic rhinitis patients (Article)

2000-01-01T00:00:00Z

Allergic rhinitis and asthma often coexist and share a genetic background. Pathophysiologic connections between the nose and lungs are still not entirely understood. This study was undertaken to compare allergic inflammation and clinical findings in the upper and lower airways after segmental bronchial provocation (SBP) in nonasthmatic allergic rhinitis patients. Eight nonasthmatic, grass pollen-sensitive patients with allergic rhinitis and eight healthy controls were included. Bronchial biopsies and blood samples were taken before (T(0)) and 24 h (T(24)) after SBP. Nasal biopsies were obtained at T(0), 1 h after SBP (T(1)), and T(24). Immunohistochemical staining was performed for eosinophils (BMK13), interleukin (IL)-5, and eotaxin. The number of eosinophils increased in the challenged and unchallenged bronchial mucosa (p < 0.05) and in the blood (p = 0.03) of atopic subjects at T(24). We detected an increase of BMK13-positive and eotaxin-positive cells in the nasal lamina propria and enhanced expression of IL-5 in the nasal epithelium of atopic subjects only at T(24) (p < 0.05). SBP induced nasal and bronchial symptoms as well as reductions in pulmonary and nasal function in the allergic group. No significant changes could be observed in healthy controls. The study shows that SBP in nonasthmatic allergic rhinitis patients results in peripheral blood eosinophilia, and that SBP can induce allergic inflammation in the nose.

Adolescents in clinical remission of atopic asthma have elevated exhaled nitric oxide levels and bronchial hyperresponsiveness (Article)

2000-01-01T00:00:00Z

Symptoms of atopic asthma often decrease or even seem to disappear around puberty. The aim of this study was to investigate whether this so-called clinical remission is accompanied by remission of airway inflammation, since symptoms relapse in a substantial proportion of subjects later in life. To assess indicators of inflammation and/or structural damage of the airways, exhaled nitric oxide (eNO) and bronchial responsiveness to adenosine-5'-monophosphate (AMP) and methacholine (MCh) were determined in 21 subjects in clinical remission of atopic asthma. Clinical remission was defined as complete absence of symptoms of asthma without the use of any medication in the year preceding the study. Results were compared with those of 21 patients with current asthma and 18 healthy control subjects. We found significantly higher eNO values in the remission group than in healthy controls (geometric mean, 18.9 and 1.0 ppb, respectively; p < 0.001) whereas eNO values of the remission group and those of the subjects with current asthma (geometric mean, 21.9 ppb) were similar (p = 0.09). The responsiveness to both AMP and MCh of subjects in clinical remission was significantly higher as compared with responsiveness of healthy controls, and lower than responsiveness of subjects with current asthma. A significant correlation could be established between eNO and responsiveness to AMP, but not between eNO and responsiveness to MCh. The results of this study are suggestive of persistent airway inflammation during clinical remission of atopic asthma. We speculate that subclinical inflammation is a risk factor for asthma relapse later in life, and that eNO and responsiveness to both AMP and MCh can be used as different, noninvasive indices of the inflammatory process of the airways.

The complex relationships between cystic fibrosis and congenital bilateral absence of the vas deferens: clinical, electrophysiological and genetic data (Article)

1999-01-01T00:00:00Z

Congenital bilateral absence of the vas deferens (CBAVD) is found in 1-2% of infertile males and in most male cystic fibrosis (CF) patients. CF and some of the CBAVD cases were found to share the same genetic background. In this study, 21 males with CBAVD had extensive physical and laboratory testing for symptoms of CF. Possible defective cellular chloride transport was measured by interstitial current measurement of rectal suction biopsies. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation analysis was performed for 10 common CFTR mutations. CF-related symptoms were found in six men. On laboratory testing slightly abnormal liver and pancreatic function was found in seven patients. The sweat test was found to be abnormal in four patients; interstitial current measurement showed defective chloride excretion in 11 patients. CFTR gene mutations were found in 66% of the patients: eight were compound heterozygotes; in six, only one common mutation could be detected. The 5T allele in one copy of intron 8 was found in four men. CBAVD appears to be a heterogeneous clinical and genetic condition. A CFTR gene mutation was found in both copies of the allele or interstitial current measurement showed defective chloride excretion in 14/21 cases. Genetic counselling is clearly indicated for couples seeking pregnancy through epididymal or testicular sperm aspiration and intracytoplasmic sperm injection.

Eosinophils in the bronchial mucosa in relation to methacholine dose-response curves in atopic asthma (Article)

1999-01-01T00:00:00Z

Asthma is characterized by both local infiltration of eosinophils in the bronchial mucosa and bronchial hyperreactivity (BHR). A detailed characterization of BHR implies analysis of a histamine or methacholine dose-response curve yielding not only the dose at 20% fall of baseline forced expiratory volume in 1 s (FEV1), but also a plateau (P) representing the maximal narrowing response in terms of percent change in FEV1 and reactivity as the steepest slope at 50% of P (%FEV1/doubling dose). In the baseline condition, the specific airway conductance (sGaw) may be considered closely related to airway lumen diameter. In 20 nonsmoking asthmatic patients, methacholine dose-response curves were obtained, and a sigmoid model fit yielded the BHR indexes. Immunohistochemistry with the monoclonal antibodies (EG1 and EG2) was used to recognize the total number of eosinophils and activated eosinophils, respectively. The number of activated eosinophils was significantly correlated to both P (r = 0.62; P < 0.05) and sGaw (r = -0.52; P < 0.05), whereas weaker and nonsignificant correlations were found for dose at 20% fall of baseline FEV1 and the total number of eosinophils. We conclude that the number of activated eosinophils can be considered a marker of the inflammation-induced decrease of airway lumen diameter as represented by the plateau index and sGaw.

Simulating an integrated critiquing system (Article)

1998-01-01T00:00:00Z

OBJECTIVE: To investigate factors that determine the feasibility and effectiveness of a critiquing system for asthma/COPD that will be integrated with a general practitioner's (GP's) information system. DESIGN: A simulation study. Four reviewers, playing the role of the computer, generated critiquing comments and requests for additional information on six electronic medical records of patients with asthma/COPD. Three GPs who treated the patients, playing users, assessed the comments and provided missing information when requested. The GPs were asked why requested missing information was unavailable. The reviewers reevaluated their comments after receiving requested missing information. MEASUREMENTS: Descriptions of the number and nature of critiquing comments and requests for missing information. Assessment by the GPs of the critiquing comments in terms of agreement with each comment and judgment of its relevance, both on a five-point scale. Analysis of causes for the (un-)availability of requested missing information. Assessment of the impact of missing information on the generation of critiquing comments. RESULTS: Four reviewers provided 74 critiquing comments on 87 visits in six medical records. Most were about prescriptions (n = 28) and the GPs' workplans (n = 27). The GPs valued comments about diagnostics the most. The correlation between the GPs' agreement and relevance scores was 0.65. However, the GPs' agreements with prescription comments (complete disagreement, 31.3%; disagreement, 20.0%; neutral, 13.8%; agreement, 17.5%; complete agreement, 17.5%) differed from their judgments of these comments' relevance (completely irrelevant, 9.0%; irrelevant, 24.4%; neutral, 24.4%; relevant, 32.1%; completely relevant, 10.3%). The GPs were able to provide answers to 64% of the 90 requests for missing information. Reasons available information had not been recorded were: the GPs had not recorded the information explicitly; they had assumed it to be common knowledge; it was available elsewhere in the record. Reasons information was unavailable were: the decision had been made by another; the GP had not recorded the information. The reviewers left 74% of the comments unchanged after receiving requested missing information. CONCLUSION: Human reviewers can generate comments based on information currently available in electronic medical records of patients with asthma/COPD. The GPs valued comments regarding the diagnostic process the most. Although they judged prescription comments relevant, they often strongly disagreed with them, a discrepancy that poses a challenge for the presentation of critiquing comments for the future critiquing system. Requested additional information that was provided by the GPs led to few changes. Therefore, as system developers faced with the decision to build an integrated, non-inquisitive or an inquisitive critiquing system, the authors choose the former.

Inhaled corticosteroids in asthma : effects on inflammation and lung function (Doctoral Thesis)

1997-02-12T00:00:00Z

Many clinicians are frequently confronted with an adolescent who comes to the first aid department in the middle of the night, complaining of breathlessness and chest tightness. While he was in a smoky environment he became wheezy and felt out of breath. After taking some bronchodilator puffs his complaints did not improve but got even worse. Others are more familiar with the picture of the infant, out of breath sitting on the bench during gymnastics whereas other kids are busy doing their exercises. All clinicians will immediately recognize the clinical symptoms of an asthma patient. Bul what exactly is going on wilhin the airways? Asthma is one of the most common disorders, affecting approximately 10% of the population in the Western countries. Asthma, was used to describe several disorders characterized by breathlessness or pain in the chest. Sir John Floyer wrote in his "treatise of the asthma" in 1698: "I have assigned the immediate cause of asthma to the straitness, compression, or constriction of the bronchi". Laennec in the eighteenth century attributed asthma to a spasm of the smooth muscle fibers of the bronchi. In spite of the fact that our knowledge of the disease has increased since then and asthma is now considered as a chronic inflammatory disease, we still do not know the fundamental cause of asthma and all the factors that induce airway inflammation. Airway inflammation in asthma is characterized by redness and swelling of the mucosa. These classical signs of inflammation are easily visible at bronchoscopic examination. Bronchial biopsies not only show activated mast cells, eosinophils and lymphocytes, but also epithelial shedding and fragility. Structural changes include hypertrophy and hyperplasia of airway smooth muscle, and thickening of the basement mem-brane due to the deposition of collagen in the lamina reticularisb.

Is delayed introduction of inhaled corticosteroids harmful in patients with obstructive airways disease (asthma and COPD)? The Dutch CNSLD Study Group. The Dutch Chronic Nonspecific Lung Disease Study Groups (Article)

1996-01-01T00:00:00Z

BACKGROUND: The institution of inhaled corticosteroids is generally advocated for effective treatment of patients with asthma. It is yet unknown what is the best time to start inhaled corticosteroid therapy and especially whether delayed introduction is harmful. PHASE 1: In a previous study in patients with asthma and COPD, we found that 2.5 years of treatment with a beta 2-agonist plus inhaled corticosteroid (BA + CS) was more effective in improving the FEV1 and the provocative concentration of histamine causing a 20% reduction in FEV1 (PC20) than treatment with a beta 2-agonist plus anticholinergic (BA + AC) or placebo (BA + PL). PHASE 2: We extended this study with 6 months to investigate whether delayed introduction of inhaled CS therapy (800 micrograms beclomethasone dipropionate) in the groups previously not treated with inhaled CS (BA +/- AC) could also improve FEV1 and PC20 to the same degree. A distinction was made between patients with predominantly asthma (high baseline reversibility, delta FEV1 > or = 9% of predicted), and predominantly COPD (low baseline reversibility, delta FEV1 < 9% of predicted). RESULTS: Improvement of FEV1 percent predicted by inhaled CS was comparable both in the asthmatics between phase 1 (13.8% predicted) and phase 2 (8.5% predicted; p = 0.31) as well as in the patients with COPD (2.5% and 1.5% predicted, respectively). PC20, however, increased significantly more in the asthmatics in phase 1 (1.77 doubling concentration [DC]) than in phase 2 (0.79 DC; p = 0.03). Improvement of PC20 in the patients with COPD was not significantly higher in phase 1 (0.74 DC) than in phase 2 (0.00 DC; p = 0.19). CONCLUSIONS: Our study indicates that although delayed introduction of inhaled CS in asthmatics leads to similar improvements in FEV1, improvements in PC20 are significantly less. These findings in patients with longer-existing asthma concur with other findings in newly detected asthma. We suggest that institution of inhaled CS therapy should not be postponed in asthmatics with documented airways obstruction and reversibility.

Effects of fluticasone propionate on methacholine dose-response curves in nonsmoking atopic asthmatics (Article)

1996-01-01T00:00:00Z

Methacholine is frequently used to determine bronchial hyperresponsiveness (BHR) and to generate dose-response curves. These curves are characterized by a threshold (provocative concentration of methacholine producing a 20% fall in forced expiratory volume in one second (PC20) = sensitivity), slope (reactivity) and maximal response (plateau). We investigated the efficacy of 12 weeks of treatment with 1,000 microg fluticasone propionate in a double-blind, placebo-controlled study in 33 atopic asthmatics. The outcome measures used were the influence on BHR and the different indices of the methacholine dose-response (MDR) curve. After 2 weeks run-in, baseline lung function data were obtained and a MDR curve was measured with doubling concentrations of the methacholine from 0.03 to 256 mg x mL(-1). MDR curves were repeated after 6 and 12 weeks. A recently developed, sigmoid cumulative Gaussian distribution function was fitted to the data. Although sensitivity was obtained by linear interpolation of two successive log2 concentrations, reactivity, plateau and the effective concentration at 50% of the plateau value (EC50) were obtained as best fit parameters. In the fluticasone group, significant changes occurred after 6 weeks with respect to means of PC20 (an increase of 3.4 doubling doses), plateau value fall in forced expiratory volume in one second (FEV1) (from 58% at randomization to 41% at 6 weeks) and baseline FEV1 (from 3.46 to 3.75 L) in contrast to the placebo group. Stabilization occurred after 12 weeks. Changes for reactivity were less marked, whereas changes in log, EC50 were not significantly different between the groups. We conclude that fluticasone is very effective in decreasing the maximal airway narrowing response and in increasing PC20. However, it is likely that part of this increase is related to the decrease of the plateau of maximal response.

Pressure-volume analysis of the lung with an exponential and linear-exponential model in asthma and COPD. Dutch CNSLD Study Group (Article)

1995-01-01T00:00:00Z

The prevalence of abnormalities in lung elasticity in patients with asthma or chronic obstructive pulmonary disease (COPD) is still unclear. This might be due to uncertainties concerning the method of analysis of quasistatic deflation lung pressure-volume curves. Pressure-volume curves were obtained in 99 patients with moderately severe asthma or COPD. These patients were a subgroup from a Dutch multicentre trial; the entire group was selected on the basis of a moderately lowered % predicted forced expiratory volume in one second (FEV1), and a provocative concentration of histamine producing a 20% decrease in FEV1 (PC20) < 8 mg.mL-1 obtained with the 2 min tidal breathing technique. The curves were fitted with an exponential (E) model and an exponential model which took the linear appearance in the mid vital capacity range into account (linear-exponential (LE)). The linear-exponential model showed a markedly better fit ability, yielding additional parameters, such as the compliance at functional residual capacity (FRC) level as slope of the linear part (b), and the volume at which the linear part changed into the exponential part of the curve (transition volume (Vtr)). Vtr (mean value Vtr/total lung capacity (TLC) = 0.79 (SD 0.07)) showed a close positive linear correlation with obstruction and hyperinflation variables, which might be due to airway closure, already starting at elevated lung volumes. The exponential shape factor K was closely correlated with b and mean values (K = 1.32 (SD 0.05) kPa-1; b = 2.96 (SD 1.16) L,kPa-1) and the relationship with age was comparable with data reported in healthy individuals. The shape factor of the linear-exponential fit showed no correlation with any elasticity related variable. Neither the elastic recoil at 90% TLC, as obtained from the linear-exponential fit, nor its relationship with age were significantly different from healthy individuals. We conclude that, for a more accurate description of the lung pressure-volume curve, a linear-exponential fit is preferable to an exponential model. However, the physiological relevance of the shape parameter (KLE) is still unclear. These results indicate that patients with moderately severe asthma or COPD had, on average, no appreciable loss of elastic lung recoil as compared with healthy individuals.