Inhaled corticosteroids in asthma : effects on inflammation and lung function

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

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

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

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

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

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

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

Dyspnoea perception during clinical remission of atopic asthma

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

Segmental bronchial provocation induces nasal inflammation in allergic rhinitis patients

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 epitheliu

Simulating an integrated critiquing system

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

Increased numbers of dendritic cells in the bronchial mucosa of atopic asthmatic patients: Downregulation by inhaled corticosteroids

Background. Dendritic cells (DC) are the most potent antigen-presenting cells (APC) and stimulators of T cells. Dendritic cells are also likely to be essential for the initiation of allergic immune responses in the lung. However, there are not many data on the presence of dendritic cells in the airways of patients with atopic asthma and on the effects of corticosteroid-treatment on such dendritic cells. Objective. We investigated the distribution of dendritic cells in the bronchial epithelium and mucosa of 16 non-smoking atopic asthmatic patients and eight healthy control subjects using detailed immunohistochemistry (CD1a, HLA-DR, L25 as markers for dendritic cells). Methods. Eleven asthmatics were treated for 2.5 years with bronchodilators only and five with bronchodilators and inhaled beclomethasone dipropionate (BDP), 800 μg daily. The patients were randomly sampled from a double-blind multicentre study. Results. There were higher numbers of CD1a+ DC (P = 0.003), L25+ DC (P = 0.002) and HLA-DR expression (P = 0.042) in the bronchial mucosa of asthmatic patients compared with healthy controls. After 2.5 years of treatment, we found a significant increase in flow expiratory volume in 1 second (FEV1) (P = 0.009) and a significant decrease in hyperresponsiveness (PC20 histamine) (P = 0.013) in the corticosteroid group (n = 5) compared with the bronchodilator group (n = 11). This clinical improvement in the corticosteroid-treated group was accompanied by significantly lower numbers of CD1a+ DC (P=0.008), and HLA-DR expression (P=0.028) in the bronchial mucosa than in the bronchodilator-treated group. Conclusion. Our data suggest that dendritic cells are involved in asthmatic inflammation and that corticosteroids may downregulate the number of dendritic

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

Mast cells and basophils are cells that play an important role in the initiation and control of allergic inflam