Asymptomatic airway hyperresponsiveness: a curiosity or an opportunity to prevent asthma?
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Asthma↗
Biomedical subjects
Louis-Philippe Boulet
Publications and source records attributed to Louis-Philippe Boulet.
Physiopathology of airway hyperresponsiveness.
Airway hyperresponsiveness (AHR), the tendency of the airways to narrow too much and too easily in response to various stimuli, is a universal feature of asthma, although it is not exclusive to this disease. Airway responsiveness shows a unimodal distribution in the general population and might vary with time, increasing after exposure to allergens, industrial substances, or infectious agents in predisposed individuals, or decreasing for variable time periods after environmental or pharmacologic interventions. Airway inflammation and structural airway changes can lead to this heightened airway response, but the mechanisms by which they modify airway function are still unclear. They might be associated with increased contractile properties of the airways--from an increase in contractile elements, a change in smooth muscle mechanical properties, or a reduction of forces opposing bronchoconstriction, such as reduced airway-parenchymal interdependence. Other factors, such as neurohumoral influences and "geometric factors" (eg, airway caliber), can modulate the degree of AHR.
Asthma↗
Prevalence of respiratory symptoms in an athlete population.
This study aimed to look at the prevalence and type of respiratory symptoms experienced by athletes and to assess the possible influence on the perception of symptoms of training duration and environment. A group of 698 athletes (107 with diagnosed or self-reported asthma) filled out a questionnaire on their respiratory condition. They exercised either in cold air (n = 176), dry air (n = 384), humid air (n = 95) or mixed dry and humid air (n = 43). Past exercise-related symptoms reported by athletes were breathlessness (48.7%), phlegm production (22.8%), wheezing (15.6%), cough (15.2%), and chest tightness (7.4%). Only 25% of asthmatic athletes reported having current exercise-induced symptoms of breathlessness, 21.7%, wheezing and 17.4%, chest tightness; current exercise-induced symptoms of breathlessness, wheezing or chest tightness were also reported, respectively, in 38.9%, 3.6% and 2.7% of athletes without a diagnosis of asthma. The perception of exercise-induced symptoms was not influenced by the duration of training or environment. In conclusion, (1) a minority of asthmatic athletes report troublesome respiratory symptoms with exercise, (2) breathlessness is not more frequently reported in asthmatic athletes than in those without such diagnosis while cough and wheezing are more common in asthmatic subjects and (3) the prevalence of respiratory symptoms is independent of training environment and duration of training.
Adult↗
Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TGF-beta, IL-11, IL-17, and type I and type III collagen expression.
BACKGROUND: Important features of airway remodeling in asthma include the formation of subepithelial fibrosis and increased deposition of types I and III collagen. TGF-beta, IL-11, and IL-17 are profibrotic cytokines involved in the formation of subepithelial fibrosis and are increased in patients with asthma, particularly in those with severe disease. OBJECTIVE: The purpose of this study was to investigate the effect of corticosteroids on the expression of these profibrotic cytokines and on extracellular matrix deposition. METHODS: We used immunocytochemistry to measure the expression of TGF-beta, IL-11, IL-17, and collagen types I and III in the airways of patients with mild asthma (n = 9), patients with moderate-to-severe asthma (n = 10), and control subjects without asthma (n = 6). Baseline bronchial biopsy specimens were obtained in all groups. In addition, repeat biopsies were obtained in the patients with moderate-to-severe asthma after a 2-week course of oral corticosteroids. RESULTS: TGF-beta expression was significantly higher in all groups with asthma, and it did not decrease after treatment with oral corticosteroids. Levels of IL-11 and IL-17 were increased in patients with moderate-to-severe asthma compared with patients with mild asthma and normal controls (P <.05). The expression of these cytokines decreased with oral corticosteroids in the moderate-to-severe group to levels that were comparable to those seen in the patients with mild asthma and in the normal controls (P <.005). Expression of types I and III collagens was higher in the patients with moderate-to-severe asthma than in the patients with mild asthma and the controls (P <.05; P <.001). Treatment with corticosteroids did not decrease the expression of types I and III collagens. CONCLUSIONS: These results confirm the association of increased levels of TGF-beta, IL-11, IL-17, and types I and III collagens with severe disease and suggest that the failure of cortico-steroids to decrease collagen deposition might be due to persistently elevated TGF-beta expression.
Administration, Oral↗
The effects of an anti-CD11a mAb, efalizumab, on allergen-induced airway responses and airway inflammation in subjects with atopic asthma.
BACKGROUND: Efalizumab is a humanized IgG(1) mAb against the lymphocyte function antigen-1 (LFA-1) alpha chain, CD11a. Blocking of LFA-1/intercellular adhesion molecule interactions could inhibit asthmatic inflammation by blocking adhesion and activation of LFA-1-positive leukocytes. OBJECTIVE: A randomized, double-blinded, placebo-controlled, parallel group, multicenter study investigated the effects of efalizumab on allergen-induced airway responsiveness and airway inflammation. METHODS: Thirty-five nonsmoking subjects with mild allergic asthma were randomized to receive efalizumab (n = 24) or placebo (n = 11) in 8 weekly subcutaneous doses (0.7 mg/kg conditioning dose followed by 7 weekly doses of 2.0 mg/kg). Allergen challenges were performed at screening and after 4 and 8 weeks of treatment. Samples of sputum (n = 18 subjects) and blood (n = 35 subjects) were collected the day before challenges, and sputum was collected again at 7 and 24 hours after each challenge. Nonparametric tests were used to compare allergen-induced differences between efalizumab and placebo groups. RESULTS: Subjects receiving efalizumab developed headache (48%) and flu syndrome (28%) compared to subjects receiving placebo (0%). After 8 weeks of efalizumab, the maximum late percent fall in FEV(1) (late asthmatic response) was inhibited by 50%, but neither the late response nor the late area under the curve was statistically different than placebo (P =.098 and.062, respectively). Efalizumab had no effect on the maximum early percent fall in FEV(1) (early asthmatic response) or early area under the curve compared to placebo (P >.59). Efalizu-mab significantly reduced the postallergen increase in sputum EG2-positive cells and metachromatic cells (P <.05). No other comparisons were statistically different. CONCLUSIONS: Blocking of LFA-1/intercellular adhesion module interactions by efalizumab inhibits the development of allergen-induced cellular inflammatory responses measured in induced sputum and might attenuate the late asthmatic response. Larger studies are needed to confirm this.
Adult↗
Are questionnaires on respiratory symptoms reliable predictors of airway hyperresponsiveness in athletes and sedentary subjects?
This study aimed at determining the frequency of respiratory symptoms in high-level athletes and whether respiratory questionnaires are reliable predictors of airway hyperresponsiveness (AHR) in this population compared with control subjects. One hundred high-level athletes exercising in different conditions of ambient air (dry, humid, cold or mixed dry and humid) and 50 sedentary control subjects answered four question sets on exercise-induced symptoms of postnasal drip (Q1), breathlessness, chest tightness and wheezing (Q2), and cough (Q3). Another question set (Q4) evaluated the self-description of nociceptive sensations associated with respiratory symptoms. Methacholine inhalation tests were performed in all subjects to obtain a 20% fall in forced expiratory volume in 1 second (PC20). AHR could be detected by questionnaires in 37 of 44 (84%) subjects with a PC20 < 8 mg/mL. Sensitivity to detect AHR varied between the different subgroups of athletes with each of the question sets; however, no significant differences in sensitivity were observed between the groups of athletes and controls except for Q3 (P=.007), in which athletes exercising in cold air reported more exercise-induced cough. Q2 had a better specificity (83%) than Q3 (77%) and Q4 (64%). Combined question sets revealed that three swimmers, two triathletes, and two controls, who answered negatively to all question sets, had a PC20 < 8 mg/mL. Questionnaires on symptoms and on associated nociceptive sensations may help to detect AHR as well in athletes and controls, although for some subgroups of athletes such as swimmers and triathletes and in some controls, false negative questionnaires can be observed and AHR underreported.
Adult↗
The relationships between atopy, rhinitis and asthma: pathophysiological considerations.
PURPOSE OF REVIEW: A close relationship has been described between atopy, allergic rhinitis and asthma. The purpose of this work was to review recent data that have become available on the interactions between these conditions and the ways in which they influence one another. RECENT FINDINGS: Recent findings support previous observations suggesting that atopic dermatitis and rhinitis often accompany or precede the development of asthma. Further data support the notion that early-life exposure to domestic animals, a farming environment, passive smoking, and being raised in a large family, may be protective against the development of atopy and/or allergic diseases, although this seems modulated by genetic factors. Furthermore, the appearance of house-dust-mite-specific immunoglobulin E antibodies in early childhood has been identified as a major risk factor for the development of asthma in children with atopic dermatitis; and the association between sensitization to specific allergens and airway hyperresponsiveness was reported to be the strongest for indoor allergens such as house-dust-mite and cat. Allergen exposure can increase airway responsiveness in non-asthmatic subjects with allergic rhinitis and is associated with an increase in markers of lower airway inflammation, particularly with indoor allergens. Furthermore, nasal allergen provocation can induce bronchial inflammation and vice versa, suggesting close interrelations between upper and lower airways. SUMMARY: In summary, the recent observations on the relationships between atopy, rhinitis and asthma support the hypothesis of a unique systemic condition with variable manifestations, which may develop following an imbalance between T helper cell types 1 and 2 lymphocyte populations. The latter may be influenced by environmental exposure in early life. Upper- and lower-airway inflammatory events influence each other, supporting the concept of 'united airways'. Further studies should look at the relationships between these conditions to identify individuals at high-risk of developing them and develop strategies to possibly prevent their onset.
Adult↗
Airway response to low-dose allergen exposure in allergic nonasthmatic and asthmatic subjects: eosinophils, fibronectin, and vascular endothelial growth factor.
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Allergens↗
Should combination therapy with inhaled corticosteroids and long-acting beta2-agonists be prescribed as initial maintenance treatment for asthma?
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Adrenergic beta-Agonists↗
Diisocyanate antigen-stimulated monocyte chemoattractant protein-1 synthesis has greater test efficiency than specific antibodies for identification of diisocyanate asthma.
We previously reported that diisocyanate-human serum albumin (DIISO-HSA) stimulated production of monocyte chemoattractant protein-1 (MCP-1) by peripheral blood mononuclear cells is significantly associated with a clinical diagnosis of diisocyanate asthma (DA). Others have reported that antibodies for DIISO-HSA are specific but insensitive markers of DA. This study was performed to evaluate test characteristics of the in vitro MCP-1 assay compared with DIISO-HSA-specific immunoglobulin (Ig) G and IgE in identifying workers with DA. MCP-1 was quantitated in peripheral blood mononuclear cell supernatants 48 hours after incubation with DIISO-HSA antigens. Assay results were compared with outcomes of specific inhalation challenge (SIC) testing. Nineteen of 54 (35%) workers assayed for antibodies and MCP-1 stimulation had SIC-confirmed DA. Mean MCP-1 produced by SIC-positive workers was greater than SIC-negative workers (p < or = 0.001). Diagnostic sensitivity, specificity, and test efficiency for specific IgG were 47%, 74%, and 65%, respectively, and for specific IgE were 21%, 89%, and 65%, respectively. Sensitivity, specificity, and test efficiency of the MCP-1 test were 79%, 91%, and 87%, respectively. This study indicates that the MCP-1 stimulation assay has greater sensitivity and specificity than the specific antibody assays in correctly identifying DA.
Adult↗
Correlation between airway responsiveness and proteoglycan production by bronchial fibroblasts from normal and asthmatic subjects.
Asthma is characterized by an airway remodeling process involving altered extracellular matrix deposition such as collagen, fibronectin and proteoglycans. Proteoglycans determine tissue mechanical properties and are involved in many important biological aspects. Not surprisingly, it has been suggested that proteoglycan deposition may alter airway properties in asthma including airway hyperresponsiveness. In chronically inflamed airway tissues, fibroblasts likely represent an activated fibrotic phenotype that contributes to the excessive deposition of different extracellular matrix components. To investigate whether this was the case for proteoglycans, the production of hyaluronan, perlecan, versican, small heparan sulphate proteoglycans (HSPGs), decorin and biglycan was quantified in the culture medium of primary bronchial fibroblast cultures, established from four normal and six asthmatic subjects. Values were further correlated to the airway responsiveness (PC(20) methacholine) of donor subjects. Fibroblasts from subjects with the most hyperresponsive airways produced up to four times more total proteoglycans than cells from subjects with less hyperresponsive or normoresponsive airways. We observed a significant negative correlation between the PC(20) and perlecan, small HSPGs and biglycan, while such correlation was absent for decorin and close to significant for hyaluronan and versican. Altered proteoglycan metabolism by bronchial fibroblasts may contribute to the increased proteoglycan deposition in the bronchial mucosa and to airway hyperresponsiveness characterizing asthma.
Asthma↗
Effects of a selective ET(A)-receptor antagonist, atrasentan (ABT-627), in murine models of allergic asthma: demonstration of mouse strain specificity.
Asthma is a chronic respiratory disease that is characterized by airway inflammation, bronchoconstriction and the influx of pro-inflammatory cells, mostly eosinophils in the lung tissue and bronchoalveolar space. Amongst the many physiopathological roles attributed to endothelins (ETs), one is to modulate pulmonary functions. It is established that Balb/c mice develop allergen-induced Th(2)-cytokine gene expression, airway inflammation and hyper-responsiveness whereas C57Bl/6 mice are much less reactive. In the present study, we investigated the roles of ETs in these two murine models of allergic asthma (AA). Mice were sensitized and challenged with either saline (S) and/or ovalbumin (O) over 6 weeks (groups S/S and O/O) and treated chronically with ABT-627 or its vehicle. Twenty-four hours after the last sensitization, challenged mice developed a marked airway inflammatory response characterized by the accumulation of total inflammatory cells (a 21-fold increase) in the bronchoalveolar space, similar in both mouse strains. The increase in eosinophils was marked in both groups, representing 98% of total cell count in O/O versus <1% in S/S. Macrophages were also increased 3-fold in both strains. ABT-627 did reduce the accumulation of macrophages in both stains (36 to 53%) whereas it blocked by 76% the influx of eosinophils in Balb/c but not in C57Bl/6 mice. These results show that ET(A)-receptor antagonism is more effective against O/O-induced AA in Balb/c mice, even though both strains were associated with the same increase in key pro-inflammatory cells in the bronchoalveolar space. It is unclear whether this is due to a lack or a disproportionate expression of ET(A) receptors in these two murine strains, or in post-receptor transduction modulation, or different regulation of ET receptors in various pulmonary cells, after sensitization and challenge.
Animals↗
Towards excellence in asthma management (TEAM): a populational disease-management model.
Asthma management is not always optimal, and deficiencies such as inadequate treatment and insufficient patient education are often reported. Towards Excellence in Asthma Management (TEAM) is a four-phase disease management program of the Quebec Asthma Education Network (QAEN), to be carried out over a 5-year period. The program aims to achieve a continuous improvement of asthma management by caregivers and patients. The first phase, completed in January 2000, consisted of determining the actual level of asthma-associated morbidity and mortality in various Quebec regions. The second phase, which began in September 1999, included three parts: 1. Definition of the burden of asthma, taking into account the socioeconomic consequences of the disease and the quality of life of the patients, 2. Comparison of current medical practices with the Canadian Asthma Consensus Guidelines for adult and pediatric populations, 3. Evaluation of the level of compliance with medical treatment and with the environmental changes recommended to asthmatic patients. This phase is carried out via a cohort study of physicians, mainly general practitioners and pediatricians, generating a patient cohort study, in addition to substudies evaluating specific aspects of asthma care. Once the care gap is identified, it will be possible to define, apply, and evaluate a series of interventions for physicians, other health professionals, and patients. The interventions will be particularly targeted at regions where asthma incidence and morbidity are higher. We hope that this model of disease management will progressively reduce the burden associated with asthma, and potentially other chronic diseases, and will result in the more effective use of health services.
Asthma↗
Influence of natural exposure to pollens and domestic animals on airway responsiveness and inflammation in sensitized non-asthmatic subjects.
BACKGROUND: Atopy may be a risk factor in the development of asthma. Indoor allergens are considered to be more potent asthma inducers than outdoor ones such as pollens. Lower airway inflammation may be present in non-asthmatic subjects during natural exposure to relevant allergens and may eventually lead to the development of asthma. AIMS: To document seasonal variation in lower airway responsiveness and inflammation in sensitized non-asthmatic subjects, during natural exposure to allergens, and to determine whether it is more marked in those exposed to animals to which they are sensitized. METHODS: Twenty-two atopic subjects were seen during and out of the pollen season. All (but the controls) were sensitized to domestic animals, and to trees, grasses or ragweed. Eleven were not exposed to animals at home and 8 were exposed. They were compared with 3 normal controls. A respiratory questionnaire was administered, allergy skin prick tests, spirometry, methacholine challenge, blood and induced sputum with differential cell counts were obtained during the pollen season for all subjects. These tests were repeated out of the pollen season. RESULTS: Throughout the study, none of the subjects had asthma symptoms. Mean PC(20) was significantly lower in subjects exposed to animals compared with unexposed subjects or controls, both during and out of the pollen season. In season, subjects exposed to animals had significantly higher sputum eosinophil numbers than unexposed or normal control subjects. CONCLUSIONS: Non-asthmatic atopic subjects show variable degrees of airway responsiveness and inflammation. However, subjects exposed to animals show higher airway eosinophilia, which may suggest they are at increased risk of developing airway hyperresponsiveness and asthma.
Adolescent↗
How should we quantify asthma control? A proposal.
BACKGROUND: Current asthma guidelines suggest a series of criteria to assess if asthma is controlled. However, there is a need to develop a simple and practical method to quantify the degree of such control, both in clinical practice and research. STUDY OBJECTIVES: This report describes a new method to quantify asthma control based on a percentage score. It also aims at comparing the percentage scores obtained with patient's self-evaluation of asthma control and a current validated Mini Asthma Quality of Life (MAQOL) questionnaire. SETTING AND SUBJECTS: Forty-two subjects (25 female and 17 male patients) with asthma of different severity recruited from a tertiary center asthma clinic. METHODS: The asthma scoring method provided a percentage control for symptoms, baseline expiratory flows and, an optional parameter, for airway inflammation assessed from induced-sputum eosinophil count. These control parameters were compared to an overall assessment of asthma control by the patient (also on a 100% scale) and the score obtained from a validated MAQOL questionnaire. RESULTS: Mean +/- SEM scores for symptoms, expiratory flows, and airway eosinophilia (last 2 weeks) were 87.8 +/- 1.4%, 88.6 +/- 1.8%, and 66.2 +/- 3.9%, respectively. No significant correlation was found between these three parameters (p > 0.05). The mean global asthma control score and the score estimated by the patient were 80.9 +/- 1.5% and 91.7 +/- 1.5%, respectively (not significantly different). There was a significant correlation between asthma control score (percentage) and percentage symptom score (p < 0.001), while it almost achieved significance for FEV(1) (p = 0.05). Only symptom scores correlated with the MAQOL questionnaire. CONCLUSIONS: We developed a simple easy-to-use asthma control scoring system based on a percentage of optimal control. The percentage symptom score but not the global control score of this new method correlated with patient's global assessment of asthma control. This could be a simple tool that is potentially useful both for the clinician and for research purposes, to quantify global or specific aspects of asthma control.
Asthma↗
Evaluation of asthma control by physicians and patients: comparison with current guidelines.
BACKGROUND: Current asthma consensus guidelines recommend a series of criteria for determining whether asthma is controlled. It is not known whether physicians are using these criteria to assess treatment needs and how effective such assessments are compared with patient assessment of asthma control. OBJECTIVE: To compare the parameters used by physicians and patients with asthma to determine whether asthma control is acceptable, according to the current Canadian asthma consensus guidelines. DATA AND METHODS: A total of 183 Canadian physicians, mostly general practitioners, evaluated 856 patients with mildly to moderately uncontrolled asthma who were not using anti-inflammatory medications at the time of entry in the study. Physician characteristics and patient demographics were obtained. The physicians completed two questionnaires, one assessing the level of asthma control of the patient on an ordinal scale from 1 (very poor) to 5 (very good) and another indicating the parameters that were used to evaluate this level of control. Patients answered an asthma control questionnaire identical to the one completed by the physician and completed a six-question asthma control questionnaire, with each question scored on a 0- to 6-point scale. RESULTS: Although according to current asthma guidelines all patients surveyed had uncontrolled asthma, 66.2% of patients and 43.3% of physicians rated control of asthma symptoms as adequate to very good. The average scores for patient- and physician-rated asthma control were 3.0 0.2 and 2.6 0.2, respectively. The average patient score on the Juniper asthma questionnaire was 12.2 6.3. Physicians used a mean of seven parameters to assess the patient's level of asthma control, mostly beta2-agonist need, followed by cough, wheezing, shortness of breath, limitation of physical activities and night-time awakenings. Pediatricians used cough more frequently as an evaluation parameter, and respirologists measured pulmonary function more often than other physcians. Some parameters not usually included in guideline criteria for control, such as fatigue, need to clear throat, colored sputum, headache and dizziness, were sometimes used by physicians. Only 10% and 18% of physicians used measurements of forced expiratory volume in 1 s and peak expiratory flow, respectively, in asthma control assessments. CONCLUSIONS: The present study shows that the selection of asthma control criteria among physicians varies and is not always in keeping with current asthma guidelines. Both patients and physicians often consider asthma to be controlled, when according to current guidelines, it is not, and patients consider their asthma better controlled than do physicians. Objective measures of airflow obstruction are rarely used to assess asthma control. The present study stresses the need for improved dissemination - to both patients and physicians - of current recommendations on how asthma control should be determined.
Adolescent↗