Limited short-term steroid responsiveness is associated with thickening of bronchial basement membrane in severe asthma.

BACKGROUND: The clinical manifestations of bronchial remodeling in asthma and the potential impact of this process on lung function remain unclear. We aimed to determine whether the presence of pathologic features of airway remodeling in patients with asthma was associated with steroid responsiveness in the short term. METHODS: Sixty-three consecutive patients with severe asthma with chronic airflow impairment (post-bronchodilator FEV(1) < 80% predicted values) were recruited, clinically characterized, and had an initial bronchoscopy where endobronchial biopsy and BAL were performed. BAL cellular content was reported and reticular basement membrane (RBM) thickness was measured by validated repeated measures. Patients were then treated with 1 mg/kg/d of methyl prednisone, directly administered IV, for 10 days. A threshold of 15% FEV(1) improvement was used to discriminate responsive (group 1) and refractory patients (group 2). RESULTS: Thirty-eight patients had a steroid responsiveness > 15% (group 1) and a thinner RBM at the biopsy level (5.78 ± 2.0 µm vs 7.60 ± 2.2 µm; P = .001) compared with nonsteroid responsive group 2 patients as defined. The best predictors for being unresponsive were no long-term treatment with oral steroids and increased RBM thickness. The associated receiver operating characteristic curve indicated that RBM thickness could predict steroid responsiveness below 15% with an area under the curve of 0.747 (P = .0002) at a threshold of 7 µm. CONCLUSIONS: Features of airway remodeling are associated with limited short-term steroid responsiveness in severe asthma.

Severe asthma and adherence to peak flow monitoring: longitudinal assessment of psychological aspects.

BACKGROUND: Adherence in severe asthma is a difficult health problem. Although psychosocial factors may be responsible for non-adherence, few longitudinal studies have investigated their link with adherence, with most studies having focused on pharmacology. METHODS: Sixty patients with severe asthma were recruited. Adherence was electronically monitored using peak flow measurements at entry and after 1 year of follow-up. Eysenck's Personality Inventory, Rotter's Locus of Control (LOC), and health control beliefs were all studied. Multiple logistic regression (MLR) was used for risk calculations. RESULTS: Initially, subjects with poor adherence had an external LOC (P=.001) and a high extraversion score (P=.003) compared to those with good adherence. The lie score was high in all patients. Nocturnal awakenings were highly significantly correlated with poor adherence (P=.006). After 1 year, patient adherence, extraversion, and neuroticism remained unchanged. The LOC changed in subjects with poor adherence, showing a less "external" orientation (P=.007). The health parameters were better at the end of the study. By MLR analysis, externality, extraversion, and low social desirability were associated with poor adherence. Patients with poor adherence had a greater probability of nocturnal symptoms. CONCLUSION: No specific personality type was associated with lack of adherence in the present study, but a high extraversion score, a low social desirability score, and a high level of externality were all predictors of poor adherence.

Impact of rhinitis on asthma control in children: association with FeNO.

BACKGROUND: The prevalence of rhinitis is high and frequently observed in association with asthma. Although the persistence of predisposing factors such as rhinitis is frequently observed in adults, this has not yet been confirmed in children. AIMS: The aim of this present work is to show the relationship between rhinitis and asthma control in asthmatic children. METHODS: The authors carried out a cross-sectional study by collecting clinical, spirometric, and fractional exhaled nitric oxide (FeNO) data in children aged from 4 to 17 years. RESULTS: One hundred seventeen children were included. Asthma control was optimal in 37.6%, suboptimal in 55.5% and poor in 7.3% of cases. A 74.3% of children were atopic and 62.5% had symptoms 34 of rhinitis. Rhinitis was more frequent when control of asthma was worse (p = .0001). Age (p = .002), asthma control (p < .001), atopy (p = .001), and presence of rhinitis (p = .012) were significantly associated with FeNO. CONCLUSIONS: Our study confirms the strong relationship between upper airways and poor asthma control in the asthmatic child. Symptoms of rhinitis may be partly responsible for the increased fractional exhaled nitric oxide (FeNO) level, independently of the control of asthma. Evaluation of rhinitis should be included to improve assessment of asthma control in children.

Mild asthma in overweight women: A new phenotype?

BACKGROUND: Epidemics of asthma and overweight have been linked recently. They might be associated with systemic inflammation. In asthma hyperresponsiveness to adenosine (AMP) is more closely related to inflammation than to methacholine (MCh). The aim of the study was to determine responsiveness to AMP and MCh in overweight compared with normal weight asthmatics. METHODS: Thirty women were enrolled (19 overweight) with mild controlled asthma according to GINA. A Body Mass Index (BMI) less than 25kg/m(2) was considered as normal and a BMI above 25kg/m(2) as overweight. We assessed the recent control of asthma (ACQ), pulmonary function tests, bronchial responsiveness to MCh and AMP (PC(20) and O'Connor two-point dose-response slope), perception of symptoms (Borg scale), and blood inflammatory markers (leptin and hs-CRP by ELISA). RESULTS: Overweight had a significant lower dose-response slope of the MCh challenge (p=0.009) as compared to normal weight patients, whereas no significant difference was observed for AMP challenge (p=0.27). Overweight patients had higher intercepts of the Borg scale measured before the MCh and AMP challenge tests (p=0.01 and p=0.03). Plasma leptin (p=0.001) and hs-CRP (p=0.05) concentrations were higher in overweight than normal weight patients. There was no correlation between challenges and inflammatory markers. CONCLUSIONS: Overweight asthmatic women have more pronounced systemic inflammation, but are less responsive to MCh. AMP responsiveness appeared to be comparable between both groups. Our findings suggest that overweight asthmatic women do not feature increased airway inflammation, but do represent a distinct phenotype as compared to normal weight patients.

Regulation of CXCR/IL-8 in human airway epithelial cells.

BACKGROUND: Severe asthma is characterized by neutrophilic inflammation and high levels of interleukin (IL)-8. Airway epithelial cells play a pivotal role in the pathogenesis and chronicity of asthma. The objective of this work was to determine whether CXC receptors were involved in human small airway epithelial cell (SAEC) activity by incubating them with IL-8; the investigation also included a proteomic approach. METHODS: IL-6 and intercellular adhesion molecule-1 (ICAM-1) were assessed by ELISA and flow cytometry, respectively. CXCR-1 and CXCR-2 receptor mRNA and protein expressions were analyzed by RT-PCR, immunocytochemistry and flow cytometry. Cells were incubated with different concentrations (0-100 ng/ml) of IL-8. The involvement of both receptors was assessed using specific antibodies. RESULTS: Only the CXCR-1 receptor was expressed in SAECs. IL-8 (50 ng/ml, 12 h) induced the release of IL-6 and had no effect on ICAM-1. Supernatants analyzed by surface enhanced laser desorption ionization time of flight mass spectrometry (SELDI-TOF MS) showed very weak differences in peptide profiles. Interestingly, 4,820-m/z peptide release was detected in the presence of IL-8 and abolished by CXCR-1 antibody. DISCUSSION: The present study illustrated the fact that IL-8 mediated by CXCR-1 increased IL-6. We also highlight the usefulness of SELDI ProteinChip technology to confirm the potential variation of peptide profile. Moreover, we were able to detect the 4,820-m/z peptide secreted in vitro by human airway epithelial cells induced by IL-8 via CXCR-1 receptor. Determination of the protein secretion profile in response to inflammatory stimuli could be an important therapeutic strategy in severe asthma.

[Treatment education for patients with asthma]. / Education thérapeutique du patient asthmatique.

Randomized studies show that the best results come from patient-focused educational programs based on self-management (written and individualized action plan, self-monitoring, and regular medical review). The simple provision of information about asthma does not improve health outcomes. Teenagers with asthma are the most fragile patients, because of the lack of specific management for them. Repeated sessions are recommended and educational programs, started in childhood, might make it possible to prevent or at least decrease the risks of non-adherence during adolescence. The absence of consensus on educational interventions impedes the legibility of their impact.

Thiazolidinediones induce proliferation of human bronchial epithelial cells through the GPR40 receptor.

Thiazolidinediones (TZDs) are synthetic peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands that are widely used in type II diabetes treatment. In addition to their ability to improve glucose homeostasis, TZDs possess anti-inflammatory properties and inhibit growth of many cells, particularly cancerous airway epithelial cells. However, the functional effects of PPARgamma ligands on nonmalignant human bronchial epithelial cells have never been investigated. In the present study, we questioned whether PPARgamma ligands may regulate proliferation of human bronchial epithelial cells, and we studied their potential molecular mechanisms. We found that synthetic PPARgamma agonists, rosiglitazone (RGZ) and troglitazone (TGZ), induced proliferation of human bronchial epithelial cells, whereas the endogenous PPARgamma ligand, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), inhibited cell growth. RGZ and TGZ (10 microM) induced a rapid and transient intracellular Ca(2+) mobilization from thapsigargin-sensitive intracellular stores, whereas 15d-PGJ(2) (5 microM) did not induce any Ca(2+) signal. The PPARgamma antagonist GW-9662 did not inhibit any biological responses, but it reversed the effect of 15d-PGJ(2) on cell growth. Using RT-PCR, we detected mRNA expression of the GPR40 receptor, a G protein-coupled receptor recently identified as a receptor for free fatty acids and TZDs, in human bronchial epithelial cells. Downregulation of GPR40 by small-interfering RNA led to a significant inhibition of TZD-induced Ca(2+) mobilization and proliferation. This study provides evidence for the proliferative effect of anti-diabetic drug TZDs in nonmalignant human bronchial epithelial cells through GPR40 receptor activation, involving an intracellular Ca(2+) signaling pathway.

The Asthma Insights and Reality in the Maghreb (AIRMAG) study: perspectives and lessons.

Asthma is the most frequently encountered allergic respiratory disease, and one that has a potentially serious impact on patients' functioning and well-being. From a public health perspective, it is important to collect data on the prevalence, burden and management of asthma in order to improve understanding of the pathogenesis of asthma and to ensure that national healthcare policies are adapted and appropriate. In this respect, the different AIR surveys, which have collected standardised data on asthma in the general population of a large number of countries around the world, have made an important contribution. The latest of these surveys is the AIRMAG survey, performed in the three Maghreb countries of Algeria, Morocco and Tunisia. In these countries, the prevalence of asthma (3.4% to 3.9%) is in the low to moderate range. This is consistent with rates observed elsewhere in the Mediterranean basin. Nonetheless, the prevalence of asthma in the Maghreb may be expected to rise in the future as populations become more urbanized and adopt a more 'Westernized' lifestyle. Indeed the prevalence of asthma is already higher in the urban coastal regions of these countries than in the more rural mountainous and desert regions. Asthma control in the Maghreb is relatively poor compared to other regions evaluated in previous AIR studies, with control being unacceptable in around three-quarters of respondents. Although part of the explanation may reside in limited access to care, treatment rates for inhaled corticosteroids (26.1% of adults and 29.1% of children) were no worse than those reported in previous AIR studies. On the other hand, asthma monitoring through regular follow-up visits, home flow-meter use and preparation of individualised asthma management plans was in general unsatisfactory. In addition, awareness of asthma in the general population of the Maghreb countries was low. Education measures directed at the patient, together with programmes directed at the physician to ensure systematic monitoring and the use of a 'treat to target' approach to therapy, could do much to increase quality of life and minimise restrictions on activities in patients with asthma in the Maghreb.

Maintaining asthma control in persistent asthma: comparison of three strategies in a 6-month double-blind randomised study.

UNLABELLED: In patients controlled with SFC250 Diskus bd, this double-blind, randomised 6-month study compared continuing SFC250 to stepping down to either SFC100 bd or FP250 bd. Six hundred and three patients previously using 1,000 microg BDP (or equivalent) daily +LABA and controlled according to investigator's judgement were recruited. Patients received SFC250 bd during an 8-week open run-in period. Four hundred and seventy six patients (mean age=43 years, mean FEV(1)=2.9+/-1.0) who fulfilled the randomisation criterion ('Well-controlled' asthma according to the GOAL weekly definition for the last 2 weeks of the run-in period) entered a 24-week treatment period. The statistical hypothesis was based on a non-inferiority of SFC100 or FP250 compared to SFC250. The main criterion was the change from baseline in morning PEF over weeks 1-12 in the per-protocol population. The non-inferiority limit was -15 L/min. At inclusion, the three treatment groups were well balanced. Mean morning PEF was 476, 470 and 465 L/min in the SFC250, SFC100 and FP250 groups, respectively. The adjusted mean change in morning PEF over weeks 1-12 was +1.76+/-2.43 L/min for SFC250, -3.07+/-2.32 L/min for SFC100 and -16.51+/-2.46 L/min for FP250. SFC100 was at least as effective as SFC250 (treatment difference -4.83 [-12.39; 2.72], p=0.151) whereas FP250 was not (treatment difference -18.27 [-26.05; -10.49], p<0.001). Similar results were observed over weeks 13-24 in morning PEF (SFC100-SFC250=-4.54+/-3.84, p=0.238; FP250-SFC250=-20.11+/-3.92, p<0.0001). Secondary endpoints showed a similar pattern. Over weeks 1-12, SFC250 was significantly more effective than FP250 on evening PEF, daily symptoms and bronchodilator use. There was no difference between SFC100 and SFC250. The mean annual rate of moderate exacerbations was 0.16 in both SFC 250 and SFC 100 groups, and 0.21 in FP 250 group (ns, Poisson analysis). All treatments were well tolerated. CONCLUSION: In patients achieving asthma control with SFC250, stepping treatment down with SFC100 was at least as effective on lung function and symptoms as continuing SFC250, whereas FP250 was not.

Asthma and allergy: short texts and recommendations of the expert conference of the French Speaking Pneumology Society (SPLF), in partnership with the French Society of Allergology and Clinical Immunology (SFAIC), the French Society of Occupational Medicine (SFMT) and the "Asthma-Allergy" association.

The Asthma Plan published by the French Health Ministry in 2002, the experts conferences edited by ANAES on therapeutic education and follow-up of asthma, the inclusion of this disease in the Public Health Law have been remarkable steps in France during the last few years. The medical community, more particularly the pneumological community, has shown its commitment in the treatment of this public health problem. But allergy was not sufficiently taken into account, although it is responsible for nearly 50 to 60% cases of asthma. In most so-called developed countries the prevalence of asthma and of allergies has increased in the last twenty years. Its progress varies according to country and age group: the increased prevalence of allergy, more specifically of rhinitis and eczema, is most marked in children aged 6-7 year. The prevalence of asthma seems to have reached a plateau in certain northern countries or seems to have decreased in 13-14 year olds (Anglo-Saxon countries). There were multiple reasons, generally attributed to changes in life-style. Asthma is the result of an interaction between a genetic predisposition and the environment, where allergens are present, but also smoking. The relationships between allergy and asthma are complex. This conference discussed the various essential issues that face doctors who treat patients with asthma in their daily practice. The risk factors, the methods of exploration in children and adults and the specific treatments are, indeed, essential issues to be evaluated in a frequent pathology that interests a large number of physicians. The variety of experts is wide, representing pneumology (French Speaking Pneumology Society), the occupational medicine world (French Society of Occupational Medicine), the allergic pathology (French Society of Allergology and Clinical Immunology), and patients with the patient association "Asthma & Allergy", physicians belonging to the general medicine community, general hospitals, private hospitals and academic hospitals in France. The proposed guidelines are aimed at helping practitioners in distinguishing what is established from what remains to be demonstrated and/or assessed with respect to the different modalities for the exploration or treatment of allergic asthma.

Specificity of basement membrane thickening in severe asthma.

BACKGROUND: Reticular basement membrane (RBM) thickness is considered a hallmark for airway remodeling in airway diseases such as asthma. It is still unclear whether this measurement could be associated with disease severity or apply to chronic obstructive pulmonary disease (COPD). A wide range of results, at baseline or after therapeutic intervention, have been reported using different measurement methods. OBJECTIVE: To determine whether increased RBM thickness could be associated specifically with severe asthma and in COPD in large samples. METHODS: We blindly measured RBM thickness in endobronchial biopsies from 50 patients with severe asthma (mean age, 53 years; FEV(1) 66% predicted, inhaled steroids > or =1500 microg and 20 mg daily dose of oral corticosteroids, lifelong nonsmokers), 50 untreated patients with mild asthma (mean age, 33 years; FEV(1) 93%pred, lifelong nonsmokers), 50 patients with COPD (mean age, 57 years; FEV(1) 53%pred, all current smokers), and 18 control subjects using 2 different validated quantitative and computer-assisted methods (repeated multiple point-to-point vs area by length ratio). RESULTS: Reticular basement membrane thickness was higher in severe asthma compared with mild asthma and COPD (P = .0053). On the basis of receiver operating characteristic curves, RBM thickness was effective in differentiating severe asthma from other groups (sensitivity and specificity, 98% and 95%, respectively, above a threshold of 5 microm vs control, 70% and 75% at 7 microm vs mild, 83% and 68% at 6 microm vs COPD). CONCLUSION: Increased RBM thickness was specifically associated with severe asthma, whereas surprisingly, COPD and mild asthma had similar remodeling features. CLINICAL IMPLICATIONS: Reticular basement membrane thickness can be considered a hallmark of severe asthma.

Synthesis and anti-inflammatory effect of lipoxins in human airway epithelial cells.

In this study, we investigated the synthesis of lipoxins (LXs) and their anti-inflammatory effects in different human airway epithelial cell culture models. After cell incubation with exogenous 5(S),6(R)-dihydroxy-7,9-trans-11,14-cis-eicosatetraenoic acid, LXA(4) was detected in supernatants of differentiated human bronchial epithelial cells by contrast to non-differentiated cells. Exogenous LXA(4) significantly inhibited tumor necrosis factor-alpha (TNF-alpha)-induced interleukin-8 (IL-8) release in the different epithelial cell types and the potency of inhibition was dependent of the accessibility of the specific LXA(4) receptor, formyl-peptide receptor like-1 (FPRL-1) expressed by all these cells. Immunohistochemistry analysis on human bronchial biopsies showed a high expression of FPRL-1 in the epithelium. Finally, an FPRL-1 receptor antagonist, boc-2 peptide reversed LXA(4) effect on IL-8 generation. Together, these findings indicate that differentiated human bronchial epithelium synthesizes LX in vivo which could have autocrine actions through its specific receptor FPRL-1 to promote resolution of airway inflammation.

Interference of psychological factors in difficult-to-control asthma.

BACKGROUND: Most patients with asthma can be controlled with suitable medication, but 5-10% of them remain difficult to control despite optimal management. OBJECTIVE: We investigated whether patients with difficult-to-control asthma (DCA) or controlled asthma (CA) differ with respect to psychological factors, such as general control beliefs on life events. METHODS: DCA was defined as an absence of control despite optimal management. Recent control was measured using the Asthma Control Questionnaire. General control beliefs were investigated using a Locus of Control scale (LOC). RESULTS: Patients with DCA had a significantly higher external LOC as compared to patients with CA (P=0.01). In the DCA group, the hospital admission rate was highly significant in association with the external LOC (P=0.004) as compared to the internal LOC trend. CONCLUSION: This study showed that patients with DCA had different general control beliefs which might have hampered their management and interfered with their therapeutic adherence. The present findings could enhance management of DCA in a clinical setting.

[Difficult asthma]. / Asthme difficile.

Difficult asthma is a major issue in pulmonary medicine today because of its cost for patients and society. Difficult asthma is asthma that remains uncontrolled despite optimal specialist management. The validity of the diagnosis must be reconsidered in these cases: associated or differential diagnoses may be involved in the lack of control, and it is always necessary to assess the patient's treatment adhesion. Sufficient time--at least a year--must be taken to get to know the patient and to meet the objectives set. The standard asthma therapies should be tested objectively. Severe asthma is the reality of difficult asthma that endures despite a reaffirmed diagnosis, optimal compliance and controlled comorbidities. Better knowledge is needed of the pathophysiology of these patients' asthma. Improved knowledge of these phenotypes will make it possible to develop innovative treatments. They will need to be validated in clinical research for subsequent use that is wider but more rational because targeted at phenotypes likely to benefit from them.

Implementing practice guidelines: a workshop on guidelines dissemination and implementation with a focus on asthma and COPD.

The present supplement summarizes the proceedings of the symposium "Implementing practice guidelines: A workshop on guidelines dissemination and implementation with a focus on asthma and COPD", which took place in Quebec City, Quebec, from April 14 to 16, 2005. This international symposium was a joint initiative of the Laval University Office of Continuing Medical Education (Bureau de la Formation Médicale Continue), the Canadian Thoracic Society and the Canadian Network for Asthma Care, and was supported by many other organizations and by industrial partners. The objectives of this meeting were to examine the optimal implementation of practice guidelines, review current initiatives for the implementation of asthma and chronic obstructive pulmonary disease (COPD) guidelines in Canada and in the rest of the world, and develop an optimal strategy for future guideline implementation. An impressive group of scientists, physicians and other health care providers, as well as policy makers and representatives of patients' associations, the pharmaceutical industry, research and health networks, and communications specialists, conveyed their perspectives on how to achieve these goals. This important event provided a unique opportunity for all participants to discuss key issues in improving the care of patients with asthma and COPD. These two diseases are responsible for an enormous human and socioeconomic burden around the world. Many reports have indicated that current evidence-based guidelines are underused by physicians and others, and that there are many barriers to an effective translation of recommendations into day-to-day care. There is therefore a need to develop more effective ways to communicate key information to both caregivers and patients, and to promote appropriate health behaviours. This symposium contributed to the initiation of what could become the "Canadian Asthma and COPD Campaign", aimed at improving care and, hence, the quality of life of those suffering from these diseases. It is hoped that this event will be followed by other meetings that focus on how to improve the transfer of key recommendations from evidence-based guidelines into current care, and how to stimulate research to accomplish this.

The public health implications of asthma.

Asthma is a very common chronic disease that occurs in all age groups and is the focus of various clinical and public health interventions. Both morbidity and mortality from asthma are significant. The number of disability-adjusted life years (DALYs) lost due to asthma worldwide is similar to that for diabetes, liver cirrhosis and schizophrenia. Asthma management plans have, however, reduced mortality and severity in countries where they have been applied. Several barriers reduce the availability, affordability, dissemination and efficacy of optimal asthma management plans in both developed and developing countries. The workplace environment contributes significantly to the general burden of asthma. Patients with occupational asthma have higher rates of hospitalization and mortality than healthy workers. The surveillance of asthma as part of a global WHO programme is essential. The economic cost of asthma is considerable both in terms of direct medical costs (such as hospital admissions and the cost of pharmaceuticals) and indirect medical costs (such as time lost from work and premature death). Direct costs are significant in most countries. In order to reduce costs and improve quality of care, employers and health plans are exploring more precisely targeted ways of controlling rapidly rising health costs. Poor control of asthma symptoms is a major issue that can result in adverse clinical and economic outcomes. A model of asthma costs is needed to aid attempts to reduce them while permitting optimal management of the disease. This paper presents a discussion of the burden of asthma and its socioeconomic implications and proposes a model to predict the costs incurred by the disease.