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.

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.

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.

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.

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.

[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.

Clinical practice guidelines: medical follow-up of patients with asthma--adults and adolescents.

The follow-up of patients with asthma should focus on asthma control (disease course over a number of weeks).

Phenotypes of asthma revisited upon the presence of atopy.

Immunological studies claimed that atopic and non-atopic asthma share more similarities than differences. However, these two phenotypes of asthma are considered to be distinguishable upon distinct clinical patterns, which were not systematically assessed before in a large population. We studied characteristics discriminating atopic from non-atopic asthma among 751 asthmatic patients and 80 factors were analysed in univariate and multivariate analysis. Age, age of onset of asthma, female/male ratio were higher in non-atopic (n=200) than in atopic (n=551) asthmatics. Familial asthma, seasonal symptoms, rhinitis, conjunctivitis, allergen-triggered symptoms, improvement in altitude, exercise-induced asthma were associated with atopy. Non-atopic asthmatics displayed lower FEV(1) and FVC. Smoking was more frequent and asthma was more severe in these patients. Younger age, early onset, male sex, rhinitis and smoking were independent factors discriminating atopic from non-atopic asthma. This study establishes in a large population of asthmatics that although similarities exist between atopic and non-atopic asthma, two clinical phenotypes can still distinguish both kinds of asthma.

Drug provocation tests in patients with a history suggesting an immediate drug hypersensitivity reaction.

BACKGROUND: Drug hypersensitivity reactions are common and can be life-threatening. Confirmation of the diagnosis should be rigorous and based on clinical history and a physical examination, possibly followed by skin tests and drug provocation tests. OBJECTIVE: To describe the outcome of drug provocation tests in evaluating patients with histories suggesting drug allergy. DESIGN: Retrospective analysis of clinic case series. SETTING: The department for drug allergy at a university hospital. PATIENTS: 898 consecutive patients with suspected immediate drug allergy referred to the clinic between September 1996 and August 2001. Patients with severe skin reactions and those with positive results on skin tests for beta-lactams were excluded. INTERVENTION: Single-blinded administration of increasing doses of the suspected drug, up to the usual daily dose, under strict hospital surveillance. RESULTS: 1372 drug provocation tests were performed using various drugs, including beta-lactams (30.3%), aspirin (14.5%), other nonsteroidal anti-inflammatory drugs (11.7%), paracetamol (8.9%), macrolides (7.4%), and quinolones (2.4%). There were 241 (17.6%) positive drug provocation test results. Drug provocation reproduced the same symptoms, albeit milder and of a shorter duration, in the following patients: 13 (5.4%) with a history of anaphylactic shock, 17 (7.0%) with a history of anaphylaxis without shock, 10 (4.1%) with a history of laryngeal edema, 19 (7.9%) with a history of bronchospasm, 160 (66.4%) with a history of urticaria, and 22 (9.1%) with a history of maculopapular eruption. All adverse reactions were completely reversed by prednisolone, H(1)-antihistamines, and epinephrine as needed. LIMITATIONS: Falsely negative results on drug provocation tests may have occurred because of loss of sensitization, rare cofactors not included in the diagnostic procedure, and tolerance induction during provocation. CONCLUSIONS: Drug provocation tests in individuals with suspected drug allergy performed in carefully controlled settings can confirm drug hypersensitivity.

[Nasal allergy and asthma: one or two diseases?]. / Allergie nasale et asthme: maladies uniques ou différentes?

Epidemiological studies have shown that rhinitis and asthma are associated. At least four out of five asthmatics suffer from rhinitis and one out of four rhinitic subjects develop asthma. Recent progress in cellular and molecular biology confirms that the same inflammatory cells and similar mechanisms participate in the pathophysiology of the two diseases. Histological findings show that although nasal inflammation resembles bronchial inflammation, specific remodelling features that are present in asthma are lacking in rhinitis. This may be due to the different embryologic origin of the two organs. These similarities explain certain clinical interactions and are the basis of the ARIA (Allergic Rhinitis and its Impact on Asthma)--WHO guidelines recommending that symptoms of rhinitis be sought in asthmatic subjects and symptoms of asthma in rhinitic subjects.

[Control of asthma]. / Contrôle de l'asthme.

Asthma is a chronic, variable bronchial disease in time, sometimes over short periods. the follow-up must be based on the regular evaluation of control. this represents the respiratory health during last weeks, between the two last consultations. it is a composite score which takes into account clinical and functional parameters, as well as the consumption of beta2-mimetics of immediate action. recommendations have been just published by the anaes, defining the importance of respiratory functional testing in the follow-up of asthmatics, and proposing a gradation in the therapeutic adaptation to each consultation according to the levels of control and requirement that the patient and his doctor have defined together.

High levels of urinary leukotriene E4 excretion in steroid treated patients with severe asthma.

Urinary LTE4 reflects the whole body production of the cysteinyl-leukotrienes (LTC4, LTD4 and LTE4) that are established mediators in asthma. The influence of chronic inhaled and oral glucocorticoid treatment on urinary excretion of leukotriene (LT) E4 was investigated in subjects with asthma. Enzyme immunoassay analysis of LTE4 was performed in spot urine samples collected from 40 patients with severe asthma, 25 patients with mild-moderate asthma and 20 non-asthmatic control subjects. Urinary LTE4 was significantly higher in patients with severe asthma (69.7 +/- 5.5) as compared to mild-moderate asthma (45.7 +/- 3.3 with P < 0.0004) and control (42.5 +/- 2.5 with P < 0.0001). Despite chronic systemic treatment with glucocorticoids, chronically severe asthma had presented with higher levels of LTE4 compared to mild moderate asthma and healthy controls. The findings support previous indications that one important component in asthmatic airway inflammation, the cysteinyl-leukotriene pathway remains relatively unopposed by oral glucocorticoids.

[Identifying and understanding drug allergies]. / Identifier et comprendre les allergies médicamenteuses.

Drug hypersensitivity reactions frequently occur in hospitalized and out-patients. Clinical presentations are numerous and heterogeneous, from a mild urticaria to a dramatic anaphylactic shock and an extensive bullous skin disease. Allergic reactions are unpredictable reactions, related to immunologic mechanisms. Some reactions mimic allergic reactions but no drug specific antibody or T cell proliferation can be demonstrated. A true diagnosis is rarely set up and the tools for it are lacking. In this review, we will focus on the available epidemiological data concerning these reactions, including data on incidence and mortality and on the most recent advances in the pathophysiology and allergy diagnosis of drug hypersensitivity reactions.

[The measurement of exhaled nitric oxide, a new tool in the management of asthma?]. / La mesure du monoxyde d'azote exhalé, un nouvel outil dans la prise en charge de l'asthme?

A GOOD DIAGNOSTIC TEST FOR ASTHMA: Chronic airway inflammation, main feature of asthma, can be assessed by measuring the exhaled nitric oxide (NO) level. Measurement of NO is standardized, non-invasive and easy to use in both children and adults. Studies have shown that it is a good diagnostic test for asthma when NO is high. However, other conditions or pathologies must be searched for because they may influence the results. ITS PLACE IN TREATMENT: Although exhaled NO helps to characterise the patients with asthma, other studies are required to show that it can help to improve the follow-up of such patients. Nevertheless, this tool has not yet been validated in the daily treatment of asthma and further research is still ongoing.

[Small cell lung carcinoma]. / Cancer bronchique à petites cellules.

In most of the cases, small cell lung cancer is diagnosed at the extensive disease stage. Regarding the micrometastatic process, it might be considered as a metastatic disease in almost all cases. Therefore, chemotherapy is the cornerstone of small cell lung cancer therapy. Cisplatin and VP-16-based combinations are recommended. Chemotherapy alone remains the only recommended therapy in extensive disease, whereas radiochemotherapy is the treatment of limited disease. Concomitant or alternate modalities are acceptable standards in this latter setting. Prophylactic cranial irradiation is recommended for complete responders with initially limited disease.

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.

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.