Search

© 2018 John Wiley & Sons Ltd Background: Asthma is a chronic respiratory disease without a cure, although there exists spontaneous remission. Genome-wide association (GWA) studies have pinpointed genes associated with asthma development, but did not investigate asthma remission. Objective: We performed a GWA study to develop insights in asthma remission. Methods: Clinical remission (ClinR) was defined by the absence of asthma treatment and wheezing in the last year and asthma attacks in the last 3 years and complete remission (ComR) similarly but additionally with normal lung function and absence of bronchial hyperresponsiveness (BHR). A GWA study on both ClinR and ComR was performed in 790 asthmatics with initial doctor diagnosis of asthma and BHR and long-term follow-up. We assessed replication of the 25 top single nucleotide polymorphisms (SNPs) in 2 independent cohorts (total n = 456), followed by expression quantitative loci (eQTL) analyses of the 4 replicated SNPs in lung tissue and epithelium. Results: Of the 790 asthmatics, 178 (23%) had ClinR and 55 ComR (7%) after median follow-up of 15.5 (range 3.3-47.8) years. In ClinR, 1 of the 25 SNPs, rs2740102, replicated in a meta-analysis of the replication cohorts, which was an eQTL for POLI in lung tissue. In ComR, 3 SNPs replicated in a meta-analysis of the replication cohorts. The top-hit, rs6581895, almost reached genome-wide significance (P-value 4.68 × 10−7) and was an eQTL for FRS2 and CCT in lung tissue. Rs1420101 was a cis-eQTL in lung tissue for IL1RL1 and IL18R1 and a trans-eQTL for IL13. Conclusions and Clinical Relevance: By defining a strict remission phenotype, we identified 3 SNPs to be associated with complete asthma remission, where 2 SNPs have plausible biological relevance in FRS2, CCT, IL1RL1, IL18R1 and IL13.

International audience; Regular physical activity is recognized as an effective health promotion measure. Among various activities, swimming is preferred by a large portion of the population. Although swimming is generally beneficial to a person's overall health, recent data suggest that it may also sometimes have detrimental effects on the respiratory system. Chemicals resulting from the interaction between chlorine and organic matter may be irritating to the respiratory tract and induce upper and lower respiratory symptoms, particularly in children, lifeguards and high-level swimmers. The prevalence of atopy, rhinitis, asthma and airway hyper-responsiveness is increased in elite swimmers compared with the general population. This may be related to the airway epithelial damage and increased nasal and lung permeability caused by the exposure to chlorine subproducts in indoor swimming pools, in association with airway inflammatory and remodelling processes. Currently, the recommended management of swimmers' respiratory disorders is similar to that of the general population, apart from the specific rules for the use of medications in elite athletes. Further studies are needed to better understand the mechanisms related to the development or worsening of respiratory disorders in recreational or competitive swimmers, to determine how we can optimize treatment and possibly help prevent the development of asthma.

International audience; Background: Cardiorespiratory disorders are common in athletes. However, these conditions are often underdiagnosed, which potentially results in impaired performance and increased health risks. The aim of this study was to evaluate, in a research setting, the prevalence of cardiorespiratory disorders in athletes in order to determine the potential value of a screening program.Methods: One hundred thirty-three athletes were studied. Each subject underwent a physical examination. A eucapnic voluntary hyperventilation (EVH) test and a methacholine inhalation test were performed to confirm the diagnosis of asthma. A cardiovascular evaluation was also performed, including maximal exercise test with electrocardiogram, 24-hour ambulatory blood pressure monitoring, 24-hour Holter monitoring, and blood sampling.Results: Seventy-four (56%) athletes had airway hyperresponsiveness to EVH or the methacholine inhalation test. Among those with airway hyperresponsiveness, 45 (61%) athletes were only hyperresponsive to EVH, and 10 (14%) were only hyperresponsive to the methacholine inhalation test (using the criteria of a PC20 ≤ 4 mg/mL). Thirty-two (24%) athletes had a known diagnosis of asthma, while 34 (26%) athletes received a new asthma diagnosis. Ninety-seven (73%) athletes were sensitized to common airborne allergens. Forty-seven (35%) athletes completed the cardiovascular evaluation. Three (6%) and 7 (15%) athletes had a previous or new diagnosis of cardiovascular disease, respectively. Resting systemic hypertension was documented in 2 (4%) athletes and exaggerated blood pressure response to exercise was found in 12 (26%) athletes.Conclusion: This cardiorespiratory screening data set in athletes showed a high prevalence of exercise-induced asthma and exercise hypertension, which in many cases were not previously diagnosed.

Background The influence of genetic predictors of inflammation and atopy on occupational asthma in apprentices is not known. Objectives To assess the influence of genetic polymorphisms of IL4RA , IL13 , TNFA , IL1A , and IL5 on the decline of lung function and bronchial hyperresponsiveness in a prospective follow-up study of baker/pastry maker and hairdresser apprentices. Methods A total of 351 apprentices were included in the study. We performed skin testing, spirometry, fractional exhaled nitric oxide measurement, and methacholine hyperreactivity testing at the initial visit and during and at the end of the 18-month training period. Gene variants of IL4RA, IL13, TNFA, IL1A , and IL5 were determined in DNA from nasal lavage. Results IL13 R130Q /IL4RA S478P or IL13 R130Q//IL4RA Q551R were significant predictors of the decrease of forced expiratory volume and forced vital capacity ( P ≤ .006). Genotype GG of TNFAG308A was associated with bronchial hyperresponsiveness in the whole population and in nonatopic individuals (90.63% vs 9.38%; odds ratio, 3.78; 95% confidence interval, 1.10-12.83). TNFA GA and IL5 CC and TNFA GA and IL1A CC were 2 epistatic predictors of exhaled nitrogen monoxide decrease during follow-up ( P = .02 and P = .004, respectively). The association with TNFA GA and IL1A CC was the most significant in nonatopic bakers ( P Conclusion We evidenced a predicting influence of IL13/IL4RA and TNFA in the early exposure to allergens and irritants that precedes occupational asthma. The significance of the associations in the absence of atopy suggests an influence of the genetics predictors related to inflammatory pathways.

International audience; There is a need to improve asthma characterisation by integrating multiple aspects of the disease. The aim of the present study was to identify distinct asthma phenotypes by applying latent class analysis (LCA), a model-based clustering method, to two large epidemiological studies. Adults with asthma who participated in the follow-up of the Epidemiological Study on the Genetics and Environment of Asthma (EGEA2) (n = 641) and the European Community Respiratory Health Survey (ECRHSII) (n = 1,895) were included. 19 variables covering personal characteristics, asthma symptoms, exacerbations and treatment, age of asthma onset, allergic characteristics, lung function and airway hyperresponsiveness were considered in the LCA. Four asthma phenotypes were distinguished by the LCA in each sample. Two phenotypes were similar in EGEA2 and ECRHSII: active treated allergic childhood-onset asthma and active treated adult-onset asthma. The other two phenotypes were composed of subjects with inactive or mild untreated asthma, who differed by atopy status and age of asthma onset (childhood or adulthood). The phenotypes clearly discriminated populations in terms of quality of life, and blood eosinophil and neutrophil counts. The LCAs revealed four distinct asthma phenotypes in each sample. Considering these more homogeneous phenotypes in future studies may lead to a better identification of risk factors for asthma.

International audience; Allergic asthma is a T helper type 2 (T(H)2)-dominated disease of the lung. In people with asthma, a fraction of CD4(+) T cells express the CX3CL1 receptor, CX3CR1, and CX3CL1 expression is increased in airway smooth muscle, lung endothelium and epithelium upon allergen challenge. Here we found that untreated CX3CR1-deficient mice or wild-type (WT) mice treated with CX3CR1-blocking reagents show reduced lung disease upon allergen sensitization and challenge. Transfer of WT CD4(+) T cells into CX3CR1-deficient mice restored the cardinal features of asthma, and CX3CR1-blocking reagents prevented airway inflammation in CX3CR1-deficient recipients injected with WT T(H)2 cells. We found that CX3CR1 signaling promoted T(H)2 survival in the inflamed lungs, and injection of B cell leukemia/lymphoma-2 protein (BCl-2)-transduced CX3CR1-deficient T(H)2 cells into CX3CR1-deficient mice restored asthma. CX3CR1-induced survival was also observed for T(H)1 cells upon airway inflammation but not under homeostatic conditions or upon peripheral inflammation. Therefore, CX3CR1 and CX3CL1 may represent attractive therapeutic targets in asthma.

Infection with the fish parasiteAnisakisfollowing exposure to contaminated fish can lead to allergic reactions in humans. The present study examined the immunological mechanisms underlying the development of allergic airway inflammation in mice after different routes of sensitization toAnisakis. Wild-type and interleukin-4 receptor alpha (IL-4Rα)-deficient BALB/c mice were sensitized intraperitoneally with live or heat-killedAnisakislarvae or by intranasal administration of anAnisakisextract and were subsequently challenged intranasally with anAnisakisextract. Both routes of sensitization induced IL-4Rα-dependent allergic airway responses, whereas allergen-specific antibody responses developed only when mice were sensitized intraperitoneally. Intranasal sensitization induced airway hyperresponsiveness (AHR) in wild-type mice only, showing that AHR was IL-4/IL-13 dependent. Unexpectedly, infection withAnisakislarvae induced AHR in both wild-type and IL-4Rα-deficient mice. IL-4Rα-independent AHR was mediated by gamma interferon (IFN-γ), as evidenced by the fact thatin vivoneutralization of IFN-γ abrogated AHR. Together, these results demonstrate that both infection with larvae and inhalational exposure toAnisakisproteins are potent routes of allergic sensitization toAnisakis, explaining food- and work-related allergies in humans. Importantly for diagnosis, allergic airway inflammation can be independent of detectableAnisakis-specific antibodies. Moreover, depending on the route of sensitization, AHR can be induced either by IL-4/IL-13 or by IFN-γ.

Respiratory viral infections have been implicated in exacerbations of allergic asthma, characterized by a Th2-biased immune response. Respiratory viruses target airway epithelial cells and dendritic cells (DCs). Their activation is, at least in part, mediated by the TLR3-dependent recognition of virus-derived dsRNA. To elucidate the role of epithelial cells and DCs and the implication of TLR3/Toll/IL-1R domain-containing adaptor-inducing IFN-beta (TRIF) pathway, we developed a mouse model of lung allergic exacerbation. The effect of intranasal administration of dsRNA in OVA-sensitized wild-type mice and TRIF(-/-) mice was evaluated on airway hyperresponsiveness and pulmonary inflammation. Our data demonstrated that treatment with dsRNA significantly increased the airway hyperresponsiveness, the lung inflammation, and the OVA-specific Th2 response. This was associated with an infiltrate of eosinophils, myeloid DCs, and T lymphocytes. TRIF activation was required for the development of dsRNA-induced exacerbation of the allergic reaction. Intratracheal transfer of IL-4/dsRNA/OVA-pretreated DCs also triggered exacerbation of the allergic reaction, whereas cells primed with dsRNA/OVA had a more limited effect. dsRNA-induced production of CCL20 by airway epithelium was associated with DC recruitment. In vivo and in vitro treatment with dsRNA amplified airway epithelial production of the pro-Th2 chemokines CCL11 and CCL17, their secretion being enhanced by Th2 cytokines. In conclusion, dsRNA derived from respiratory viruses trigger exacerbation of the pulmonary allergic reaction through TLR3/TRIF-dependent pathway. Moreover, Th2 cytokines participate in this process by modulating the response of airway epithelium and DCs to dsRNA., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Background Bronchial Hyperresponsiveness (BHR) is considered a hallmark of asthma. Other methods are helpful in epidemiological respiratory health studies including Fractional Exhaled Nitric Oxide (FENO) and Eosinophils Percentage (EP) in nasal lavage fluid measuring markers for airway inflammation along with the Forced Oscillatory Technique measuring Airway resistance (AR). Can their outcomes discriminate profiles of respiratory health in healthy subjects starting apprenticeship in occupations with a risk of asthma? Methods Rhinoconjunctivitis, asthma-like symptoms, FEV1 and AR post-Methacholine Bronchial Challenge (MBC) test results, FENO measurements and EP were all investigated in apprentice bakers, pastry-makers and hairdressers not suffering from asthma. Multiple Correspondence Analysis (MCA) was simultaneously conducted in relation to these groups and this generated a synthetic partition (EI). Associations between groups of subjects based on BHR and EI respectively, as well as risk factors, symptoms and investigations were also assessed. Results Among the 441 apprentice subjects, 45 (10%) declared rhinoconjunctivitis-like symptoms, 18 (4%) declared asthma-like symptoms and 26 (6%) suffered from BHR. The mean increase in AR post-MBC test was 21% (sd = 20.8%). The median of FENO values was 12.6 ppb (2.6-132 range). Twenty-six subjects (6.7%) had EP exceeding 14%. BHR was associated with atopy (p < 0.01) and highest FENO values (p = 0.09). EI identified 39 subjects with eosinophilic inflammation (highest values of FENO and eosinophils), which was associated with BHR and atopy. Conclusions Are any of the identified markers predictive of increased inflammatory responsiveness or of development of symptoms caused by occupational exposures? Analysis of population follow-up will attempt to answer this question.

International audience; BACKGROUND: The herbal Petasites hybridus (butterbur) extract (Ze 339, PET) is known to have leukotriene inhibiting properties, and therefore might inhibit allergic diseases. METHODS: The effect of PET was investigated in ovalbumin (OVA) immunized BALB/c mice given intranasally together with antigen challenge in the murine model of allergic airway disease (asthma) with the analysis of the inflammatory and immune parameters in the lung. RESULTS: PET given with the antigen challenge inhibited the allergic response. PET inhibited airway hyperresponsiveness (AHR) and eosinophil recruitment into the bronchoalveolar lavage (BAL) fluid upon allergen challenge, but had no effect in the saline control mice. Eosinophil recruitment was further assessed in the lung by eosinophil peroxidase (EPO) activity at a concentration of 100 microg PET. Microscopic investigations revealed less inflammation, eosinophil recruitment and mucus hyperproduction in the lung with 100 microg PET. Diminution of AHR and inflammation was associated with reduced IL-4, IL-5 and RANTES production in the BAL fluid with 30 microg PET, while OVA specific IgE and eotaxin serum levels remained unchanged. CONCLUSION: PET, which has been reported to inhibit leukotriene activity, reduced allergic airway inflammation and AHR by inhibiting the production of the Th2 cytokines IL-4 and IL-5, and RANTES.

International audience; BACKGROUND: The herbal Isatis tinctoria extract (ITE) inhibits the inducible isoform of cyclooxygenase (COX-2) as well as lipoxygenase (5-LOX) and therefore possesses anti-inflammatory properties. The extract might also be useful in allergic airway diseases which are characterized by chronic inflammation. METHODS: ITE obtained from leaves by supercritical carbon dioxide extraction was investigated in ovalbumin (OVA) immunised BALB/c mice given intranasally together with antigen challenge in the murine model of allergic airway disease (asthma) with the analysis of the inflammatory and immune parameters in the lung. RESULTS: ITE given with the antigen challenge inhibited in a dose related manner the allergic response. ITE diminished airway hyperresponsiveness (AHR) and eosinophil recruitment into the bronchoalveolar lavage (BAL) fluid upon allergen challenge, but had no effect in the saline control mice. Eosinophil recruitment was further assessed in the lung by eosinophil peroxidase (EPO) activity at a dose of 30 microg ITE per mouse. Microscopic investigations revealed less inflammation, eosinophil recruitment and mucus hyperproduction in the lung in a dose related manner. Diminution of AHR and inflammation was associated with reduced IL-4, IL-5, and RANTES production in the BAL fluid at the 30 microg ITE dose, while OVA specific IgE and eotaxin serum levels remained unchanged. CONCLUSION: ITE, which has been reported inhibiting COX-2 and 5-LOX, reduced allergic airway inflammation and AHR by inhibiting the production of the Th2 cytokines IL-4 and IL-5, and RANTES.

International audience; Sex differences in asthma-associated phenotypes are well known but the genetic factors that may account for these differences have received little attention. This study aimed to characterize sex-specific and pleiotropic genetic factors underlying four quantitative phenotypes involved in the main asthma physiopathological pathways: immunoglobulin E levels, a measure of polysensitization (SPTQ), eosinophil counts and a measure of lung function FEV(1)/H(2) (forced expiratory volume in one second divided by height square). Sex-stratified univariate and bivariate linkage analyses were conducted in 295 families from the Epidemiological study on the Genetics and Environment of Asthma study. We found genome-wide significant evidence for a male-specific pleiotropic QTL (quantitative trait loci) on 5q31 (P=7 x 10(-9)) influencing both FEV(1)/H(2) and SPTQ and for a female-specific pleiotropic QTL on 11q23 underlying SPTQ and immunoglobulin E (P=2 x 10(-5)). Three other sex-specific regions of linkage were detected for eosinophil: 4q24 and 22q13 in females, and 3p25 in males. Further, bivariate association analysis of FEV(1)/H(2) and SPTQ with 5q31 candidate genes in males showed a significant association with two single-nucleotide polymorphisms within IL9 gene, rs2069885 and rs2069882 (P=0.02 and P=0.002, respectively, after Bonferroni's correction). This study underlies the importance of taking into account complex mechanisms, such as heterogeneity according to sex and pleiotropy to unravel the genes involved in asthma phenotypes.

International audience; The association between breastfeeding and wheezing, lung function and atopy was evaluated in the International Study of Asthma and Allergy in Childhood (ISAAC) Phase II. Cross-sectional studies were performed in 27 centres in 20 countries. Information on disease and exposure factors was collected by parental questionnaires. Data from 54,000 randomly selected school children (aged 8-12 yrs, 31,759 with skin prick testing) and a stratified subsample (n = 4,888) were used for testing the correlation of breastfeeding with bronchial hyperreactivity and lung function. Random effect models for meta-analysis were applied to calculate combined odds ratios (ORs). Any breastfeeding was associated with less wheeze both in affluent (adjusted OR (OR(adj)) 0.87, 95% confidence interval (CI) 0.78-0.97) and nonaffluent countries (OR(adj) 0.80, 95% CI 0.68-0.94). Further analyses revealed that this was true only for nonatopic wheeze in nonaffluent countries (OR(adj) 0.69, 95% CI 0.53-0.90). Breastfeeding was not associated with atopic wheeze and objective measures of allergy in both affluent and nonaffluent countries. In contrast, breastfeeding was associated with higher predicted forced expiratory volume in one second in affluent countries only (mean ratio 1.11, 95% CI 1.02-1.20). Breastfeeding is associated with protection against nonatopic wheeze, which becomes particularly evident in nonaffluent countries. Overall, breastfeeding was not related to any measure of allergy. These findings may explain some of the controversy regarding breastfeeding, since the direction of the association with breastfeeding depends on the predominating wheeze phenotype (e.g. atopic, nonatopic).

International audience; To evaluate whether fine air particles could be involved in the occurrence of atopy and allergic diseases, we performed a cross-sectional epidemiological survey involving primary schoolchildren living in six French towns with contrasted air pollution levels. Air pollution was measured during a week in the school yards and by standard air monitoring networks. Children get an examination in school looking for atopic dermatitis and bronchial hyperresponsiveness assessed by a standardized run test. Besides, parents or guardians provided past medical history and environmental data, especially on passive smoking. Overall, 5,338 children, aged 10.4 (+/-0.7) years, coming from 108 different schools and 401 different classes were included in the survey. Taking into account potential confounders, high exposure to proximity PM(2.5) was linked to a higher point prevalence of atopic dermatitis and hyperresponsiveness, to a higher cumulative prevalence of allergic asthma and a higher sensitization rate to common indoor allergens. Thus, these data suggest that chronic exposure to urban fine particles could be a risk factor for atopy, hyperresponsiveness and asthma.

Allergic asthma is a chronic disease characterized by airway obstruction in response to allergen exposure. It results from an inappropriate T helper type 2 response to environmental airborne antigens and affects 300 million individuals. Its prevalence has increased markedly in recent decades, most probably as a result of changes in environmental factors. Exposure to environmental antigens during infancy is crucial to the development of asthma. Epidemiological studies on the relationship between breastfeeding and allergic diseases have reached conflicting results. Here, we have investigated whether the exposure of lactating mice to an airborne allergen affects asthma development in progeny. We found that airborne antigens were efficiently transferred from the mother to the neonate through milk and that tolerance induction did not require the transfer of immunoglobulins. Breastfeeding-induced tolerance relied on the presence of transforming growth factor (TGF)-beta during lactation, was mediated by regulatory CD4+ T lymphocytes and depended on TGF-beta signaling in T cells. In conclusion, breast milk-mediated transfer of an antigen to the neonate resulted in oral tolerance induction leading to antigen-specific protection from allergic airway disease. This study may pave the way for the design of new strategies to prevent the development of allergic diseases.

Contains fulltext : 69913.pdf (Publisher’s version ) (Closed access) Airway hyperresponsiveness (AHR) is a characteristic feature of asthma, but it is unclear whether asymptomatic AHR is associated with a higher risk of asthma. The present study assessed whether there is an association between asymptomatic AHR in adolescence and asthma in adulthood. The association between allergy and development of asthma was also investigated. A follow-up study of a general population cohort of adolescents was performed 14 yrs after baseline. Respiratory status was assessed at baseline in 1989 and at follow-up in 2003-2004 by a respiratory symptoms questionnaire, spirometry and histamine challenge. Allergy status was also assessed. The respiratory status of 199 subjects was assessed twice. In total, 91 (46%) subjects had the same AHR status in combination with respiratory symptoms at follow-up as at baseline. Adjusted for age, sex, allergy, family history of asthma and smoking history, having asymptomatic AHR was not significantly related to having asthma 14 yrs later (odds ratio (OR) 2.15, 95% confidence interval (CI) 0.67-6.83). For subjects with allergy at baseline, the OR for developing asthma was 4.45 (95% CI 1.46-13.54). Screening for asymptomatic airway hyperresponsiveness in adolescence does not identify subjects at risk of developing asthma. Conversely, the presence of allergy in adolescence does seem to be a risk factor for asthma development.

International audience; INTRODUCTION: EGEA (Epidemiological study on the genetics and environment of asthma, bronchial hyperresponsiveness and atopy), a case control and family study including 2048 individuals, was initiated to look for environmental and genetic risk factors for asthma. A synthesis of the results obtained since 2002 on phenotypic and environmental aspects of asthma severity and allergy are presented in this article. METHODS AND RESULTS: The results support a role for hormonal factors in asthma severity and in various allergic markers of asthma. A greater body mass index was related to a more severe asthma in women with early menarche. Associations between markers of allergy (eosinophils, IgE and atopy) and hormonal dependent events in women (premenstrual asthma, menopause and oral contraceptive use) have been found. In asthmatics, exposure to agents known to be associated with occupational asthma, active and passive smoking were associated with an increased clinical asthma severity score. The study underlines the protective role of country living and exposure to pets in early life on allergy markers in adulthood, supporting the hygiene hypothesis. CONCLUSIONS: New hypothesis will be tested in the near future from the second stage of this survey.

International audience; BACKGROUND: Obstructive sleep apnea syndrome (OSA) is associated with systemic and upper airway inflammation. Pharyngeal inflammation has a potential role in upper airway collapse, whereas systemic inflammation relates to cardiovascular morbidity. However, the presence of an inflammatory involvement of lower airway has been poorly investigated. OBJECTIVE: The aim of the study was to demonstrate an inflammatory process at the bronchial level in patients with OSA and to analyze effects of continuous positive airway pressure (CPAP) application and humidification on bronchial mucosa. METHODS: The study was conducted by using sequential induced sputum for cell analysis and IL-8 production, nitric oxide exhalation measurement, and methacholine challenge before and after CPAP. RESULTS: Bronchial neutrophilia and a high IL-8 concentration were observed in untreated OSA compared with controls (75% +/- 20% vs 43% +/- 12%, P < .05; and 25.02 +/- 9.43 ng/mL vs 8.6 +/- 3.7 ng/mL, P < .001, respectively). IL-8 in sputum supernatant was correlated to apnea hypopnea index (P < .01; r = 0.81). After 1 month of CPAP, this inflammatory pattern remained unchanged, and an increase in airway hyperresponsiveness (AHR) was observed (P < .001). CONCLUSION: Obstructive sleep apnea syndrome is associated with bronchial inflammation. Our data demonstrate CPAP effect on the development of AHR, possibly facilitated by the pre-existing inflammation. Both issues should be evaluated during long-term CPAP use. CLINICAL IMPLICATIONS: Results showing a spontaneous bronchial inflammation in OSA and the development of a CPAP-related AHR require a long-term follow-up to evaluate consequences on chronic bronchial obstruction.

International audience; INTRODUCTION: EGEA (Epidemiological study on the genetics and environment of asthma, bronchial hyperresponsiveness and atopy), a case control and family study including 2048 individuals, was initiated to look for environmental and genetic risk factors for asthma. A synthesis of the results obtained since 2002 on phenotypic and environmental aspects of asthma severity and allergy are presented in this article. METHODS AND RESULTS: The results support a role for hormonal factors in asthma severity and in various allergic markers of asthma. A greater body mass index was related to a more severe asthma in women with early menarche. Associations between markers of allergy (eosinophils, IgE and atopy) and hormonal dependent events in women (premenstrual asthma, menopause and oral contraceptive use) have been found. In asthmatics, exposure to agents known to be associated with occupational asthma, active and passive smoking were associated with an increased clinical asthma severity score. The study underlines the protective role of country living and exposure to pets in early life on allergy markers in adulthood, supporting the hygiene hypothesis. CONCLUSIONS: New hypothesis will be tested in the near future from the second stage of this survey.

online supplement; International audience; BACKGROUND: Delineating asthma subphenotypes is of interest to understand the cause of the disease. Few studies have addressed the interrelationships of quantitative asthma-related traits. OBJECTIVE: We sought to study the interrelationships of allergy markers and FEV(1) in relation to asthma and sex in children and adults. METHODS: Total IgE levels, skin prick test (SPT) positivity, eosinophil counts, and FEV(1) were assessed in 299 asthmatic cases (children and adults) recruited in chest clinics and 309 nonasthmatic population-based control subjects in the French Epidemiological Study on the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness, and Atopy. RESULTS: Allergy parameters were significantly higher in asthmatic cases than in control subjects for children and adults and for both sexes. Sex and age modified the pattern of concordance of high IgE levels, SPT positivity, and eosinophilia among asthmatic cases, with the greatest overlap in male children (64%) and the lowest in male adults (18%). Patterns of change over the lifespan of IgE levels, eosinophil counts, and FEV(1)/height(2) varied, with the acceleration of FEV(1) decrease being particularly evident in asthmatic adults. In adult cases and control subjects, SPT positivity (particularly to indoor allergens) was significantly related to IgE levels but not to eosinophil counts. The association of eosinophil counts with IgE levels was evident only in children. Environmental factors (smoking, pets, and country living) did not alter the patterns observed. CONCLUSIONS: Each allergy-related phenotype showed a distinct relation with asthma, with the role for eosinophils being different than that for IgE levels and SPT responses. CLINICAL IMPLICATIONS: Taking age and sex into account is essential for understanding the interrelationships of the various allergy-related phenotypes to asthma status.

online supplement; International audience; BACKGROUND: Delineating asthma subphenotypes is of interest to understand the cause of the disease. Few studies have addressed the interrelationships of quantitative asthma-related traits. OBJECTIVE: We sought to study the interrelationships of allergy markers and FEV(1) in relation to asthma and sex in children and adults. METHODS: Total IgE levels, skin prick test (SPT) positivity, eosinophil counts, and FEV(1) were assessed in 299 asthmatic cases (children and adults) recruited in chest clinics and 309 nonasthmatic population-based control subjects in the French Epidemiological Study on the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness, and Atopy. RESULTS: Allergy parameters were significantly higher in asthmatic cases than in control subjects for children and adults and for both sexes. Sex and age modified the pattern of concordance of high IgE levels, SPT positivity, and eosinophilia among asthmatic cases, with the greatest overlap in male children (64%) and the lowest in male adults (18%). Patterns of change over the lifespan of IgE levels, eosinophil counts, and FEV(1)/height(2) varied, with the acceleration of FEV(1) decrease being particularly evident in asthmatic adults. In adult cases and control subjects, SPT positivity (particularly to indoor allergens) was significantly related to IgE levels but not to eosinophil counts. The association of eosinophil counts with IgE levels was evident only in children. Environmental factors (smoking, pets, and country living) did not alter the patterns observed. CONCLUSIONS: Each allergy-related phenotype showed a distinct relation with asthma, with the role for eosinophils being different than that for IgE levels and SPT responses. CLINICAL IMPLICATIONS: Taking age and sex into account is essential for understanding the interrelationships of the various allergy-related phenotypes to asthma status.

International audience; BACKGROUND: The impact of air pollution on asthma and allergies still remains a debate. OBJECTIVE: Our cross-sectional study was intended to analyse the associations between long-term exposure to background air pollution and atopic and respiratory outcomes in a large population-based sample of schoolchildren. METHODS: Six thousand six hundred and seventy-two children aged 9-11 years recruited from 108 randomly schools in six French cities underwent a clinical examination including a skin prick test (SPT) to common allergens, exercise-induced bronchial reactivity (EIB) and skin examination for flexural dermatitis. The prevalence of asthma, allergic rhinitis (AR) and atopic dermatitis was assessed by a standardized health questionnaire completed by the parents. Three-year-averaged concentrations of air pollutants (NO2, SO2, PM10 and O3) were calculated at children' schools using measurements of background monitoring stations. RESULTS: After adjusting for confounders, EIB, lifetime asthma and lifetime AR were found to be positively related to an increase in the exposure to SO2, PM10 and O3. The adjusted odds ratios (aOR) per increase of 5 microg/m3 of SO2 was 1.39 (95% confidence interval (CI)=1.15-1.66) for EIB and 1.19 (1.00-1.41) for lifetime asthma. The aOR for lifetime AR per increase of 10 microg/m3 of PM10 was 1.32 (CI=1.04-1.68). Moreover, SPT positivity was associated with O3 (aOR=1.34; CI=1.24-1.46). Associations with past year symptoms were consistent, even if not always statistically significant. Results persisted in long-term resident (current address for at least 8 years) children. However, no consistent positive association was found with NO2. CONCLUSIONS: A moderate increase in long-term exposure to background ambient air pollution was associated with an increased prevalence of respiratory and atopic indicators in children.

International audience; Asthma severity in relation to body mass index (BMI) has rarely been studied. The relation between BMI and asthma severity was studied by sex in 366 adults with asthma from the Epidemiological Study on the Genetics and Environment of Asthma, a case-control and family study on asthma. Factors related to asthma severity and BMI such as smoking, FEV(1), bronchial hyperresponsiveness, and dyspnea were taken into account. The influence of early menarche was studied to assess the potential role of hormonal factors. Clinical asthma severity in the last 12 months was assessed by a score (0-7) based on the frequency of asthma attacks, persisting symptoms between attacks, and hospitalization. Asthma severity, which was unrelated to sex, increased with BMI in women (p = 0.0001) but not in men (p = 0.3). In women, the association remained after adjustment for age, FEV(1), smoking habits, and BMI-adjusted dyspnea and taking into account familial dependence (p = 0.0001). The association between BMI and severity was stronger in women with early menarche than in women without early menarche (p interaction = 0.02). Findings support the hypothesis of hormonal factors involved in the severity of asthma.

Background The pattern of asthma over the lifespan is different in male and female patients, but etiologic differences according to gender are only partially understood. In women, information regarding factors explaining perimenstrual asthma and the role of hormone-related aspects on asthma-related phenotypes is scanty. Objective To assess the relationships of eosinophils, IgE, and atopy with (1) asthma according to gender and age of onset and (2) hormone-related events. Methods Using data from the Epidemiological study on the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness and Atopy, adults and children with asthma recruited in chest clinics (n=313) and first-degree relatives of patients with asthma (n=214) were compared with nonasthmatic controls (n=334) and first-degree relatives without asthma (n=595). Results Among asthmatic women, eosinophilia was significantly associated with perimenstrual asthma independently from age, smoking, and asthma severity (eosinophils/mm 3 330 vs 194; P =.01). In nonasthmatic women, IgE level was significantly decreased (by half) and atopy decreased with menopause, and IgE increased with oral contraceptive use, independently from age and smoking. Considering both genders, the increase of eosinophil counts with asthma was significantly greater in women with childhood-onset asthma than in women with adulthood-onset or in men in general. No interaction between gender and asthma was observed for eosinophils in children and for IgE level and atopy in children and adults. Conclusion Results suggest a role of hormone-related events on asthma-related traits and support the hypothesis of the role of eosinophils in the persistence and severity of asthma.

International audience; When administered to mice systemically or via the airways, LPS induces bronchoconstriction (BC) and/or bronchopulmonary hyperreactivity (BHR), associated with inflammation. Accordingly, a relationship between inflammation and allergic and nonallergic BHR can be hypothesized. We therefore studied the interference of the anti-inflammatory cytokine murine IL-10 (mIL-10) with LPS-induced lung inflammation, BC, and BHR. mIL-10 was administered directly into the airways by intranasal instillation or generated in vivo after muscle electrotransfer of mIL-10-encoding plasmid. Electrotransfer led to high mIL-10 circulating levels for a longer time than after the injection of recombinant mIL-10 (rmIL-10). rmIL-10 administered intranasally reduced lung inflammation and BHR after LPS administration into airways. It also reduced the ex vivo production of TNF-alpha by LPS-stimulated lung tissue explants. Two days after electrotransfer, mIL-10 blood levels were elevated, but lung inflammation, BC, and BHR persisted unaffected. Blood mIL-10 reaches the airways poorly, which probably accounts for the ineffectiveness of mIL-10-encoding plasmid electrotransfer. When LPS was aerosolized 15 days after electrotransfer, lung inflammation persisted but BHR was significantly reduced, an effect that may be related to the longer exposure of the relevant cells to mIL-10. The dissociation between inflammation and BHR indicates that both are not directly correlated. In conclusion, this study shows that mIL-10 is efficient against BHR when present in the airway compartment. Despite this, the muscle electrotransfer with mIL-10-encoding plasmid showed a protective effect against BHR after a delay of 2 wk that should be further investigated.

We previously showed that the seminatural surfactant Curosurf inhibits the in vitro synthesis of secretory type IIA phospholipase A2 (sPLA2-IIA) in alveolar macrophages (AM). These cells are the main source of sPLA2-IIA in a guinea pig model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Here, we investigate the effect of Curosurf on the pulmonary synthesis of sPLA2-IIA in this ALI model. Our results showed that intratracheal administration of LPS (330 μg/kg) induced an increase in pulmonary expression of sPLA2-IIA, which was inhibited when animals received Curosurf (16 mg/guinea pig) 30 min or 8 h after LPS instillation. When AM were isolated from LPS-treated animals and cultured in conditioned medium, they expressed higher levels of sPLA2-IIA than AM from saline-treated animals. This ex vivo sPLA2-IIA expression was significantly reduced when guinea pigs received Curosurf 30 min after LPS instillation. Finally, we examined the effect of Curosurf on pulmonary inflammation measured 8 or 24 h after LPS administration. Curosurf instillation 30 min or 8 h after LPS reversed the increase in tumor necrosis factor-α expression, polymorphonuclear cell extravasation, and protein concentration in bronchoalveolar lavage fluids. Curosurf also decreased the bronchial reactivity induced by LPS. We conclude that Curosurf inhibits the pulmonary expression of sPLA2-IIA and exhibits palliative anti-inflammatory effects in an animal model of ALI.

International audience; BACKGROUND: The EGEA study combines a case-control study and a family study to assess genetic and environmental risk factors and their interactions for asthma, bronchial hyperresponsiveness and atopy. Information is scanty regarding potential selection biases, in particular regarding familial ressemblance in epidemiological surveys of this kind. METHODS: Asthmatic probands (adult and paediatric) were recruited in chest clinics of six clinical centres. Controls were mostly population-based (electoral rolls) for adults and recruited in surgery departments for children. RESULTS: The population examined includes 348 nuclear families ascertained by one asthmatic and 416 controls, totalling 1847 subjects (EGEA I) and an additional sample of 40 families ascertained by two asthmatic siblings (EGEA II). Potential biases for the various types of analyses have been studied. Quantification of the consequences of the greater participation of probands with a parental history of asthma shows it does not introduce a major bias in the estimates of familial resemblance. Cases and controls showed a good comparability regarding sex, age, area of residence and familial geographical origin, allowing proper associations studies for environmental and candidate genetic factors. CONCLUSIONS: The case-control component of the study will allow to perform studies on environmental factors and association studies for various genetic polymorphisms. Using the family base collected, segregation and genetic linkage/association analyses with DNA markers may be performed.

International audience; The increase of total IgE in relation to active smoking has been shown in the general population, but little is known about subjects with a personal or family history of asthma. The objective of this report is to analyze the relationships of active and passive smoking to total IgE in the Epidemiological Study of the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness, and Atopy (EGEA). The sample studied includes 122 asthmatic probands, 430 first-degree relatives, and 190 control subjects, age 25 to 54 yr. As expected, first-degree relatives had total IgE intermediate between cases and control subjects and men had higher values than women. Current smokers had significantly higher IgE than never smokers. The relationship was statistically significant restricting the analysis in asthmatic probands. In a model taking into account gender, personal and familial history of asthma, socio- occupational class, and the nonindependence of subjects from the same family, IgE were in current smokers, ex-smokers, and never smokers 128, 61, and 76 IU/ml and 77, 41, and 55 IU/ml in men (p = 0.01) and women (p = 0. 05), respectively. The relation was independent of skin test response. Some increase in IgE was observed in both men and women first-degree relatives in relation to passive smoking. That relation was statistically significant in women only (adjusted for asthma values: 103 IU/ml versus 48 IU/ ml, p = 0.02). Results show that an increase in total IgE in relation to active smoking may be evidenced even in asthmatics despite the healthy smoker effect. Susceptible subjects, such as women who are first-degree relatives of asthmatics, may increase total IgE in relation to passive smoking.

International audience; The Epidemiological Study of the Genetics and Environment of Asthma (EGEA) combined a case-control study and a family study. The total sample of 1,854 consisted of 348 patients with asthma selected through chest clinics and 416 control subjects and nuclear families ascertained through the cases. The protocol included standardized questionnaires, bronchial responsiveness, allergen skin-prick tests according to international protocols, total serum immunoglobulin E (IgE) level measurements, and blood eosinophilia. Criteria used to select subjects with asthma and determine asthma status of relatives for affected sibling pair linkage analysis are described. Based on figures from the 348 asthma cases of the EGEA study, issues relative to the definition of severe asthma and intermediate phenotypes such as bronchial responsiveness and allergic markers are discussed. Given the phenotypic heterogeneity involved, relevant phenotypes that may lead to the detection of genetic factors will depend on the hypothesis tested. Standardization of primary data and subphenotypes is a prerequisite for pooling data, which will be needed in the future to better understand the genetics and environmental factors of asthma.

International audience; We assessed the relationship between bronchial hyperresponsiveness (BHR) and the onset of wheezing 5 years later, by epidemiological analysis of 194 working men without asthma or wheezing at the first examination. In 1985/ 1986 and 1990/1991, subjects answered a British Medical Research Council questionnaire and performed lung function measurements and methacholine challenge tests (total dose 6 mg). BHR was measured in three ways: (1) FEV1 fall > or = 20% (PD20+); (2) the two-point response slope expressed as percentage decline of FEV1/dose, and (3) a four-parameter model: FEV1 at dose (d)/ prechallenge FEV1 = ONE-k(d-delta)+a, where 'k' is the slope of the relative variation of FEV1 with the dose, 'delta' the threshold dose, and 'alpha' a shape factor. In the 13 new wheezers, the mean values of the two-point slope and of k were significantly increased, and the proportion of reactors was almost threefold (the latter was not statistically significant). Among nonsmokers, delta was significantly lower in new wheezers than in the others, whereas the slope and k had similar mean values. Among smokers, new wheezers had increased mean values for the slope and k, and an increased proportion of reactors, whereas delta was not decreased. Thus, BHR was a significant predictor of wheezing, independent of the method of analysis. Moreover, the model distinguished between two components of bronchial response: wheezing was predicted by sensitivity (delta) in nonsmokers, and by reactivity (k) in smokers.

International audience

The occurrence of a late reaction following exercise induced asthma is questionable and its relationship with the non specific bronchial hyperreactivity is poorly known. In this study, nine patients (age 15-21 years) underwent an exercise challenge in order to (a) determine the incidence of immediate and late phase reaction and (b) analyse the modifications of non specific bronchial hyperreactivity. Study design was a follow; day-3: determination of bronchial responsiveness to metacholine; day 0: control day with FEV1 measurements every hour for 11 hours; day 1: exercise challenge followed by a careful observation of change in FEV1; day 2: new determination of bronchial responsiveness to metacholine. An immediate exercise induced bronchial obstruction was observed in 5 patients. A late phase reaction (6th hour) with a fall of FEV1 equal to or more than 20% has been demonstrated in two patients. For the former, the change in FEV1 did not differ from the value of the control day. For the second, the FEV1 changed spontaneously during the control day so that decreases of FEV1 during control and challenge days were parallel. Thus, no late phase reaction were observed (F = 0.46; ns). There was no modification of bronchial responsiveness to metacholine (pre-exercise: 1,784 +/- 1,970 [SD]; post-exercise 1,827 +/- 2,231 micrograms [SD]). The lack of true late phase reaction when the post-exercise change in FEV1 is compared to the one of a control day and the absence of modification of non specific bronchial hyperreactivity weaken the hypothesis of an inflammatory mechanism of exercise induced asthma.

International audience; Associations of upper airways disorders (UAD) with forced expiratory volume in one second (FEV1) and bronchial methacholine response were studied, taking smoking habits into account. We used epidemiological data drawn from a population of 324 men, aged 27-58 yrs. Lower FEV1 level was related to hay fever (p = 0.01), usual (p = 0.01) and chronic (p = 0.02) rhinitis and common cold on the day of examination (p = 0.04). Allowance for the major potential confounding factor, tobacco smoking, showed similar results. Bronchial methacholine response was heightened in men reporting hay fever compared to those without (p = 0.01) but also in men reporting chronic rhinitis (p = 0.06), a group which did not exhibit skin prick test positivity more often than other subjects. Exclusion of asthmatics and taking into account smoking and skin prick test positivity yielded mostly similar results. Our data support the hypothesis of an association between lung impairment, as assessed by lower FEV1 and bronchial hyperresponsiveness to methacholine, and different types of UAD, allergic or not.

International audience; The relationships of haptoglobin level to respiratory and allergic parameters have been assessed in an epidemiological study conducted in a working population surveyed twice 5 years apart. At the first survey conducted in 892 working men, haptoglobin level was significantly related to FEV1 (r = -0.18; P less than 0.001) and smoking habits. After adjustment for smoking, a history of wheezing was significantly related to lower haptoglobin level. A second survey conducted in 304 men of the original sample 5 years later confirmed that haptoglobin was related to FEV1 (r = -0.21; P less than 0.001) and that wheezing was significantly related to hypohaptoglobinaemia (lower decile; P = 0.04). Men who exhibited bronchial hyper-responsiveness to methacholine had haptoglobin levels 0.35 g/l higher than those who did not (P = 0.01). Haptoglobin level was unrelated to IgE level and skin prick tests. These results support the hypothesis of the role of inflammation in both lower lung function and bronchial hyper-responsiveness. They suggest that some heterogeneity exists within subjects with a history of wheezing.

T he Epidemiologic Study on the Genetics and Environment of Asthma (EGEA) was planned to assess genetic and environmental risk factors and their interactions in patients with asthma and for the two related traits of bronchial hyperresponsiveness and atopy. The study was performed from 1991 to 1995 and combined a case control study and a study of the families of the asthmatic patients. A synthesis of the results already obtained is presented. Smoking was related to IgE levels, even in asthma patients. Smoking was clearly related to the clinical severity of the asthma, which is clinically insufficiently taken into account. The relationships of occupational exposures to asthma have been assessed using a job exposure matrix. Segregation analyses of IgE have shown, after correction for the mode of ascertainment, the existence of a dominant major gene and a familial residual correlation. A systematic genome screen used in families with two asthmatic siblings showed a linkage of various regions in the genome that are related to asthma or related phenotypes (ie, 1p, 11p, 11q, 12q, 13q, 17q, and 19q), results that are in agreement with those of genome screens used in other studies. Regarding candidate genes, no association was shown between asthma and the F508 mutation of the cystic fibrosis gene. The analysis is still in progress with studies on the heterogeneity of asthma, with refined genetic studies, and by searching to integrate the results regarding environmental and genetic factors and studying their interactions.

International audience; A genome-wide search was conducted in 107 nuclear families with at least two siblings with asthma, as part of the French EGEA study. A two-stage analysis strategy was applied to the 107 families divided into two independent subsets of 46 and 61 families, where all regions detected in the first set of families were tested for replication in the second set. In addition, all regions reported by published genome scans in different populations were examined in the total sample. A total of 254 markers were typed in the first set of families and 70% of them in the second set. Linkage was investigated by model-free methods for asthma and four asthma-related phenotypes: bronchial responsiveness (BR), skin test response, total immunoglobulin E (IgE) levels, and eosinophil count. The two-stage analysis led to the detection of three regions: 11p13 for IgE, 12q24 for eosinophils, and 17q12-21 for asthma and skin tests. Among the regions reported by published genome screens, seven were found in the 107 French EGEA families: three being already detected by the two-stage analysis, 11p13 (p = 0.005), 12q24 (p = 0.0008), and 17q12-21 (p = 0.001), and four additional ones, 1p31 (p = 0.005) for asthma, 11q13 (p = 0.006) for IgE, 13q31 (p = 0.001) for eosinophils, and 19q13 (p = 0.02) for BR.

International audience; The Epidemiological study on the Genetics and Environment of Asthma (EGEA) was planned to assess genetic, environmental risk factors and their interactions for asthma and for the two related traits of bronchial hyperresponsiveness and atopy. The population examined includes 348 nuclear families ascertained by one asthmatic (213 adult and 135 paediatric probands) and 416 controls, totalling 1,847 subjects (EGEA I). Prevalences of asthma, skin prick test response, high IgE and bronchial hyperresponsiveness were for parents, siblings, and offspring of cases intermediate between cases and spouses or controls, both in adults and children, confirming the familial resemblance for asthma and related traits. With an additional sample of 40 families ascertained by two asthmatic siblings (EGEA II), a total of 119 families with two asthmatic siblings has been ascertained for a genome screening.