Serum club cell protein 16 is associated with asymptomatic airway responsiveness in adults: Findings from the French epidemiological study on the genetics and environment of asthma.

BACKGROUND AND OBJECTIVE: Club cell secretory protein (CC-16) is a sensitive biomarker of airways epithelium integrity. It has gained interest as a biological marker in chronic lung diseases because of its presumed relationship to inflammation. Little is known about the association between CC-16 serum level and asthma, lung function and airway responsiveness (AR). METHODS: Serum CC-16 level was determined by latex immunoassay in 1298 participants from the French Epidemiological case-control and family-based study on Genetics and Environment of Asthma (EGEA) (mean age 43 years; 49% men, 38% with asthma). Pre-bronchodilator lung function (forced expiratory volume in 1 s (FEV1 ), forced vital capacity (FVC) and FEV1 /FVC) and degree of AR, expressed as a function of the dose-response slope to methacholine test were measured. Standardized residuals CC-16 z-scores were obtained by regressing CC-16 level on the glomerular filtration rate. CC-16 z-scores were correlated with asthma, lung function and AR in participants with and without asthma. RESULTS: CC-16 geometric mean level was 12.4 µg/L (range: 2.2-70.6 µg/L). In participants without asthma, lower CC-16 z-scores was associated with impaired FEV1 /FVC% (ß = 0.50 (95% CI: 0.06, 0.95) and with higher degree of AR (ß = 0.24 (95% CI: 0.09, 0.39)). CC-16 was not associated with impaired lung function or AR in participants with asthma. CONCLUSIONS: Lower CC-16 serum level was associated with impaired lung function and AR, suggesting that serum CC-16 level may reflect early damages to the lung epithelium in adults without asthma.

Ambient air pollution and adult asthma incidence in six European cohorts (ESCAPE).

BACKGROUND: Short-term exposure to air pollution has adverse effects among patients with asthma, but whether long-term exposure to air pollution is a cause of adult-onset asthma is unclear. OBJECTIVE: We aimed to investigate the association between air pollution and adult onset asthma. METHODS: Asthma incidence was prospectively assessed in six European cohorts. Exposures studied were annual average concentrations at home addresses for nitrogen oxides assessed for 23,704 participants (including 1,257 incident cases) and particulate matter (PM) assessed for 17,909 participants through ESCAPE land-use regression models and traffic exposure indicators. Meta-analyses of cohort-specific logistic regression on asthma incidence were performed. Models were adjusted for age, sex, overweight, education, and smoking and included city/area within each cohort as a random effect. RESULTS: In this longitudinal analysis, asthma incidence was positively, but not significantly, associated with all exposure metrics, except for PMcoarse. Positive associations of borderline significance were observed for nitrogen dioxide [adjusted odds ratio (OR) = 1.10; 95% CI: 0.99, 1.21 per 10 µg/m3; p = 0.10] and nitrogen oxides (adjusted OR = 1.04; 95% CI: 0.99, 1.08 per 20 µg/m3; p = 0.08). Nonsignificant positive associations were estimated for PM10 (adjusted OR = 1.04; 95% CI: 0.88, 1.23 per 10 µg/m3), PM2.5 (adjusted OR = 1.04; 95% CI: 0.88, 1.23 per 5 µg/m3), PM2.5absorbance (adjusted OR = 1.06; 95% CI: 0.95, 1.19 per 10-5/m), traffic load (adjusted OR = 1.10; 95% CI: 0.93, 1.30 per 4 million vehicles × meters/day on major roads in a 100-m buffer), and traffic intensity (adjusted OR = 1.10; 95% CI: 0.93, 1.30 per 5,000 vehicles/day on the nearest road). A nonsignificant negative association was estimated for PMcoarse (adjusted OR = 0.98; 95% CI: 0.87, 1.14 per 5 µg/m3). CONCLUSIONS: Results suggest a deleterious effect of ambient air pollution on asthma incidence in adults. Further research with improved personal-level exposure assessment (vs. residential exposure assessment only) and phenotypic characterization is needed.

Adult lung function and long-term air pollution exposure. ESCAPE: a multicentre cohort study and meta-analysis.

The chronic impact of ambient air pollutants on lung function in adults is not fully understood. The objective of this study was to investigate the association of long-term exposure to ambient air pollution with lung function in adult participants from five cohorts in the European Study of Cohorts for Air Pollution Effects (ESCAPE). Residential exposure to nitrogen oxides (NO2, NOx) and particulate matter (PM) was modelled and traffic indicators were assessed in a standardised manner. The spirometric parameters forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) from 7613 subjects were considered as outcomes. Cohort-specific results were combined using meta-analysis. We did not observe an association of air pollution with longitudinal change in lung function, but we observed that a 10 µg·m(-3) increase in NO2 exposure was associated with lower levels of FEV1 (-14.0 mL, 95% CI -25.8 to -2.1) and FVC (-14.9 mL, 95% CI -28.7 to -1.1). An increase of 10 µg·m(-3) in PM10, but not other PM metrics (PM2.5, coarse fraction of PM, PM absorbance), was associated with a lower level of FEV1 (-44.6 mL, 95% CI -85.4 to -3.8) and FVC (-59.0 mL, 95% CI -112.3 to -5.6). The associations were particularly strong in obese persons. This study adds to the evidence for an adverse association of ambient air pollution with lung function in adults at very low levels in Europe.

Perceived 10-year change in respiratory health: reliability and predictive ability.

OBJECTIVE: To investigate the usefulness of a self-reported respiratory health transition question over 10 years through reliability, ability to capture long-term asthma trajectory and predictive ability. SETTINGS: In two 20-year cohorts (Asthma-E3N, n = 16,371, 61-88 years; EGEA, n = 1254, 27-82 years), perceived 10-year change in respiratory health ("Overall, in the last 10 years, do you think that your bronchial or respiratory health has changed?" if yes: "Has it improved/deteriorated?") was studied in relation with change in respiratory medication dispensation and lung function, with change in asthma status measured over the same period of time, and with subsequent asthma-related outcomes. RESULTS: Perceived deterioration (14% in Asthma-E3N) was associated with increased dispensations of respiratory medications over time (from 17% with >2 dispensations in 2004 to 26% in 2010). Report of perceived deterioration (13% in EGEA) was related to a lung function decline steeper by 9.3 mL/year as compared to perceived improvement. In both cohorts, change (improvement or deterioration) was more often perceived by participants with than without asthma (>45% vs <20%) and was dominant among participants with persistent current asthma (77%). Perceived deterioration was related to poorer asthma control 7 years later and to higher use of oral corticosteroids in the following 18 months. CONCLUSION: The proposed simple self-reported respiratory health transition question over 10 years allows predicting part of the long-term trajectory of asthma.

Long-term benefits of inhaled corticosteroids in asthma: the propensity score method.

PURPOSE: The aim of this study was to apply a propensity score approach to assess the long-term benefits of inhaled corticosteroids (ICS) on respiratory health in asthma. METHODS: This analysis was conducted on adults with persistent asthma from the Epidemiological study on the Genetics and Environment of Asthma, a 12-year follow-up study. ICS exposure was assessed by questionnaire. Change in lung function over the follow-up period, asthma control, and health-related quality of life (asthma quality of life questionnaire) were assessed by standardized and validated methods. RESULTS: Among 245 adults with persistent asthma, 78 (31.8%) were regularly/continuously exposed to ICS (≥6 months/year, ICS++ ) and 167 never/irregularly exposed to ICS (<6 months/year, ICS+/- ) over the follow-up period. Compared with ICS+/- subjects, a nonsignificant trend for a slower lung function decline (mL/year) was observed in ICS++ subjects (ß [95%CI] = -11.4 [-24.9; 2.0]). The ICS++ subjects did not have better controlled asthma and higher health-related quality of life as compared with ICS+/- subjects. CONCLUSIONS: Applying a propensity score method did not offer evidence of a statistical significant long-term benefit of ICS on respiratory health in adults with persistent asthma regularly or continuously exposed to ICS over a long period.

Cross-sectional associations between air pollution and chronic bronchitis: an ESCAPE meta-analysis across five cohorts.

BACKGROUND: This study aimed to assess associations of outdoor air pollution on prevalence of chronic bronchitis symptoms in adults in five cohort studies (Asthma-E3N, ECRHS, NSHD, SALIA, SAPALDIA) participating in the European Study of Cohorts for Air Pollution Effects (ESCAPE) project. METHODS: Annual average particulate matter (PM(10), PM(2.5), PM(absorbance), PM(coarse)), NO(2), nitrogen oxides (NO(x)) and road traffic measures modelled from ESCAPE measurement campaigns 2008-2011 were assigned to home address at most recent assessments (1998-2011). Symptoms examined were chronic bronchitis (cough and phlegm for ≥3 months of the year for ≥2 years), chronic cough (with/without phlegm) and chronic phlegm (with/without cough). Cohort-specific cross-sectional multivariable logistic regression analyses were conducted using common confounder sets (age, sex, smoking, interview season, education), followed by meta-analysis. RESULTS: 15 279 and 10 537 participants respectively were included in the main NO(2) and PM analyses at assessments in 1998-2011. Overall, there were no statistically significant associations with any air pollutant or traffic exposure. Sensitivity analyses including in asthmatics only, females only or using back-extrapolated NO(2) and PM10 for assessments in 1985-2002 (ECRHS, NSHD, SALIA, SAPALDIA) did not alter conclusions. In never-smokers, all associations were positive, but reached statistical significance only for chronic phlegm with PM(coarse) OR 1.31 (1.05 to 1.64) per 5 µg/m(3) increase and PM(10) with similar effect size. Sensitivity analyses of older cohorts showed increased risk of chronic cough with PM(2.5abs) (black carbon) exposures. CONCLUSIONS: Results do not show consistent associations between chronic bronchitis symptoms and current traffic-related air pollution in adult European populations.

Human leukocyte antigen class II variants and adult-onset asthma: does occupational allergen exposure play a role?

Recently, a locus centred on rs9273349 in the HLA-DQ region emerged from genome-wide association studies of adult-onset asthma. We aimed to further investigate the role of human leukocyte antigen (HLA) class II in adult-onset asthma and a possible interaction with occupational exposures. We imputed classical HLA-II alleles from 7579 single-nucleotide polymorphisms in 6025 subjects (1202 with adult-onset asthma) from European cohorts: ECRHS, SAPALDIA, EGEA and B58C, and from surveys of bakers and agricultural workers. Based on an asthma-specific job-exposure matrix, 2629 subjects had ever been exposed to high molecular weight (HMW) allergens. We explored associations between 23 common HLA-II alleles and adult-onset asthma, and tested for gene-environment interaction with occupational exposure to HMW allergens. Interaction was also tested for rs9273349. Marginal associations of classical HLA-II alleles and adult-onset asthma were not statistically significant. Interaction was detected between the DPB1*03:01 allele and exposure to HMW allergens (p = 0.009), in particular to latex (p = 0.01). In the unexposed group, the DPB1*03:01 allele was associated with adult-onset asthma (OR 0.67, 95%CI 0.53-0.86). HMW allergen exposures did not modify the association of rs9273349 with adult-onset asthma. Common classical HLA-II alleles were not marginally associated with adult-onset asthma. The association of latex exposure and adult-onset asthma may be modified by DPB1*03:01.

Occupational irritants and asthma: an Estonian cross-sectional study of 34,000 adults.

Occupational exposures make important contributions to asthma morbidity. The role of low/moderate level irritant exposures remains unclear. We aimed to determine which occupational exposures are associated with asthma in an eastern European country with low asthma prevalence. The Estonian Genome Center of University of Tartu collected data from 50 077 adults in 2002-2011. Asthma was assessed through a questionnaire regarding diagnosed diseases, current health status and medication. Exposures to 22 agents during the current and longest held jobs were estimated using an asthma-specific job-exposure matrix. Analyses included 34 015 subjects (aged 18-65 years, 67.0% females), of which 1209 (3.6%) reported asthma (608 with physician-confirmed diagnosis). After adjusting for age, sex and smoking habits, lifetime occupational exposure to known asthmagens (20.4%) was significantly associated with physician-diagnosed asthma (OR 1.28, 95% CI 1.03-1.59), especially high molecular weight agents (flour: OR 2.36, 95% CI 1.31-4.27; animals: OR 1.62, 95% CI 1.00-2.60). Exposure to low/moderate levels of irritants (17.4%) was associated with physician-diagnosed asthma (OR 1.88, 95% CI 1.48-2.37). More pronounced associations were observed in subjects reporting current treated asthma. Beyond confirming the effect of known asthmagens (which are well-known, mostly from observations in western countries), the results provide evidence for a role of low/moderate exposure to irritants. This finding, observed in a country with a low prevalence of asthma and atopy, provides new insight into the understanding of asthma heterogeneity.

Association of ambient air pollution with the prevalence and incidence of COPD.

The role of air pollution in chronic obstructive pulmonary disease (COPD) remains uncertain. The aim was to assess the impact of chronic exposure to air pollution on COPD in four cohorts using the standardised ESCAPE exposure estimates. Annual average particulate matter (PM), nitrogen oxides (NOx) and road traffic exposure were assigned to home addresses using land-use regression models. COPD was defined by NHANES reference equation (forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) less than the lower limit of normal) and the Global Initiative for Chronic Obstructive Lung Disease criterion (FEV1/FVC <0.70) and categorised by severity in non-asthmatics. We included 6550 subjects with assigned NOx and 3692 with PM measures. COPD was not associated with NO2 or PM10 in any individual cohort. In meta-analyses only NO2, NOx, PM10 and the traffic indicators were positively, although not significantly, associated with COPD. The only statistically significant associations were seen in females (COPD prevalence using GOLD: OR 1.57, 95% CI 1.11-2.23; and incidence: OR 1.79, 95% CI 1.21-2.68). None of the principal results were statistically significant, the weak positive associations of exposure with COPD and the significant subgroup findings need to be evaluated in further well standardised cohorts followed up for longer time, and with time-matched exposure assignments.

Cleaning sprays, household help and asthma among elderly women.

OBJECTIVE: There is increasing evidence on the deleterious role in asthma of the use of household cleaning products in spray forms in adults. Household help might induce misclassification errors. The aim of the present analysis was to study associations between household exposure to cleaning sprays and current asthma in elderly women, taking into account household help. METHODS: A nested case-control survey on respiratory health was undertaken among a random sample of French women from the E3N study. Data were available for 570 women (235 with current asthma and 335 without asthma history; 68 years old on average, 59% never smokers). Three estimates of domestic exposure were used: 1) self-reported, 2) using principal component analysis, 3) a composite score for sprays. Associations between domestic exposures and asthma were assessed by logistic regression, adjusted for age, educational level, BMI and smoking status. Analyses were further stratified on household help in order to evaluate a potential misclassification bias. RESULTS: Among women without household help (n = 325), a significant association was observed between weekly use of at least one spray and current asthma (OR [95% CI]: 1.86[1.04-3.33]). No association was observed among women with household help. CONCLUSIONS: Weekly household use of cleaning sprays may have a deleterious effect on asthma. It is important to take into account household help to limit misclassification bias.

Cleaning and asthma characteristics in women.

BACKGROUND: We aimed to assess the associations between occupational exposure to cleaning products, a gender-related exposure, and asthma characteristics, considering clinical, immunological and inflammatory aspects. METHODS: Analyses were conducted in 391 women (73 with adult-onset asthma) from the follow-up of the Epidemiological Study on the Genetics and Environment of Asthma (EGEA). Occupational exposure to cleaning/disinfecting products was estimated using the asthma-specific job-exposure-matrix (44 women exposed). RESULTS: Occupational exposures were associated with more symptomatic asthma (odds ratio (95% CI): 2.8(1.2-6.4)) and severe asthma (5.1(1.7-15.3)). An association was suggested for poorly controlled asthma (2.2(0.9-5.5)). Associations were observed for asthma without positive skin prick test (3.0(1.1-8.3)), with a low IgE level (2.8(1.2-6.2)), and with a low eosinophil count (3.2(1.5-7.1)). CONCLUSIONS: Results strengthen the evidence of a deleterious role of cleaning products in asthma and are consistent with the hypothesis of non-allergic mechanisms in relation to workplace cleaning exposures.

Ambient air pollution: a cause of COPD?

The role of ambient air pollution in the development of chronic obstructive pulmonary disease (COPD) is considered to be uncertain. We review the evidence in the light of recent studies. Eight morbidity and six mortality studies were identified. These were heterogeneous in design, characterisation of exposure to air pollution and methods of outcome definition. Six morbidity studies with objectively defined COPD (forced expiratory volume in 1 s/forced vital capacity ratio) were cross-sectional analyses. One longitudinal study defined incidence of COPD as the first hospitalisation due to COPD. However, neither mortality nor hospitalisation studies can unambiguously distinguish acute from long-term effects on the development of the underlying pathophysiological changes. Most studies were based on within-community exposure contrasts, which mainly assess traffic-related air pollution. Overall, evidence of chronic effects of air pollution on the prevalence and incidence of COPD among adults was suggestive but not conclusive, despite plausible biological mechanisms and good evidence that air pollution affects lung development in childhood and triggers exacerbations in COPD patients. To fully integrate this evidence in the assessment, the life-time course of COPD should be better defined. Larger studies with longer follow-up periods, specific definitions of COPD phenotypes, and more refined and source-specific exposure assessments are needed.

Genetic heterogeneity of asthma phenotypes identified by a clustering approach.

The aim of the study was to identify genetic variants associated with refined asthma phenotypes enabling multiple features of the disease to be taken into account. Latent class analysis (LCA) was applied in 3001 adults ever having asthma recruited in the frame of three epidemiological surveys (the European Community Respiratory Health Survey (ECRHS), the Swiss Study on Air Pollution and Lung Disease in Adults (SAPALDIA) and the Epidemiological Study on the Genetics and Environment of Asthma (EGEA)). 14 personal and phenotypic characteristics, gathered from questionnaires and clinical examination, were used. A genome-wide association study was conducted for each LCA-derived asthma phenotype, compared to subjects without asthma (n=3474). The LCA identified four adult asthma phenotypes, mainly characterised by disease activity, age of asthma onset and atopic status. Associations of genome-wide significance (p<1.25 × 10(-7)) were observed between "active adult-onset nonallergic asthma" and rs9851461 flanking CD200 (3q13.2) and between "inactive/mild nonallergic asthma" and rs2579931 flanking GRIK2 (6q16.3). Borderline significant results (2.5 × 10(-7) < p <8.2 × 10(-7)) were observed between three single nucleotide polymorphisms (SNPs) in the ALCAM region (3q13.11) and "active adult-onset nonallergic asthma". These results were consistent across studies. 15 SNPs identified in previous genome-wide association studies of asthma have been replicated with at least one asthma phenotype, most of them with the "active allergic asthma" phenotype. Our results provide evidence that a better understanding of asthma phenotypic heterogeneity helps to disentangle the genetic heterogeneity of asthma.

Environment and asthma in adults.

The present review addresses recent advances and especially challenging aspects regarding the role of environmental risk factors in adult-onset asthma, for which the causes are poorly established. In the first part of the review, we discuss aspects regarding some environmental risk factors for adult-onset asthma: air pollution, occupational exposures with a focus on an emerging risk represented by exposure to cleaning agents (both at home and in the workplace), and lifestyle and nutrition. The second part is focused on perspectives and challenges, regarding relevant topics on which research is needed to improve the understanding of the role of environmental factors in asthma. Aspects of exposure assessment, the complexity of multiple exposures, the interrelationships of the environment with behavioral characteristics and the importance of studying biological markers and gene-environment interactions to identify the role of the environment in asthma are discussed. We conclude that environmental and lifestyle exposures play an important role in asthma or related phenotypes. The changes in lifestyle and the environment in recent decades have modified the specific risk factors in asthma even for well-recognized risks such as occupational exposures. To better understand the role of the environment in asthma, the use of objective (quantitative measurement of exposures) or modern tools (bar code, GPS) and the development of multidisciplinary collaboration would be very promising. A better understanding of the complex interrelationships between socio-economic, nutritional, lifestyle and environmental conditions might help to study their joint and independent roles in asthma.

Impact of geocoding methods on associations between long-term exposure to urban air pollution and lung function.

BACKGROUND: Errors in address geocodes may affect estimates of the effects of air pollution on health. OBJECTIVE: We investigated the impact of four geocoding techniques on the association between urban air pollution estimated with a fine-scale (10 m × 10 m) dispersion model and lung function in adults. METHODS: We measured forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC) in 354 adult residents of Grenoble, France, who were participants in two well-characterized studies, the Epidemiological Study on the Genetics and Environment on Asthma (EGEA) and the European Community Respiratory Health Survey (ECRHS). Home addresses were geocoded using individual building matching as the reference approach and three spatial interpolation approaches. We used a dispersion model to estimate mean PM10 and nitrogen dioxide concentrations at each participant's address during the 12 months preceding their lung function measurements. Associations between exposures and lung function parameters were adjusted for individual confounders and same-day exposure to air pollutants. The geocoding techniques were compared with regard to geographical distances between coordinates, exposure estimates, and associations between the estimated exposures and health effects. RESULTS: Median distances between coordinates estimated using the building matching and the three interpolation techniques were 26.4, 27.9, and 35.6 m. Compared with exposure estimates based on building matching, PM10 concentrations based on the three interpolation techniques tended to be overestimated. When building matching was used to estimate exposures, a one-interquartile range increase in PM10 (3.0 µg/m3) was associated with a 3.72-point decrease in FVC% predicted (95% CI: -0.56, -6.88) and a 3.86-point decrease in FEV1% predicted (95% CI: -0.14, -3.24). The magnitude of associations decreased when other geocoding approaches were used [e.g., for FVC% predicted -2.81 (95% CI: -0.26, -5.35) using NavTEQ, or 2.08 (95% CI -4.63, 0.47, p = 0.11) using Google Maps]. CONCLUSIONS: Our findings suggest that the choice of geocoding technique may influence estimated health effects when air pollution exposures are estimated using a fine-scale exposure model.

Are operating room nurses at higher risk of severe persistent asthma? The Nurses' Health Study.

OBJECTIVE: To assess the associations between operating room (OR) nursing, a category of health care workers at high risk of exposure to various inhaled agents, and asthma severity/control among women with asthma. METHODS: The level of severity/control in nurses with prevalent doctor-diagnosed asthma in 1998/2000 was compared, using nominal logistic regression, in OR nursing (n = 69) and administrative nursing (n = 546) from the US Nurses' Health Study for whom detailed information on asthma and nursing employment status was available. RESULTS: We observed a significant association between OR nursing, compared with administrative nursing, and severe persistent asthma (adjusted odds ratio, 2.48; 95% confidence interval, 1.06 to 5.77). CONCLUSIONS: Our findings suggest that nurses working in the OR are at a higher risk of severe persistent asthma. Further studies with detailed estimates of occupational exposures, especially to disinfectant/cleaning agents, are warranted.

Temporal asthma patterns using repeated questionnaires over 13 years in a large French cohort of women.

Variable expression is one aspect of the heterogeneity of asthma. We aimed to define a variable pattern, which is relevant in general health epidemiological cohorts. Our objectives were to assess whether: 1) asthma patterns defined using simple asthma questions through repeated measurements could reflect disease variability 2) these patterns may further be classified according to asthma severity/control. Among 70,428 French women, we used seven questionnaires (1992-2005) and a comprehensive reimbursement database (2004-2009) to define three reliable asthma patterns based on repeated positive answers to the ever asthma attack question: "never asthma" (n = 64,061); "inconsistent" ("yes" followed by "no", n = 3,514); "consistent" (fully consistent positive answers, n = 2,853). The "Inconsistent" pattern was related to both long-term (childhood-onset asthma with remission in adulthood) and short-term (reported asthma attack in the last 12 months, associated with asthma medication) asthma variability, showing that repeated questions are relevant markers of the variable expression of asthma. Furthermore, in this pattern, the number of positive responses (1992-2005) predicted asthma drug consumption in subsequent years, a marker of disease severity. The "Inconsistent" pattern is a phenotype that may capture the variable expression of asthma. Repeated answers, even to a simple question, are too often neglected.

Ten-year follow-up of cluster-based asthma phenotypes in adults. A pooled analysis of three cohorts.

RATIONALE: The temporal stability of adult asthma phenotypes identified using clustering methods has never been addressed. Longitudinal cluster-based methods may provide novel insights in the study of the natural history of asthma. OBJECTIVES: To compare the stability of cluster-based asthma phenotype structures a decade apart in adults and to address the individuals' phenotypic transition across these asthma phenotypes. METHODS: The latent transition analysis was applied on longitudinal data (twice, 10 yr apart) from 3,320 adults with asthma who took part in the European Community Respiratory Health Survey, the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults, or the Epidemiological Study on Genetics and Environment of Asthma. Nine variables covering personal and phenotypic characteristics measured twice, 10 years apart, were simultaneously considered. MEASUREMENTS AND MAIN RESULTS: Latent transition analysis identifies seven asthma phenotypes (prevalence range, 8.4-20.8%), mainly characterized by the level of asthma symptoms (low, moderate, high), the allergic status, and pulmonary function. Phenotypes observed 10 years apart showed strong similarities. The probability of membership in the same asthma phenotype at both times varied across phenotypes from 54 to 88%. Different transition patterns were observed across phenotypes. Transitions toward increased asthma symptoms were more frequently observed among nonallergic phenotypes as compared with allergic phenotypes. Results showed a strong stability of the allergic status over time. CONCLUSIONS: Adult asthma phenotypes identified by a clustering approach, 10 years apart, were highly consistent. This study is the first to model the probabilities of transitioning over time between comprehensive asthma phenotypes.

Work related asthma. A causal analysis controlling the healthy worker effect.

OBJECTIVES: The healthy worker effect usually leads to underestimation of the association between occupational exposure and asthma. The role of irritants in work-related asthma is disputed. We estimated the effect of occupational exposure on asthma expression in a longitudinal study, using marginal structural modelling to control for the healthy worker effect. METHODS: Analyses included 1284 participants (17-79 years, 48% men) from the follow-up (2003-2007) of the French Epidemiological study on the Genetics and Environment of Asthma (case-control study). Age at asthma onset, periods with/without attacks over lifetime and occupational history were recorded retrospectively. Exposures to known asthmagens, irritants or low level of chemicals/allergens were evaluated through a job-exposure matrix. The job history was reconstructed into 5-year intervals. RESULTS: Thirty-one per cent of subjects had ever been exposed to occupational asthmagens. Among the 38% of subjects who had asthma (ever), presence of attacks was reported in 52% of all time periods. Using standard analyses, no association was observed between exposure to known asthmagens (OR (95% CI): 0.99 (0.72 to 1.36)) or to irritants/low level of chemicals/allergens (0.82 (0.56 to 1.20)) and asthma attacks. Using a marginal structural model, all associations increased with suggestive evidence for known asthmagens (1.26 (0.90 to 1.76)), and reaching statistical significance for irritants/low level of chemicals/allergens (1.56 (1.02 to 2.40)). CONCLUSIONS: The healthy worker effect has an important impact in risk assessment in work-related asthma studies. Marginal structural models are useful to eliminate imbalances in exposure due to disease-driven selection. Results support the role of irritants in work-related asthma.