Determinants of immunoglobulin G responses to respiratory syncytial virus and rhinovirus in children and adults.

Introduction: Exposure to respiratory viruses is a significant cause of morbidity and affects virus-specific antibody levels. Little is known about determinants associated with immune response to these viruses. We aimed to investigate the determinants of respiratory syncytial virus (RSV)- and rhinovirus (RV)- specific IgG responses in both children and adults. Methods: The study is based on the EGEA cohort, composed of 530 samples of children in EGEA1 (1991-95) and 1241 samples of adults in EGEA2 (2003-07). Cumulative RV-specific IgG levels (species A, B and C) and IgG levels to RSV-G protein were measured by using micro-array technoloy. Multiple linear mixed models (random effect to account for familial dependence) were performed to assess associations between age, sex, body mass index (BMI), tobacco smoke exposure and season of blood sampling with RSV-and RV-specific IgG levels. Results: In children (11.1 ± 2.8 years old, 57% boys), higher RV-specific IgG levels were associated with older age (only for RV-B), female sex and lower BMI, while only older age was associated with higher RSV-specific IgG levels. In adults (43.5 ± 16.7 years old, 48% men), younger age, female sex, lower BMI, active smoking and all seasons except summer were associated with higher RV-specific IgG levels. Older age, active smoking and all seasons except summer were associated with higher RSV-specific IgG levels. Conclusion: Personal and seasonal determinants of RSV- and RV-specific IgG levels seem to vary according to the respiratory virus type and between children and adults, suggesting different patterns of responses along the life course.

Impact of long-term exposure to ambient ozone on lung function over a course of 20 years (The ECRHS study): a prospective cohort study in adults.

Background: While the adverse effects of short-term ambient ozone exposure on lung function are well-documented, the impact of long-term exposure remains poorly understood, especially in adults. Methods: We aimed to investigate the association between long-term ozone exposure and lung function decline. The 3014 participants were drawn from 17 centers across eight countries, all of which were from the European Community Respiratory Health Survey (ECRHS). Spirometry was conducted to measure pre-bronchodilation forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) at approximately 35, 44, and 55 years of age. We assigned annual mean values of daily maximum running 8-h average ozone concentrations to individual residential addresses. Adjustments were made for PM2.5, NO2, and greenness. To capture the ozone-related change in spirometric parameters, our linear mixed effects regression models included an interaction term between long-term ozone exposure and age. Findings: Mean ambient ozone concentrations were approximately 65 µg/m³. A one interquartile range increase of 7 µg/m³ in ozone was associated with a faster decline in FEV1 of -2.08 mL/year (95% confidence interval: -2.79, -1.36) and in FVC of -2.86 mL/year (-3.73, -1.99) mL/year over the study period. Associations were robust after adjusting for PM2.5, NO2, and greenness. The associations were more pronounced in residents of northern Europe and individuals who were older at baseline. No consistent associations were detected with the FEV1/FVC ratio. Interpretation: Long-term exposure to elevated ambient ozone concentrations was associated with a faster decline of spirometric lung function among middle-aged European adults over a 20-year period. Funding: German Research Foundation.

Environmental exposures in early-life and general health in childhood.

BACKGROUND: Early-life environmental exposures are suspected to be involved in the development of chronic diseases later in life. Most studies conducted so far considered single or few exposures and single-health parameter. Our study aimed to identify a childhood general health score and assess its association with a wide range of pre- and post-natal environmental exposures. METHODS: The analysis is based on 870 children (6-12 years) from six European birth cohorts participating in the Human Early-Life Exposome project. A total of 53 prenatal and 105 childhood environmental factors were considered, including lifestyle, social, urban and chemical exposures. We built a general health score by averaging three sub-scores (cardiometabolic, respiratory/allergy and mental) built from 15 health parameters. By construct, a child with a low score has a low general health status. Penalized multivariable regression through Least Absolute Shrinkage and Selection Operator (LASSO) was fitted in order to identify exposures associated with the general health score. FINDINGS: The results of LASSO show that a lower general health score was associated with maternal passive and active smoking during pregnancy and postnatal exposure to methylparaben, copper, indoor air pollutants, high intake of caffeinated drinks and few contacts with friends and family. Higher child's general health score was associated with prenatal exposure to a bluespace near residency and postnatal exposures to pets, cobalt, high intakes of vegetables and more physical activity. Against our hypotheses, postnatal exposure to organochlorine compounds and perfluorooctanoate were associated with a higher child's general health score. CONCLUSION: By using a general health score summarizing the child cardiometabolic, respiratory/allergy and mental health, this study reinforced previously suspected environmental factors associated with various child health parameters (e.g. tobacco, air pollutants) and identified new factors (e.g. pets, bluespace) warranting further investigations.

Residential greenspace and lung function decline over 20 years in a prospective cohort: The ECRHS study.

BACKGROUND: The few studies that have examined associations between greenspace and lung function in adulthood have yielded conflicting results and none have examined whether the rate of lung function decline is affected. OBJECTIVE: We explored the association between residential greenspace and change in lung function over 20 years in 5559 adults from 22 centers in 11 countries participating in the population-based, international European Community Respiratory Health Survey. METHODS: Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were measured by spirometry when participants were approximately 35 (1990-1994), 44 (1999-2003), and 55 (2010-2014) years old. Greenness was assessed as the mean Normalized Difference Vegetation Index (NDVI) in 500 m, 300 m, and 100 m circular buffers around the residential addresses at the time of lung function measurement. Green spaces were defined as the presence of agricultural, natural, or urban green spaces in a circular 300 m buffer. Associations of these greenspace parameters with the rate of lung function change were assessed using adjusted linear mixed effects regression models with random intercepts for subjects nested within centers. Sensitivity analyses considered air pollution exposures. RESULTS: A 0.2-increase (average interquartile range) in NDVI in the 500 m buffer was consistently associated with a faster decline in FVC (-1.25 mL/year [95% confidence interval: -2.18 to -0.33]). These associations were especially pronounced in females and those living in areas with low PM10 levels. We found no consistent associations with FEV1 and the FEV1/FVC ratio. Residing near forests or urban green spaces was associated with a faster decline in FEV1, while agricultural land and forests were related to a greater decline in FVC. CONCLUSIONS: More residential greenspace was not associated with better lung function in middle-aged European adults. Instead, we observed slight but consistent declines in lung function parameters. The potentially detrimental association requires verification in future studies.

Maternal imprinting and determinants of neonates' immune function in the SEPAGES mother-child cohort.

Introduction: Immune function in pregnancy is influenced by host-specific and environmental factors. This may impact fetal immune development, but the link between maternal and neonatal immune function is still poorly characterized. Here, we investigate the relationship between maternal and neonatal immune function, and identify factors affecting the association between maternal and child cytokine secretion. Methods: In the French prospective cohort SEPAGES, blood samples were obtained from pregnant women (n=322) at gestational week 20 ± 4 and from their child at birth (n=156). Maternal and cord blood cytokine and chemokine (CK) levels were measured at baseline in all subjects and after T cell or dendritic cell activation with phytohemagglutinin or R848 (in total 29 and 27 measures in maternal and cord blood samples, respectively). Associations between environmental, individual factors and CK level were estimated by linear regression modeling. The maternal-cord blood CK relations were assessed by Pearson correlation and regression models. Results: We observed that pregnant women and neonates displayed specific CK secretion profiles in the innate and adaptive compartments at baseline and upon activation. Activation of T cells in cord blood induced high levels of IL-2, but low levels of IFNγ, IL-13 or IL-10, in comparison to maternal blood samples. Elsewhere, neonatal innate immune responses were characterized by low production of IFNα, while productions of IL-1ß, IL-6, IL-8, IL-10 and TNFα were higher than maternal responses. Strong correlations were observed between most CK after activation in maternal and cord blood samples. Strikingly, a statistical association between global mother and child cytokine profiles was evidenced. Correlations were observed between some individual CK of pregnant women and their children, both at baseline (MCP1, RANTES) and after activation with R848 (IL-6, IL-8 and IL-10). We looked for factors which could influence cytokine secretion in maternal or cord blood, and found that leucocyte counts, maternal age, pre-conception BMI, smoking and season were associated with the levels of several CK in mothers or children. Discussion: Our study reveals in utero immune imprinting influencing immune responses in infants, opening the way to investigate the mechanisms responsible for this imprinting. Whether such influences have long lasting effects on children health warrants further investigation.

Pre-natal exposure to NO2 and PM2.5 and newborn lung function: An approach based on repeated personal exposure measurements.

CONTEXT: While strong evidence supports adverse effects of pre-natal air pollution on child's lung function, previous studies rarely considered fine particulate matter (PM2.5) or the potential role of offspring sex and no study examined the effects of pre-natal PM2.5 on the lung function of the newborn. AIM: We examined overall and sex-specific associations of personal pre-natal exposure to PM2.5 and nitrogen (NO2) with newborn lung function measurements. METHODS: This study relied on 391 mother-child pairs from the French SEPAGES cohort. PM2.5 and NO2 exposure was estimated by the average concentration of pollutants measured by sensors carried by the pregnant women during repeated periods of one week. Lung function was assessed with tidal breathing analysis (TBFVL) and nitrogen multiple breath washout (N2MBW) test, performed at 7 weeks. Associations between pre-natal exposure to air pollutants and lung function indicators were estimated by linear regression models adjusted for potential confounders, and then stratified by sex. RESULTS: Mean exposure to NO2 and PM2.5 during pregnancy was 20.2 µg/m3 and 14.3 µg/m3, respectively. A 10 µg/m3 increase in PM2.5 maternal personal exposure during pregnancy was associated with an adjusted 2.5 ml (2.3%) decrease in the functional residual capacity of the newborn (p-value = 0.11). In females, functional residual capacity was decreased by 5.2 ml (5.0%) (p = 0.02) and tidal volume by 1.6 ml (p = 0.08) for each 10 µg/m3 increase in PM2.5. No association was found between maternal NO2 exposure and newborns lung function. CONCLUSIONS: Personal pre-natal PM2.5 exposure was associated with lower lung volumes in female newborns, but not in males. Our results provide evidence that pulmonary effects of air pollution exposure can be initiated in utero. These findings have long term implications for respiratory health and may provide insights into the underlying mechanisms of PM2.5 effects.

Systems prediction of chronic lung allograft dysfunction: Results and perspectives from the Cohort of Lung Transplantation and Systems prediction of Chronic Lung Allograft Dysfunction cohorts.

Background: Chronic lung allograft dysfunction (CLAD) is the leading cause of poor long-term survival after lung transplantation (LT). Systems prediction of Chronic Lung Allograft Dysfunction (SysCLAD) aimed to predict CLAD. Methods: To predict CLAD, we investigated the clinicome of patients with LT; the exposome through assessment of airway microbiota in bronchoalveolar lavage cells and air pollution studies; the immunome with works on activation of dendritic cells, the role of T cells to promote the secretion of matrix metalloproteinase-9, and subpopulations of T and B cells; genome polymorphisms; blood transcriptome; plasma proteome studies and assessment of MSK1 expression. Results: Clinicome: the best multivariate logistic regression analysis model for early-onset CLAD in 422 LT eligible patients generated a ROC curve with an area under the curve of 0.77. Exposome: chronic exposure to air pollutants appears deleterious on lung function levels in LT recipients (LTRs), might be modified by macrolides, and increases mortality. Our findings established a link between the lung microbial ecosystem, human lung function, and clinical stability post-transplant. Immunome: a decreased expression of CLEC1A in human lung transplants is predictive of the development of chronic rejection and associated with a higher level of interleukin 17A; Immune cells support airway remodeling through the production of plasma MMP-9 levels, a potential predictive biomarker of CLAD. Blood CD9-expressing B cells appear to favor the maintenance of long-term stable graft function and are a potential new predictive biomarker of BOS-free survival. An early increase of blood CD4 + CD57 + ILT2+ T cells after LT may be associated with CLAD onset. Genome: Donor Club cell secretory protein G38A polymorphism is associated with a decreased risk of severe primary graft dysfunction after LT. Transcriptome: blood POU class 2 associating factor 1, T-cell leukemia/lymphoma domain, and B cell lymphocytes, were validated as predictive biomarkers of CLAD phenotypes more than 6 months before diagnosis. Proteome: blood A2MG is an independent predictor of CLAD, and MSK1 kinase overexpression is either a marker or a potential therapeutic target in CLAD. Conclusion: Systems prediction of Chronic Lung Allograft Dysfunction generated multiple fingerprints that enabled the development of predictors of CLAD. These results open the way to the integration of these fingerprints into a predictive handprint.

Longitudinal associations of household use of cleaning agents and asthma symptoms in women: the EGEA study.

OBJECTIVE: To evaluate the associations between the evolution of household use of cleaning products with the asthma symptom score and its evolution over 8 years. METHODS: Our study is based on 509 women participating in the last two surveys of the Epidemiological study on the Genetics and Environment of Asthma (EGEA) study (EGEA2: 2003-2007 (44 years, 19% current smokers) and EGEA3: 2011-2013). We assessed an asthma symptom score and the use of household cleaning products through standardised questionnaires. We studied longitudinal associations of the evolution of weekly use of irritant or spayed cleaning products with (1) the asthma symptom score at EGEA3 and a stable symptom score between EGEA2-EGEA3 (negative binomial models) and (2) the incidence/evolution of asthma symptoms between EGEA2-EGEA3 (logistic/polytomous logistic regressions). Models accounted for familial dependence and were adjusted for age, smoking status, body mass index and occupational exposure to asthmagens. RESULTS: Persistent and increased (40% and 16%, respectively) weekly use of irritants or sprays were associated with a higher risk of asthma symptoms at EGEA3 (Mean Score Ratio (MSR)=1.51 (95% CI 1.06 to 2.14) and 1.33 (95% CI 0.85 to 2.08), respectively). A decreased use (19%) was associated with a lower risk of symptoms at EGEA3, compared with a persistent use (MSR=0.59 (95% CI 0.39 to 0.88)). We also observed an association between an increased use of sprays and the incidence of asthma symptoms (OR=2.30 (95% CI 1.08 to 4.91)), compared with no weekly use of irritants/sprays. CONCLUSIONS: This longitudinal study, with repeated assessment of exposure and respiratory health, supports the hypothesis that a persistent or increased weekly use of sprayed cleaning products over time may have an adverse effect on the evolution of asthma symptoms.

Plasma thymic stromal lymphopoietin (TSLP) in adults with non-severe asthma: the EGEA study.

Thymic stromal lymphopoietin (TSLP), a cytokine involved in severe asthma treatment, was never studied in non-severe asthma.Among 969 adults from a large epidemiological study, cross-sectional analyses showed that plasma TSLP levels were associated with increased age and BMI, male sex, smoking and high TSLP levels (one IQR increase) with current asthma and poor lung function. High TSLP levels were also associated with persistence of asthma attacks (aOR=2.14 (95% CI 1.23 to 3.72)) and dyspnoea (aOR=2.71 (95% CI 1.39 to 5.28)) 10 years later.Our results suggest that TSLP could be a cytokine of interest in non-severe asthma, and its determinants of circulating levels could be considered in asthma management.

Exposome Profiles and Asthma among French Adults.

Rationale: Although previous studies in environmental epidemiology focused on single or a few exposures, a holistic approach combining multiple preventable risk factors is needed to tackle the etiology of multifactorial diseases such as asthma. Objectives: To investigate the association between combined socioeconomic, external environment, early-life environment, and lifestyle-anthropometric factors and asthma phenotypes. Methods: A total of 20,833 adults from the French NutriNet-Santé cohort were included (mean age, 56.2 yr; SD, 13.2; 72% women). The validated asthma symptom score (continuous) and asthma control (never asthma, controlled asthma, and uncontrolled asthma) were considered. The exposome (n = 87 factors) covered four domains: socioeconomic, external environment, early-life environment, and lifestyle-anthropometric. Cluster-based analyses were performed within each exposome domain, and the identified profiles were studied in association to asthma outcomes in negative binomial (asthma symptom score) or multinomial logistic (asthma control) regression models. Measurements and Main Results: In total, 5,546 (27%) individuals had an asthma symptom score ⩾1, and 1,206 (6%) and 194 (1%) had controlled and uncontrolled asthma, respectively. Three early-life exposure profiles ("high passive smoking-own dogs," "poor birth parameters-daycare attendance-city center," or "⩾2 siblings-breastfed" compared with "farm-pet owner-molds-low passive smoking") and one lifestyle-anthropometric profile ("unhealthy diet-high smoking-overweight" compared with "healthy diet-nonsmoker-thin") were associated with more asthma symptoms and uncontrolled asthma. Conclusions: This large-scale exposome-based study revealed early-life and lifestyle exposure profiles that were at risk for asthma in adults. Our findings support the importance of multiinterventional programs for the primary and secondary prevention of asthma, including control of specific early-life risk factors and promotion of a healthy lifestyle in adulthood.

Association between household cleaning product profiles evaluated by the Ménag'Score® index and asthma symptoms among women from the SEPAGES cohort.

OBJECTIVE: Considering household disinfectants and cleaning products (HDCP) as mixture of ingredients, rather than each ingredient individually, might help in characterizing their role in asthma. We investigated the association between HDCP and asthma, using the recently developed Ménag'Score®, a health risk assessment score based on exhaustive ingredient lists of HDCP. METHODS: The study is based on 103 female volunteers of the SEPAGES cohort (2014-2019), with repeated data (up to 3 collection times, 200 observations). HDCP use was assessed from a barcode-based smartphone application linked with an ingredient database. The Ménag'score® risks for health and environment were computed for each weekly used HDCP from their exhaustive ingredient data (from A: no known risk to E: highest risk). The association between the use of HDCP with a poor Ménag'score® (D or E; overall, health, environment scores) and asthma symptoms, was estimated by generalized estimating equations models adjusted for age, BMI and smoking status. RESULTS: Participants were on average 33 years old, 11% smoked and 20% had at least one asthma symptom. The Ménag'score® was computed for 540 HDCP scanned by participants. Weekly use of HDCP with a poor Ménag'score®-health (around 60% of the participants) was associated with a higher risk of asthma symptoms (OR 3.13, 95% CI [1.32-7.43]). No association was observed for the Ménag'score®-environment. CONCLUSION: The use of HDCP with a poor Ménag'score®-health was associated with asthma symptoms. The results support the use of the Ménag'score®-health to further evaluate the health risks of HDCP in observational studies and as a potential public health tool.

Blood eosinophil cationic protein and eosinophil-derived neurotoxin are associated with different asthma expression and evolution in adults.

BACKGROUND: Eosinophil-derived neurotoxin (EDN) and eosinophil cationic protein (ECP) are proteins released by activated eosinophils whose role in adult asthma remains unclear. OBJECTIVE: To study associations between ECP, EDN and various asthma characteristics in adults from the Epidemiological Study on the Genetics and Environment of Asthma (EGEA). METHODS: Plasma ECP and EDN levels were measured by ELISA. Cross-sectional analyses were performed in 941 adults (43±16 years old, 39% with asthma) at EGEA2 (2003-2007). Longitudinal analyses investigated the associations between EDN level at EGEA2 and changes in asthma characteristics between EGEA2 and EGEA3 (2011-2013, n=817). We used generalised estimated equations adjusted for age, sex, smoking status and body mass index to take into account familial dependence. RESULTS: At EGEA2, both high ECP and EDN levels were associated with current asthma (adjusted OR (aOR) (95% CI): 1.69 (1.35-2.12) and 2.12 (1.76-2.57)). Among asthmatics, high EDN level was associated with asthma attacks (aOR: 1.50 (1.13-1.99)), wheezing and breathlessness (aOR: 1.38 (1.05-1.80)), use of asthma treatments (aOR: 1.91 (1.37-2.68)) and bronchial hyper-responsiveness (aOR: 2.03 (1.38-2.97)), even after further adjustment on ECP. High ECP level was associated with high neutrophil count and tended to be associated with chronic bronchitis. High EDN level at EGEA2 was associated with persistent asthma (aOR: 1.62 (1.04-2.52)), nocturnal symptoms (aOR from 2.19 to 3.57), worsening wheezing and breathlessness (aOR: 1.97 (1.36-2.85)) and nocturnal shortness of breath (aOR: 1.44 (1.04-1.98)) between EGEA2 and EGEA3. CONCLUSIONS: EDN and ECP were associated with different asthma expression in adults. EDN could be a potential biomarker to monitor asthma evolution in adults.

Association between occupational exposure to irritant agents and a distinct asthma endotype in adults.

AIM: The biological mechanisms of work-related asthma induced by irritants remain unclear. We investigated the associations between occupational exposure to irritants and respiratory endotypes previously identified among never asthmatics (NA) and current asthmatics (CA) integrating clinical characteristics and biomarkers related to oxidative stress and inflammation. METHODS: We used cross-sectional data from 999 adults (mean 45 years old, 46% men) from the case-control and familial Epidemiological study on the Genetics and Environments of Asthma (EGEA) study. Five respiratory endotypes have been identified using a cluster-based approach: NA1 (n=463) asymptomatic, NA2 (n=169) with respiratory symptoms, CA1 (n=50) with active treated adult-onset asthma, poor lung function, high blood neutrophil counts and high fluorescent oxidation products level, CA2 (n=203) with mild middle-age asthma, rhinitis and low immunoglobulin E level, and CA3 (n=114) with inactive/mild untreated allergic childhood-onset asthma. Occupational exposure to irritants during the current or last held job was assessed by the updated occupational asthma-specific job-exposure matrix (levels of exposure: no/medium/high). Associations between irritants and each respiratory endotype (NA1 asymptomatic as reference) were studied using logistic regressions adjusted for age, sex and smoking status. RESULTS: Prevalence of high occupational exposure to irritants was 7% in NA1, 6% in NA2, 16% in CA1, 7% in CA2 and 10% in CA3. High exposure to irritants was associated with CA1 (adjusted OR aOR, (95% CI) 2.7 (1.0 to 7.3)). Exposure to irritants was not significantly associated with other endotypes (aOR range: 0.8 to 1.5). CONCLUSION: Occupational exposure to irritants was associated with a distinct respiratory endotype suggesting oxidative stress and neutrophilic inflammation as potential associated biological mechanisms.

Plant-Based Diets and the Incidence of Asthma Symptoms among Elderly Women, and the Mediating Role of Body Mass Index.

We aimed to test the hypothesis that adherence to a healthful plant-based diet (hPDI) is associated with a subsequent decrease in the incidence of asthma symptoms, with an opposite association with adherence to an unhealthful plant-based diet (uPDI). In addition, we evaluated a potential mediating role of body mass index (BMI) and the modifying effect of smoking. Among 5700 elderly women from the French Asthma-E3N study with dietary data in 1993 and 2005, we assessed the incidence of asthma symptoms in 2018 among women with no asthma symptoms in 2011. BMI was evaluated in 2008. Mediation analyses in the counterfactual framework were used to disentangle total, direct, and indirect effects mediated by BMI. We found that both healthful and unhealthful plant-based diets were associated with a lower incidence of asthma symptoms over time, mediated by BMI (OR (95%CI) for the indirect effect: 0.94 (0.89-1.00) for hPDI and 0.92 (0.70-1.00) for uPDI)). Associations with both healthful and unhealthful PDIs were mediated by changes in BMI by 33% and 89%, respectively. Plant-based diets (healthful and unhealthful) were associated with subsequently reduced incidences of asthma symptoms over time, partly or almost totally mediated by BMI according to their nutritional quality.

Risk factors for severe adult-onset asthma: a multi-factor approach.

BACKGROUND: The aim was to identify risk factors for severe adult-onset asthma. METHODS: We used data from a population-based sample (Adult Asthma in Finland) of 1350 patients with adult-onset asthma (age range 31-93 years) from Finnish national registers. Severe asthma was defined as self-reported severe asthma and asthma symptoms causing much harm and regular impairment and ≥ 1 oral corticosteroid course/year or regular oral corticosteroids or waking up in the night due to asthma symptoms/wheezing ≥ a few times/month. Sixteen covariates covering several domains (personal characteristics, education, lifestyle, early-life factors, asthma characteristics and multiple morbidities) were selected based on the literature and were studied in association with severe asthma using logistic regressions. RESULTS: The study population included 100 (7.4%) individuals with severe asthma. In a univariate analysis, severe asthma was associated with male sex, age, a low education level, no professional training, ever smoking, ≥ 2 siblings, ≥ 1 chronic comorbidity and non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) (p < 0.05), and trends for association (p < 0.2) were observed for severe childhood infection, the presence of chronic rhinosinusitis with nasal polyps, and being the 1st child. The 10 variables (being a 1st child was removed due to multicollinearity) were thus entered in a multivariate regression model, and severe asthma was significantly associated with male sex (OR [95% CI] = 1.96 [1.16-3.30]), ever smoking (1.98 [1.11-3.52]), chronic comorbidities (2.68 [1.35-5.31]), NERD (3.29 [1.75-6.19]), and ≥ 2 siblings (2.51 [1.17-5.41]). There was a dose-response effect of the total sum of these five factors on severe asthma (OR [95% CI] = 2.30 [1.81-2.93] for each one-unit increase in the score). CONCLUSIONS: Male sex, smoking, NERD, comorbidities, and ≥ 2 siblings were independent risk factors for self-reported severe asthma. The effects of these factors seem to be cumulative; each additional risk factor gradually increases the risk of severe asthma.

Household Cleaning and Poor Asthma Control Among Elderly Women.

BACKGROUND: Asthma control is suboptimal in nearly half of adults with asthma. Household exposure to disinfectants and cleaning products (DCP) has been associated with adverse respiratory effects, but data on their association with asthma control are scant. OBJECTIVES: To investigate the association between household use of DCP and asthma control in a large cohort of French elderly women. METHODS: We used data from a case-control study on asthma (2011-2013) nested in the E3N cohort. Among 3023 women with current asthma, asthma control was defined by the Asthma Control Test (ACT). We used a standardized questionnaire to assess the frequency of cleaning tasks and DCP use. We also identified household cleaning patterns using a clustering approach. Associations between DCP and ACT were adjusted for age, smoking status, body mass index, and education. RESULTS: Data on ACT and DCP use were available for 2223 women (70 ± 6 years old). Asthma was controlled (ACT = 25), partly controlled (ACT = 20-24), and poorly controlled (ACT ≤ 19) in 29%, 46%, and 25% of the participants, respectively. Weekly use of sprays and chemicals was associated with poorly controlled asthma (odds ratio [95% confidence interval]: 1 spray: 1.31 [0.94-1.84], ≥2 sprays: 1.65 [1.07-2.53], P trend: .01; 1 chemical: 1.24 [0.94-1.64], ≥2 chemicals: 1.47 [1.03-2.09], P trend: .02). Risk for poor asthma control increased with the patterns "very frequent use of products" (1.74 [1.13-2.70]) and "infrequent cleaning tasks and intermediate use of products" (1.62 [1.05-2.51]). CONCLUSION: Regular use of DCP may contribute to poor asthma control in elderly women. Limiting their use may help improve asthma management.

Profile of exposures and lung function in adults with asthma: An exposome approach in the EGEA study.

BACKGROUND: Environmental research on multifactorial health outcomes calls for exposome approaches able to assess the joint effect of multiple exposures. OBJECTIVE: Our aim was to identify profiles of exposure to lifestyle/environmental factors associated with lung function in adults with asthma using a cluster-based approach. METHODS: We used data from 599 adults of the Epidemiological study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy (EGEA) (mean age 39.0 years, 52% men) who ever had asthma. Exposures to 53 lifestyle/environmental factors were assessed by questionnaires or geographic information systems-based models. A two-step approach was developed: 1) exposome dimension reduction by selecting factors showing association with forced expiratory volume in 1 s (FEV1) (p < 0.20) in an exposome-wide association study (ExWAS), 2) clustering analysis using the supervised Bayesian Profile Regression (sBPR) to group individuals according to FEV1 level and to their profile of exposure to a reduced set of uncorrelated exposures (each paired correlation<0.70) identified in step 1. RESULTS: The ExWAS identified 21 factors showing suggestive association with FEV1 (none significant when controlling for multiple tests). The sBPR conducted on 15 uncorrelated exposures identified in step 1, revealed 3 clusters composed of 30, 115 and 454 individuals with a mean ± SD FEV1(%pred) of 79% ± 21, 90% ± 19 and 93% ± 16, respectively. Cluster 1 was composed of individuals with heavy smoking, poor diet, higher outdoor humidity and proximity to traffic, while cluster 2 and 3 included individuals with moderate/low levels of exposure to these factors. DISCUSSION: This exposome study identified a specific profile of joint lifestyle and environmental factors, associated with a low FEV1 in adults with asthma. None of the exposures revealed significant association when considered independently.

Immediate and durable effects of maternal tobacco consumption alter placental DNA methylation in enhancer and imprinted gene-containing regions.

BACKGROUND: Although exposure to cigarette smoking during pregnancy has been associated with alterations of DNA methylation in the cord blood or placental cells, whether such exposure before pregnancy could induce epigenetic alterations in the placenta of former smokers has never been investigated. METHODS: Our approach combined the analysis of placenta epigenomic (ENCODE) data with newly generated DNA methylation data obtained from 568 pregnant women, the largest cohort to date, either actively smoking during their pregnancy or formerly exposed to tobacco smoking. RESULTS: This strategy resulted in several major findings. First, among the 203 differentially methylated regions (DMRs) identified by the epigenome-wide association study, 152 showed "reversible" alterations of DNA methylation, only present in the placenta of current smokers, whereas 26 were also found altered in former smokers, whose placenta had not been exposed directly to cigarette smoking. Although the absolute methylation changes were smaller than those observed in other contexts, such as in some congenital diseases, the observed alterations were consistent within each DMR. This observation was further supported by a demethylation of LINE-1 sequences in the placentas of both current (beta-coefficient (ß) (95% confidence interval (CI)), - 0.004 (- 0.008; 0.001)) and former smokers (ß (95% CI), - 0.006 (- 0.011; - 0.001)) compared to nonsmokers. Second, the 203 DMRs were enriched in epigenetic marks corresponding to enhancer regions, including monomethylation of lysine 4 and acetylation of lysine 27 of histone H3 (respectively H3K4me1 and H3K27ac). Third, smoking-associated DMRs were also found near and/or overlapping 10 imprinted genes containing regions (corresponding to 16 genes), notably including the NNAT, SGCE/PEG10, and H19/MIR675 loci. CONCLUSIONS: Our results pointing towards genomic regions containing the imprinted genes as well as enhancers as preferential targets suggest mechanisms by which tobacco could directly impact the fetus and future child. The persistence of significant DNA methylation changes in the placenta of former smokers supports the hypothesis of an "epigenetic memory" of exposure to cigarette smoking before pregnancy. This observation not only is conceptually revolutionary, but these results also bring crucial information in terms of public health concerning potential long-term detrimental effects of smoking in women.

Domestic exposure to irritant cleaning agents and asthma in women.

An adverse role of frequent domestic use of cleaning agents, especially in spray form, on asthma has been reported. However, sparse studies have investigated respiratory health effects of chronic domestic exposure to irritant cleaning agents. This study aims to investigate associations between weekly use of irritant domestic cleaning products and current allergic and non-allergic asthma in a large cohort of elderly women. We used data from the Asthma-E3N nested case-control study on asthma (n = 19,404 women, response rate: 91%, 2011), in which participants completed standardized questionnaires on asthma and on the use of domestic cleaning products including irritants (bleach, ammonia, solvents and acids). Allergic multimorbidity in asthma was assessed from allergic-related medications recorded in drug refunds database. The association between use of irritants and current asthma was estimated by logistic regression (current vs. never asthma) and multinomial logistic regression (never asthma, non-allergic asthma, allergic asthma) adjusted on age, smoking status and body mass index (BMI). In the 12,758 women included in the analysis (mean age: 70 years, current smokers: 4%, BMI ≥ 25 kg/m2: 32%, low education: 11%, current asthma: 23%), 47% reported weekly use of at least one irritant cleaning product at home. Weekly use of irritant products was associated with a higher risk of current asthma (adjusted Odds-Ratio: 1.17, 1.07-1.27). A statistically significant dose-response association was reported (p trend < 0.0001), with both the number of irritant products used weekly (1 irritant: 1.12, 1.02-1.23; 2 irritants: 1.21, 1.05-1.39; 3 irritants or more: 2.08, 1.57-2.75) and the frequency of use (1-3 days/week: 1.12, 1.02-1.23; 4-7 days/week: 1.41,1.22-1.64). A dose-response association was observed with the frequency of products used (p trend < 0.05), for both non-allergic (4-7 days/week: 1.27, 1.02-1.57) and allergic asthma (1.52, 1.27-1.82). In conclusion, weekly use of common cleaning irritants was associated with an increased risk of current asthma, whatever the allergic status.