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.

Intra-breath changes in respiratory mechanics are sensitive to history of respiratory illness in preschool children: the SEPAGES cohort.

BACKGROUND: Intra-breath oscillometry has been proposed as a sensitive means of detecting airway obstruction in young children. We aimed to assess the impact of early life wheezing and lower respiratory tract illness on lung function, using both standard and intra-breath oscillometry in 3 year old children. METHODS: History of doctor-diagnosed asthma, wheezing, bronchiolitis and bronchitis and hospitalisation for respiratory problems were assessed by questionnaires in 384 population-based children. Association of respiratory history with standard and intra-breath oscillometry parameters, including resistance at 7 Hz (R7), frequency-dependence of resistance (R7 - 19), reactance at 7 Hz (X7), area of the reactance curve (AX), end-inspiratory and end-expiratory R (ReI, ReE) and X (XeI, XeE), and volume-dependence of resistance (ΔR = ReE-ReI) was estimated by linear regression adjusted on confounders. RESULTS: Among the 320 children who accepted the oscillometry test, 281 (88%) performed 3 technically acceptable and reproducible standard oscillometry measurements and 251 children also performed one intra-breath oscillometry measurement. Asthma was associated with higher ReI, ReE, ΔR and R7 and wheezing was associated with higher ΔR. Bronchiolitis was associated with higher R7 and AX and lower XeI and bronchitis with higher ReI. No statistically significant association was observed for hospitalisation. CONCLUSIONS: Our findings confirm the good success rate of oscillometry in 3-year-old children and indicate an association between a history of early-life wheezing and lower respiratory tract illness and lower lung function as assessed by both standard and intra-breath oscillometry. Our study supports the relevance of using intra-breath oscillometry parameters as sensitive outcome measures in preschool children in epidemiological cohorts.

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.

In utero exposure to poly- and perfluoroalkyl substances and children respiratory health in the three first years of life.

BACKGROUND: Poly- and perfluoroalkyl substances (PFAS) are used in a wide range of products. Experimental studies suggested impaired lung development and pro-inflammatory response following exposure to some PFAS. We aimed to assess the associations between prenatal exposure to PFAS and children respiratory health. METHODS: The study is based on 433 mother-child pairs. 26 PFAS were measured in maternal serum collected during pregnancy. Lung function parameters were measured at 2 months using tidal breathing flow-volume loops and multiple-breath nitrogen washout and at 36 months using oscillometry. Incidence of respiratory health diseases (asthma, wheeze, bronchitis, bronchiolitis) in the first 36 months of life was assessed by repeated questionnaires. A cluster-based analysis was applied to identify prenatal PFAS exposure patterns. Adjusted linear and logistic regressions were performed to assess the associations between PFAS exposure patterns as well as individual PFAS, and each respiratory health parameter. RESULTS: We excluded 13 PFAS due to low quantification (<5%). Relying on the 13 remaining PFAS, we identified three exposure clusters, characterized by low (N = 163), medium (N = 236) and high (N = 51) pregnancy PFAS concentrations. Compared to children belonging to the low exposure group, children in the moderate exposure group had higher reactance at 7 Hz (X7) and lower frequency dependence of resistance between 7 Hz and 19 Hz (R7-19) at 36 months, suggesting better lung function. No association of any exposure metric was detected with respiratory diseases in the first 3 years of life. CONCLUSIONS: Our study relying on both mixture and uni-pollutant analyses, does not provide evidence for a deleterious effect of prenatal PFAS exposure on respiratory health at an early age.

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.

Prenatal exposure to synthetic phenols and phthalates and child respiratory health from 2 to 36 months of life.

Exposure to phthalates and synthetic phenols is ubiquitous. Some of them are suspected to impact child respiratory health, although evidence still remains insufficient. This study investigated the associations between prenatal exposure to phthalates and phenols, individually and as a mixture, and child respiratory health assessed by objective lung function measures since 2 months of age. Among 479 mother-child pairs from the SEPAGES cohort, 12 phenols, 13 phthalate and 2 non-phthalate plasticizer metabolites were measured in 2 pools including each 21 urine samples collected at the 2nd and 3rd pregnancy trimesters. Lung function was measured at 2 months using tidal breathing flow-volume loops and nitrogen multiple-breath washout, and at 3 years using oscillometry. Asthma, wheezing, bronchitis and bronchiolitis were assessed by repeated questionnaires. A cluster-based analysis was applied to identify exposure patterns to phenols and phthalates. Adjusted associations between clusters as well as each individual exposure biomarker and child respiratory health were estimated by regression models. We identified four prenatal exposure patterns: 1) low concentrations of all biomarkers (reference, n = 106), 2) low phenols-moderate phthalates (n = 162), 3) high concentrations of all biomarkers except bisphenol S (n = 109), 4) high parabens-moderate other phenols-low phthalates (n = 102). At 2 months, cluster 2 infants had lower functional residual capacity and tidal volume and higher ratio of time to peak tidal expiratory flow to expiratory time (tPTEF/tE) and cluster 3 had lower lung clearance index and higher tPTEF/tE. Clusters were not associated with respiratory health at 3 years but in the single-pollutant models, parabens were associated with increased area of the reactance curve, bronchitis (methyl, ethyl parabens) and bronchiolitis (propyl paraben). Our results suggested that prenatal exposure to mixtures of phthalates reduced lung volume in early life. Single exposure analyses suggested associations of parabens with impaired lung function and increased risk of respiratory diseases.

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.

Prenatal Exposure to PM2.5 Oxidative Potential and Lung Function in Infants and Preschool- Age Children: A Prospective Study.

BACKGROUND: Fine particulate matter (PM2.5) has been found to be detrimental to respiratory health of children, but few studies have examined the effects of prenatal PM2.5 oxidative potential (OP) on lung function in infants and preschool children. OBJECTIVES: We estimated the associations of personal exposure to PM2.5 and OP during pregnancy on offspring objective lung function parameters and compared the strengths of associations between both exposure metrics. METHODS: We used data from 356 mother-child pairs from the SEPAGES cohort. PM filters collected twice during a week were analyzed for OP, using the dithiothreitol (DTT) and the ascorbic acid (AA) assays, quantifying the exposure of each pregnant woman. Lung function was assessed with tidal breathing analysis (TBFVL) and nitrogen multiple-breath washout (N2MBW) test, performed at 6 wk, and airwave oscillometry (AOS) performed at 3 y. Associations of prenatal PM2.5 mass and OP with lung function parameters were estimated using multiple linear regressions. RESULTS: In neonates, an interquartile (IQR) increase in OPvDTT (0.89 nmol/min/m3) was associated with a decrease in functional residual capacity (FRC) measured by N2MBW [ß=-2.26mL; 95% confidence interval (CI): -4.68, 0.15]. Associations with PM2.5 showed similar patterns in comparison with OPvDTT but of smaller magnitude. Lung clearance index (LCI) and TBFVL parameters did not show any clear association with the exposures considered. At 3 y, increased frequency-dependent resistance of the lungs (Rrs7-19) from AOS tended to be associated with higher OPvDTT (ß=0.09 hPa×s/L; 95% CI: -0.06, 0.24) and OPvAA (IQR=1.14 nmol/min/m3; ß=0.12 hPa×s/L; 95% CI: -0.04, 0.27) but not with PM2.5 (IQR=6.9 µg/m3; ß=0.02 hPa×s/L; 95% CI: -0.13, 0.16). Results for FRC and Rrs7-19 remained similar in OP models adjusted on PM2.5. DISCUSSION: Prenatal exposure to OPvDTT was associated with several offspring lung function parameters over time, all related to lung volumes. https://doi.org/10.1289/EHP11155.

Personal exposure to PM2.5 oxidative potential and its association to birth outcomes.

BACKGROUND: Prenatal exposure to fine particulate matter (PM2.5) assessed through its mass concentration has been associated with foetal growth restriction in studies based on outdoor levels. Oxidative potential of PM2.5 (OP) is an emerging metric a priori relevant to mechanisms of action of PM on health, with very limited evidence to indicate its role on birth outcomes. OBJECTIVES: We investigated the association of OP with birth outcomes and compared it with that of PM2.5 mass concentration. METHODS: 405 pregnant women from SEPAGES cohort (Grenoble area) carried PM2.5 personal dosimeters for one or two one-week periods. OP was measured using dithiothreitol (DTT) and ascorbic acid (AA) assays from the collected filters. Associations of each exposure metric with offspring weight, height, and head circumference at birth were estimated adjusting for potential confounders. RESULTS: The correlation between PM2.5 mass concentration and [Formula: see text] was 0.7. An interquartile range increase in .. was associated with reduced weight (adjusted change, -64 g, -166 to -11, p = 0.02) and height (-4 mm, -6 to -1, p = 0.01) at birth. PM2.5 mass concentration showed similar associations with weight (-53 g, -99 to -8, p = 0.02) and height (-2 mm, -5 to 0, p = 0.05). In birth height models mutually adjusted for the two exposure metrics, the association with [Formula: see text] was less attenuated than that with mass concentration, while for weight both effect sizes attenuated similarly. There was no clear evidence of associations with head circumference for any metric, nor for [Formula: see text] with any growth parameter. IMPACT: PM2.5 pregnancy exposure assessed from personal dosimeters was associated with altered foetal growth. Personal OP exposure was associated with foetal growth restrictions, specifically decreased weight and height at birth, possibly to a larger extent than PM2.5 mass concentration alone. These results support OP assessed from DTT as being a health-relevant metric. Larger scale cohort studies are recommended to support our findings.

Long-term air pollution exposure, greenspace and health-related quality of life in the ECRHS study.

BACKGROUND: Associations of long-term exposure to air pollution and greenspace with health-related quality of life (HRQOL) are poorly studied and few studies have accounted for asthma-rhinitis status. OBJECTIVE: To assess the associations of air pollution and greenspace with HRQOL and whether asthma and/or rhinitis modify these associations. METHODS: The study was based on the participants in the second (2000-2002, n = 6542) and third (2011-2013, n = 3686) waves of the European Community Respiratory Health Survey (ECRHS) including 19 centres. The mean follow-up time was 11.3 years. HRQOL was assessed by the SF-36 Physical and Mental Component Summary scores (PCS and MCS). NO2, PM2.5 and PM10 annual concentrations were estimated at the residential address from existing land-use regression models. Greenspace around the residential address was estimated by the (i) mean of the Normalized Difference Vegetation Index (NDVI) and by the (ii) presence of green spaces within a 300 m buffer. Associations of each exposure variable with PCS and MCS were assessed by mixed linear regression models, accounting for the multicentre design and repeated data, and adjusting for potential confounders. Analyses were stratified by asthma-rhinitis status. RESULTS: The mean (SD) age of the ECRHS-II and III participants was 43 (7.1) and 54 (7.2) years, respectively, and 48 % were men. Higher NO2, PM2.5 and PM10 concentrations were associated with lower MCS (regression coefficients [95%CI] for one unit increase in the inter-quartile range of exposures were -0.69 [-1.23; -0.15], -1.79 [-2.88; -0.70], -1.80 [-2.98; -0.62] respectively). Higher NDVI and presence of forests were associated with higher MCS. No consistent associations were observed for PCS. Similar association patterns were observed regardless of asthma-rhinitis status. CONCLUSION: European adults who resided at places with higher air pollution and lower greenspace were more likely to have lower mental component of HRQOL. Asthma or rhinitis status did not modify these associations.

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.

Trajectories of IgE sensitization to allergen molecules from childhood to adulthood and respiratory health in the EGEA cohort.

BACKGROUND: Longitudinal studies assessing the association of profiles of allergen-specific IgE (sIgE) sensitization to a large range of allergen molecules and respiratory health are rare. We aimed to assess trajectories of molecular sIgE sensitization profiles from childhood to adulthood and their associations with respiratory health. METHODS: IgE reactivity to microarrayed allergen molecules were measured in childhood (EGEA1) and 12 years later in adult life (EGEA2) among 291 EGEA participants (152 with asthma). At each time point, sIgE sensitization profiles were identified by latent class analysis (LCA) by considering IgE-reactivity to the 38 most prevalent respiratory allergens. The LCA-defined profiles were then studied in association with respiratory health. RESULTS: At baseline, the mean (min-max) age of the population was 11 (4.5-16) years. The LCA identified four sIgE sensitization profiles which were very similar at both time points (% at EGEA1 and EGEA2); A: "no/few allergen(s)" (48%, 39%), B: "pollen/animal allergens" (18%, 21%), C: "most prevalent house dust mite allergens" (22%, 27%) and D: "many allergens" (12%, 13%). Overall, 73% of the participants remained in the same profile from childhood to adulthood. The profiles were associated with asthma and rhinitis phenotypes. Participants of profiles C and D had lower FEV1 % and FEF25-75 % as compared to profile A. Similar patterns of associations were observed for participants with asthma. There was no association with change in lung function. CONCLUSION: Using high-resolution sIgE longitudinal data, the LCA identified four molecular sensitization profiles, mainly stable from childhood to adulthood, that were associated with respiratory health.

Data-driven adult asthma phenotypes based on clinical characteristics are associated with asthma outcomes twenty years later.

BACKGROUND: Research based on cluster analyses led to the identification of particular phenotypes confirming phenotypic heterogeneity of asthma. The long-term clinical course of asthma phenotypes defined by clustering analysis remains unknown, although it is a key aspect to underpin their clinical relevance. We aimed to estimate risk of poor asthma events between asthma clusters identified 20 years earlier. METHODS: The study relied on two cohorts of adults with asthma with 20-year follow-up, ECRHS (European Community Respiratory Health Survey) and EGEA (Epidemiological study on Genetics and Environment of Asthma). Regression models were used to compare asthma characteristics (current asthma, asthma exacerbations, asthma control, quality of life, and FEV1 ) at follow-up and the course of FEV1  between seven cluster-based asthma phenotypes identified 20 years earlier. RESULTS: The analysis included 1325 adults with ever asthma. For each asthma characteristic assessed at follow-up, the risk for adverse outcomes differed significantly between the seven asthma clusters identified at baseline. As compared with the mildest asthma phenotype, ORs (95% CI) for asthma exacerbations varied from 0.9 (0.4 to 2.0) to 4.0 (2.0 to 7.8) and the regression estimates (95% CI) for FEV1 % predicted varied from 0.6 (-3.5 to 4.6) to -9.9 (-14.2 to -5.5) between clusters. Change in FEV1 over time did not differ significantly across clusters. CONCLUSION: Our findings show that the long-term risk for poor asthma outcomes differed between comprehensive adult asthma phenotypes identified 20 years earlier, and suggest a strong tracking of asthma activity and impaired lung function over time.

Blood granulocyte patterns as predictors of asthma phenotypes in adults from the EGEA study.

To what extent blood granulocyte patterns may predict asthma control remains under-studied. Our aim was to study associations between blood neutrophilia and eosinophilia and asthma control outcomes in adults.Analyses were conducted in 474 asthmatics from the first follow-up of the Epidemiological Study on the Genetics and Environment of Asthma (EGEA2), including 242 asthmatics who were adults a decade earlier (EGEA1). At EGEA2, asthma control was assessed using the Global Initiative for Asthma definition (2015), and asthma exacerbations by use of urgent care or courses of oral corticosteroids in the past year. Blood EOSlo/EOShi was defined as 2.10). EOShi was associated with higher bronchial hyperresponsiveness (BHR) (OR (95% CI) 2.21 (1.24-3.97)), poor lung function (p=0.02) and higher total IgE level (p=0.002). Almost 50% of asthmatics had a persistent pattern between surveys. Persistent NEUhi was associated with poor asthma control at EGEA2 (OR (95% CI) 3.09 (1.18-7.05)). EOShi at EGEA1 and persistent EOShi were associated with higher BHR (OR (95% CI) 2.36 (1.10-5.07) and 3.85 (1.11-13.34), respectively), poor lung function (p<0.06) and higher immunoglobulin E level (p<10-4) at EGEA2.Granulocyte patterns were differently associated with asthma outcomes, suggesting specific roles for each one, which could be tested as predictive signatures.

Forced midexpiratory flow between 25% and 75% of forced vital capacity is associated with long-term persistence of asthma and poor asthma outcomes.

BACKGROUND: Whether small-airway obstruction contributes to the long-term evolution of asthma remains unknown. OBJECTIVES: Our aim was to assess whether the level of forced midexpiratory flow between 25% and 75% of forced vital capacity (FEF25-75) was associated with the persistence of current asthma over 20 years and the subsequent risk for uncontrolled asthma independently of FEV1. METHODS: We studied 337 participants (142 children and 225 adults) with current asthma (asthma attacks or treatment in the past 12 months) recruited to the Epidemiological Study on the Genetics and Environment of Asthma (EGEA1) and followed up at the 12- and 20-year surveys. Persistent current asthma was defined by current asthma reported at each survey. A lung function test and a methacholine challenge test were performed at EGEA1 and EGEA2. Adjusted odds ratios (ORs) were estimated for FEF25-75 decreased by 10% of predicted value. RESULTS: A reduced level of FEF25-75 at EGEA1 increased the risk of long-term asthma persistence (adjusted OR, 1.14; 95% CI, 1.00-1.29). In children the association remained significant after further adjustment for FEV1 and in participants with FEV1 of greater than 80% of predicted value. A reduced FEF25-75 level at EGEA1 was significantly associated with more severe bronchial hyperresponsiveness (P < .0001) and with current asthma a decade later, with an association that tended to be stronger in those with (adjusted OR, 1.44; 95% CI, 1.14-1.81) compared with those without (adjusted OR, 1.21; 95% CI, 1.05-1.41) asthma exacerbation. CONCLUSION: Our analysis is the first to suggest that small-airway obstruction, as assessed based on FEF25-75, might contribute to the long-term persistence of asthma and the subsequent risk for poor asthma outcomes independently from effects of the large airways.

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.

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.

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.