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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. [ABSTRACT FROM AUTHOR]

Background The nature of allergens and route and dose of exposure may affect the natural development of IgE and IgG responses. Objective We sought to investigate the natural IgE and IgG responses toward a large panel of respiratory and food allergens in subjects exposed to different respiratory allergen loads. Methods A cross-sectional analysis was conducted in 340 adults of the EGEA (Epidemiological study of the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy) (170 with and 170 without asthma) cohort. IgE and IgG responses to 47 inhalant and food allergen components were analyzed in sera using allergen microarray and compared between 5 French regions according to the route of allergen exposure (inhaled vs food allergens). Results Overall 48.8% of the population had allergen-specific IgE levels of 0.3 ISAC standardized units (ISU) or more to at least 1 of the 47 allergens with no significant differences across the regions. For ubiquitous respiratory allergens (ie, grass, olive/ash pollen, house dust mites), specific IgE did not show marked differences between regions and specific IgG (≥0.5 ISU) was present in most subjects everywhere. For regionally occurring pollen allergens (ragweed, birch, cypress), IgE sensitization was significantly associated with regional pollen exposure. For airborne allergens cross-reacting with food allergens, frequent IgG recognition was observed even in regions with low allergen prevalence (Bet v 1) or for allergens less frequently recognized by IgE (profilins). Conclusions The variability in allergen-specific IgE and IgG frequencies depends on exposure, route of exposure, and overall immunogenicity of the allergen. Allergen contact by the oral route might preferentially induce IgG responses. [ABSTRACT FROM AUTHOR]

Background Ambient temperature, particularly heat, is increasingly acknowledged as a trigger for preterm delivery but study designs have been limited and results mixed. We aimed to comprehensively evaluate the association between ambient temperature throughout pregnancy and preterm delivery. Methods We estimated daily temperature throughout pregnancy using a cutting-edge spatiotemporal model for 5347 live singleton births from three prospective cohorts in France, 2002–2018. We performed Cox regression (survival analysis) with distributed lags to evaluate time-varying associations with preterm birth simultaneously controlling for exposure during the first 26 weeks and last 30 days of pregnancy. We examined weekly mean, daytime, night-time and variability of temperature, and heatwaves accounting for adaptation to location and season. Results Preterm birth risk was higher following cold (5th vs 50th percentile of mean temperature) 7–9 weeks after conception [relative risk (RR): 1.3, 95% CI: 1.0–1.6 for 2°C vs 11.6°C] and 10–4 days before delivery (RR: 1.6, 95% CI: 1.1–2.1 for 1.2°C vs 12.1°C). Night-time heat (95th vs 50th percentile of minimum temperature; 15.7°C vs 7.4°C) increased risk when exposure occurred within 5 weeks of conception (RR: 2.0, 95% CI: 1.05–3.8) or 20–26 weeks after conception (RR: 2.9, 95% CI: 1.2–6.8). Overall and daytime heat (high mean and maximum temperature) showed consistent effects. We found no clear associations with temperature variability or heatwave indicators, suggesting they may be less relevant for preterm birth. Conclusions In a temperate climate, night-time heat and chronic and acute cold exposures were associated with increased risk of preterm birth. These results suggest night-time heat as a relevant indicator. In the context of rising temperatures and more frequent weather hazards, these results should inform public health policies to reduce the growing burden of preterm births. [ABSTRACT FROM AUTHOR]

Background: A previous genome-wide linkage scan in 295 families of the French Epidemiological Study on the Genetics and Environment of Asthma (EGEA) reported strong evidence of linkage of 11p14 to eczema. Objective: Our purpose was to conduct fine-scale mapping of the 11p14 region to identify the genetic variants associated with eczema. Methods: Association analyses were first conducted in the family sample from the French EGEA by using 2 methods: the family-based association method and logistic regression. Replication of the EGEA findings was sought in French Canadian and United Kingdom family samples, which, similarly to EGEA samples, were ascertained through asthma. We also tested for association in 2 German samples ascertained through eczema. Results: We found significant association of eczema with 11p14 genetic variants in the vicinity of the linkage peak in EGEA (P = 10−4 for rs1050153 by using the family-based association method, which reached the multiple testing–corrected threshold of 10−4; P = .003 with logistic regression). Pooled analysis of the 3 asthma-ascertained samples showed strong improvement in the evidence for association (P = 6 × 10−6 for rs293974, P = 3 × 10−5 for rs1050153, and P = 8 × 10−5 for rs15783). No association was observed in the eczema-ascertained samples. Conclusion: The significant single nucleotide polymorphisms are located within the overlapping anoctamin 3 (ANO3) and mucin 15 (MUC15) genes. Several lines of evidence suggest that MUC15 is a strong candidate for eczema. Further investigation is needed to confirm our findings and to better understand the role of the ANO3/MUC15 locus in eczema and its relationship with respect to asthma. [ABSTRACT FROM AUTHOR]

Background: Integrin β3 (ITGB3) and Toll-like receptor 2 (TLR2) are candidate genes for asthma and sensitization to mold allergens. Integrin β3 forms a complex with TLR2, and this biological interaction is required for the response of monocytes to TLR2 agonists such as fungal glucan. Objective: To study whether genetic interaction between single nucleotide polymorphisms (SNPs) in genes encoding the TLR2-ITGB3 complex enhances susceptibility to mold sensitization. Methods: Association analysis was conducted in 1243 adults (524 with asthma) who participated in the follow-up of the Epidemiological Study on the Genetics and Environment of Asthma. Allergic sensitization to mold allergens was determined by skin prick testing. Association of mold sensitization with 14 ITGB3 SNPs was tested under an additive genetic model. Interaction between ITGB3 SNPs and TLR2/+596, which was previously shown to be associated with asthma, was studied. Results: A positive skin prick test to mold was found in 115 subjects with asthma (22.0%) and in 61 subjects without asthma (8.5%). The ITGB3 rs2056131 A allele was associated with mold sensitization in subjects with asthma with an odds ratio (95% CI) of 0.60 (0.43-0.83; P = .001). Ten other ITGB3 SNPs were significantly associated with mold sensitization in TLR2/+596TT subjects with asthma (P = .03-.002), whereas much weaker associations were found in carriers of the TLR2/+596 C allele (P = .60-.04). Interaction between TLR2/+596 and these ITGB3 SNPs was statistically significant (P interaction = .05-.001). Conclusion: TLR2/+596 genotype may influence the association between ITGB3 SNPs and mold sensitization in adults with asthma. [ABSTRACT FROM AUTHOR]

Objective: To evaluate parental stress after a false-positive result at the time of the cystic fibrosis (CF) newborn screening (NBS), attributable to heterozygotism or persistent hypertrypsinemia. Study design: A prospective study was conducted in 86 French families at 3, 12, and 24 months after NBS. A psychologist conducted interviews with a questionnaire, the Perceived Stress Scale, and the Vulnerable Child Scale. Results: Overall, 96.5% of parents said they had been anxious at the time of the sweat test. However, 86% felt entirely reassured 3 months after the test. The mean Perceived Stress Scale score did not differ from that observed in the French population. Mean Vulnerable Child Scale scores were high, associated with a low Parental Perception of Child Vulnerability. These results did not differ significantly at 1 and 2 years. In total, 86% to 100% of families no longer worried about CF. All parents stated that they would have the test performed again for another child. Conclusions: CF NBS can lead to false-positive results, causing parental anxiety, which quickly decreases after a sweat test performed soon after the phone call. [Copyright &y& Elsevier]

Background: Although uncontrolled asthma remains frequent, determinants of asthma control are poorly studied. Objectives: The aim was to estimate the distribution and the phenotypic characteristics of asthma control in 2 groups of subjects defined by the use of inhaled corticosteroids (ICS) in the past 12 months, in the Epidemiological study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy (EGEA). Methods: Five hundred one adult current patients with asthma who participated in the follow-up of the EGEA study were included. Asthma control was assessed from survey questions reflecting asthma control, as defined in the 2006 Global Initiative for Asthma guidelines. The factors analyzed were age, sex, educational level, body mass index, active and passive smoking, sensitization to aeroallergens, total IgE, rhinitis, chronic cough/phlegm, and age at asthma onset. Analyses were stratified according to ICS use. Results: Uncontrolled asthma was more frequent in ICS users (27.6%, 35.0%, and 37.4% with controlled, partly-controlled, and uncontrolled asthma respectively) compared with non-ICS users (60.0%, 23.9%, and 16.1%, respectively). In ICS users, chronic cough or phlegm and female sex were independently and significantly related to uncontrolled asthma. In non-ICS users, high total IgE and sensitization to molds were associated with uncontrolled asthma. Smoking and rhinitis were not associated with asthma control. Conclusion: Optimal asthma control remained unachieved in the majority of patients with asthma in this study. Factors associated with uncontrolled asthma were different in ICS users (chronic cough/phlegm, female sex) and non-ICS users (high total IgE and sensitization to molds). [Copyright &y& Elsevier]

Background: Little is known about factors associated with lung function decline in asthma. Objective: To identify the determinants of FEV1 decline in adults with asthma with and without airflow obstruction at baseline. Methods: An international cohort of 638 subjects with asthma (20-44 years old) was identified in the European Community Respiratory Health Survey (1991-1993) and followed up from 1998 to 2002. Spirometry was performed on both occasions. FEV1 decline was related to potential determinants evaluated at baseline and during the follow-up by random intercept linear regression models. The analyses were stratified by the presence of airflow obstruction (FEV1/forced vital capacity < 0.70) at baseline. Results: In the group of individuals without airflow obstruction (n = 544), a faster FEV1 decline was observed for subjects with intermediate body mass index (BMI) than for lean and obese subjects. FEV1 decline was associated with weight gain independently of baseline BMI, and this association was stronger in men (20; 95% CI, 10-30, mL/y/kg gained) than in women (6; 95% CI, 1-11, mL/y). In the group of individuals with airflow obstruction (n = 94), the absence of allergen sensitization and a low BMI at baseline were associated with a faster FEV1 decline, whereas weight gain was not associated with decline. Conclusions: The detrimental effect of weight gain on FEV1 decline is particularly relevant in subjects with asthma who still do not have an established airflow obstruction. Our findings support the importance of weight management in asthma and recommend weight loss in overweight or obese individuals with asthma. [Copyright &y& Elsevier]

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 OPDTTv (0.89nmol/min/m³) was associated with a decrease in functional residual capacity (FRC) measured by N2MBW  [β = -2.26 mL ; 95% confidence interval (CI): -4.68, 0.15]. Associations with PM2.5  showed similar patterns in comparison with OPDTTv  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 OPDTTv  (β = 0.09hPa×s/L ; 95% CI: -0.06, 0.24) and OPAAv  (IQR = 1.14nmol/min/m³ ; β = 0.12hPa×s/L ; 95% CI: -0.04, 0.27) but not with PM2.5  (IQR = 6.9µg/m³ ; β = 0.02hPa×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 OPDTTv was associated with several offspring lung function parameters over time, all related to lung volumes. [ABSTRACT FROM AUTHOR]

BACKGROUND: Studies characterizing associations between phenols, phthalates and thyroid hormones during pregnancy produce inconsistent results. This divergence may be partly attributable to false positives due to multiple comparison testing of large numbers of chemicals, and measurement error as studies rely on small numbers of biospecimens despite high intra-individual variability in urinary chemical metabolite concentrations. OBJECTIVES: This study employs a priori chemical filtering and expanded urinary biomonitoring to evaluate associations between phenol/phthalate exposures and serum thyroid hormones assessed during pregnancy. METHODS: A two-tiered approach was implemented: a) In vitro high-throughput screening results from the ToxCast/Tox21 database, as informed by a thyroid Adverse Outcome Pathway network, were evaluated to select phenols/phthalates with activity on known and putative molecular initiating events in the thyroid pathway; and b) Adjusted linear regressions were used to study associations between filtered compounds and serum thyroid hormones measured in 437 pregnant women recruited in Grenoble area (France) between 2014 and 2017. Phenol/phthalate metabolites were measured in repeated spot urine sample pools (median: 21 samples/women). RESULTS: The ToxCast/Tox21 screening reduced the chemical set from 16 to 13 and the associated number of statistical comparisons by 19%. Parabens were negatively associated with free triiodothyronine (T3) and the T3/T4 (total thyroxine) ratio. Monobenzyl phthalate was positively associated with total T4 and negatively with the T3/T4 ratio. Effect modification by iodine status was detected for several compounds (among them ∑DEHP and mono-푛-butyl phthalate) that were associated with some hormones among women with normal iodine levels. CONCLUSION: For these chemicals, screening for compounds with an increased likelihood for thyroid-related effects and relying on repeated urine samples to assess exposures improved the overall performance of multichemical analyses of thyroid disruption. This approach may improve future evaluations of human data for the thyroid pathway with implication for fetal health and may serve as a model for evaluating other toxicity outcomes. [ABSTRACT FROM AUTHOR]

Aim: This single‐centre French cohort study evaluated the relationship between standardised assessment at 2 years of corrected age and schooling level at 5 years of age in children born at ≤32 weeks' gestational age. Methods: This was a single‐centre retrospective study of children born preterm between 2010 and 2014 included in a follow‐up network. At 5 years of age, the population was divided into 2 groups: (1) 'appropriate schooling', defined as age‐appropriate schooling without support, and (2) 'schooling with support'. At 2 years of corrected age, the developmental quotient (DQ) was calculated using the revised Brunet–Lezine test. Neonatal variables and DQ categories were compared between the 2 groups on univariate and multivariate analyses. Results: DQ was available for 251 of the 270 children included (93%), with a median score of 93.0 (IQR [87.0–100.0]), and 171 children (68%) were in the schooling without support group. On multivariate analysis, DQ ≥100 (n = 67) was the only variable that significantly associated with schooling without support (OR = 13.9; 95% CI: 5.5–35.4) at 5 years of age. Conclusion: This result may be useful for clinicians in their routine practice and for information given to parents in neonatal follow‐up. [ABSTRACT FROM AUTHOR]

Background: The prevalence of obstructive sleep apnea is higher in women after menopause. This is suggested to be a result of an altered sex hormone balance but has so far not been confirmed in a population-based study. Objective: To investigate whether serum concentration of estrogens and progesterone are associated with the prevalence of sleep apnea symptoms in middle-aged women of the general population. Methods: We analyzed data from 774 women (40–67 years) from 15 study centers in seven countries participating in the second follow-up of the European Community Respiratory Health Survey (2010–2012). Multiple logistic regression models were fitted with self-reported symptoms of sleep apnea as outcomes and serum concentrations of various estrogens and progesterone as predictors. All analyses were adjusted for relevant covariates including age, BMI, education, study center, smoking habits, and reproductive age. Results: Among all included women, a doubling of serum concentrations of estrone and progesterone was associated with 19% respectively 9% decreased odds of snoring. Among snorers, a doubling of the concentrations of 17β-estradiol, estrone and estrone 3-sulfate was associated with 18%, 23% and 17% decreased odds of breathing irregularly, and a doubling of the progesterone concentration was further associated with 12% decreased odds of waking up suddenly with a chocking sensation. Other evaluated associations were not statistically significant. Conclusions: Middle-aged women with low serum estrogen and progesterone levels are more likely to snore and report symptoms of obstructive sleep apnea. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• CFRD diagnosis relies on 2h-OGTT but compliance to this latter is weak. • HOMA-%β evaluates insulin secretion deficiency. • HOMA-%β can be easily calculated based on fasting glucose and insulin values. • HOMA-%β had good sensitivity and negative predictive value for the exclusion of CFRD. • HOMA-%β could serve as a screening tool to exclude CFRD and thus avoid 2h-OGTT. We assessed the diagnostic performances of homeostasis model assessment indices (HOMA) of β-cell function (HOMA-%β) and of insulin resistance (HOMA-IR) for cystic fibrosis related diabetes (CFRD) screening. Data were collected from a prospective cohort of 228 patients with CF (117 adults and 111 children). Fasting insulin and glucose levels were measured to calculate HOMA-%β and HOMA-IR. HOMA-%β <100 indicated insulin secretion deficiency and HOMA-IR >1 insulin resistance. Both were used to calculate sensitivity, specificity, and positive and negative predictive values (PPV and NPV). Two-hour oral glucose tolerance tests (2h-OGTT) defined CFRD. Analyses were conducted separately for children and adults. Performances of HOMA-%β and HOMA-IR were calculated at inclusion, for each year of follow-up and for pooled data over the follow-up period. Sensitivity, specificity, NPV and PPV were respectively: 88%, 45%, 98% and 11% for HOMA-%β and 42%, 48%, 91% and 6% for HOMA-IR in the pooled data of children; and 83%, 18%, 90% and 10% for HOMA-%β, and 39%, 80%, 92% and 18% for HOMA-IR in the pooled data of adults. Combining HOMA-%β and HOMA-IR did not improve performances. Within both age groups, HOMA-%β <100 provided good sensitivity and NPV. HOMA-IR >1 had low sensitivity. Calculation of the HOMA-%β could be an interesting first-line screening approach to exclude CFRD and thus avoid unnecessary OGTT in patients for whom value is ≥100. However, HOMA-%β<100 does not support the diagnosis of CFRD and should be complemented by OGTT. [ABSTRACT FROM AUTHOR]

• Phenols and phthalates were frequently detected in this recent pregnancy cohort. • Weighted Quantile Sum indexes were associated with child behaviour. • Associations tended to be stronger in girls. • Bisphenol A, triclosan, MEP were the main mixture contributors for externalizing score. • MEP, MBzP, MnBP were the main mixture contributors for internalizing score. Synthetic phenols and phthalates can interfere with biological pathways involved in brain development. Despite the high within-subject temporal variability of urinary concentrations observed for their metabolites, studies investigating effects of phenols and phthalates on child behaviour often relied on a limited number of spot biospecimens to assess exposure. Besides, the majority did not consider mixture effects. To study the combined effect of prenatal exposure to synthetic phenols and phthalates on child behaviour using repeated exposure measurements. We assessed concentrations of 12 phenols, 13 phthalate and 2 non-phthalate plasticizer metabolites in within-subject pools of multiple urine samples (median = 21 samples per individual pool) collected at two distinct time points during pregnancy in 416 mother–child pairs from the French SEPAGES cohort. Child behaviour was evaluated at two years using the Child Behaviour Checklist 1.5–5 (CBCL). Associations between a mixture of biomarkers of exposure and externalizing and internalizing behaviour scores were studied using adjusted Weighted Quantile Sum (WQS) regressions with a repeated holdout validation (100 repetitions). The positive WQS indexes were associated with both the externalizing and internalizing behaviour scores in the whole population, indicating greater risk of behavioural problems. Stratification for child sex suggested stronger associations in girls than boys. On average, girls externalizing and internalizing scores increased by 3.67 points (95% CI: 1.24, 6.10) and 2.47 points (95 %CI: 0.60, 4.33) respectively, for an increase of one tertile in the WQS index, compared with 1.70 points (95 %CI: −0.42, 3.81) and 1.17 points (95 %CI: −0.50, 2.84) in boys. Main contributors for the associations observed in girls were bisphenol A (weight of 18%), triclosan (17%) and monoethyl phthalate (MEP, 15%) for the externalizing score and MEP (19%), mono-benzyl phthalate (MBzP, 19%) and mono-n-butyl phthalate (MnBP, 16%) for the internalizing score. Our results suggest adverse associations between in utero exposure to a mixture of phenols and phthalates and child behaviour, mainly in girls. Public health consequences may be substantial due to the widespread exposure of the population to these compounds. [ABSTRACT FROM AUTHOR]

Introduction: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that has demonstrated clinical benefits in phase 3 trials. We report results from a real-world study (BRIO) to assess the effectiveness of ivacaftor in people with cystic fibrosis (pwCF) in France. Methods: BRIO was an observational study conducted at 35 centers in France. Both pwCF initiating ivacaftor treatment and those already taking ivacaftor were included and prospectively followed for 24 months. The primary objective was to evaluate the effect of ivacaftor on percent predicted forced expiratory volume in 1 s (ppFEV1); secondary objectives were evaluating the effect of ivacaftor on clinical effectiveness, healthcare resource utilization (HCRU), and safety. Results: A total of 129 pwCF were enrolled; 58.9% were aged < 18 years; 64.3% had a G551D-CFTR allele. Mean age at ivacaftor initiation was 19.1 years (range, 2–64 years); ppFEV1 increased by a least squares mean of 8.49 percentage points in the first 6 months and was sustained through 36 months of ivacaftor use. Growth metrics increased during the first 12 months post-ivacaftor and remained stable. The rate of pulmonary exacerbations (PEx) decreased during the 12 months post-ivacaftor compared with the 12 months pre-ivacaftor; estimated rate ratios (95% CI) were 0.57 (0.43–0.75) for PEx events and 0.25 (0.13–0.48) for PEx requiring hospitalization. No new safety concerns were identified; no deaths occurred. Conclusions: The results from this real-world study of ivacaftor usage in France were consistent with prior clinical trial outcomes, confirming the clinical effectiveness of ivacaftor, as well as an associated reduction in HCRU. [ABSTRACT FROM AUTHOR]

Background: Allergy, the most frequent immune disorder affecting 30% of the world's population, is the consequence of immunoglobin E (IgE) sensitization to allergens. Among the genetic factors suspected to be involved in allergy, the HLA class‐II genomic region is a strong candidate. Objective: To assess the association between HLA class‐II alleles and specific IgE (sIgE) sensitization to a large number of respiratory allergen molecules. Methods: The analysis relied on 927 participants of the EGEA cohort, including 497 asthmatics. The study focuses on 26 aeroallergens recognized by sIgE in at least 5% of the study population (determined with the MEDALL chip with sIgE ≥ 0.3 ISU) and 23 imputed HLA class‐II alleles. For each sIgE sensitization and HLA class‐II allele, we fitted a logistic regression model accounting for familial dependence and adjusted for gender, age, and genetic principal components. p‐values were corrected for multiple comparisons (False Discovery Rate). Results: Most of the 19 statistically significant associations observed regard pollen allergens (mugwort Art v 1, olive tree Ole e 1, timothy grass Phl p 2, Phl p 5 and plantain Pla l 1), three were mold allergen (Alternaria Alt a 1), and a single one regards house dust mite allergen (Der p 7). No association was observed with pet allergens. The strongest associations were found with mugwort Art v 1 (OR = 5.42 (95%CI, 3.30; 8.88), 4.14 (2.65; 6.47), 3.16 (1.88; 5.31) with DQB1*05:01, DQA1*01:01 and DRB1*01:01, respectively). Conclusion: Our results support the important role of HLA class‐II alleles as immune response genes predisposing their carriers for sensitization to various major pollen allergens. [ABSTRACT FROM AUTHOR]

Background: Solar ultraviolet radiation (UVR) affects the body through pathways that exhibit positive as well as negative health effects such as immunoregulation and vitamin D production. Different vitamin D metabolites are associated with higher or lower concentrations of estrogens and may thus alter the female sex hormone balance.Objective: To study whether exposure to UVR, as a modifiable lifestyle factor, is associated with levels of sex hormones (17β-estradiol, estrone, estrone 3-sulfate, testosterone, dehydroepiandrosterone sulfate), gonadotropins (follicle stimulating hormone, luteinizing hormone) as well as sex hormone binding globulin in postmenopausal women, and thus investigate whether managing UVR exposure can influence the hormone balance, with potential benefits for the biological aging process.Methods: The study included 580 postmenopausal women from six European countries, participating in the European Community Respiratory Health Survey (2010-2014). Average UVR exposure during the month before blood sampling was estimated based on personal sun behavior and ambient levels. Hormone concentrations were measured in serum using state-of-the-art methods. Subsequently we applied linear mixed-effects models, including center as random intercept, hormone concentrations (one at a time) as outcome and UVR, age, skin type, body mass index, vitamin D from dietary sources, smoking, age at completed full-time education and season of blood sampling as fixed-effect predictors.Results: One interquartile range increase in UVR exposure was associated with decreased levels of 17β-estradiol (-15.6 pmol/L, 95 % Confidence Interval (CI): -27.69, -3.51) and estrone (-13.36 pmol/L, 95 % CI: -26.04, -0.68) and increased levels of follicle stimulating hormone (9.34IU/L, 95 % CI: 2.91, 15.77) and luteinizing hormone (13.86 IU/daL, 95 % CI: 2.48, 25.25).Conclusions: Exposure to UVR is associated with decreased estrogens and increased gonadotropins in postmenopausal women, a status associated with osteoporosis, lung function decline and other adverse health effects. This study indicates that managing UVR exposure has potential to influence the hormone balance and counteract adverse health conditions after menopause. [ABSTRACT FROM AUTHOR]

We estimated the association between regular physical activity and the incidence of restrictive spirometry pattern. Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and physical activity were assessed in 2 population-based European cohorts (European Community Respiratory Health Survey: n  = 2,757, aged 39–67 years; and Swiss Study on Air Pollution and Lung and Heart Diseases in Adults: n  = 2,610, aged 36–82 years) first in 2000–2002 and again approximately 10 years later (2010–2013). Subjects with restrictive or obstructive spirometry pattern at baseline were excluded. We assessed the association of being active at baseline (defined as being physically active at least 2–3 times/week for ≥1 hour) with restrictive spirometry pattern at follow-up (defined as a postbronchodilation FEV1/FVC ratio of at least the lower limit of normal and FVC of <80% predicted) using modified Poisson regression, adjusting for relevant confounders. After 10 years of follow-up, 3.3% of participants had developed restrictive spirometry pattern. Being physically active was associated with a lower risk of developing this phenotype (relative risk = 0.76, 95% confidence interval: 0.59, 0.98). This association was stronger among those who were overweight and obese than among those of normal weight (P for interaction = 0.06). In 2 large European studies, adults practicing regular physical activity were at lower risk of developing restrictive spirometry pattern over 10 years. [ABSTRACT FROM AUTHOR]

Concerns exist that the positive association of physical activity with better lung function, which has been suggested in previous longitudinal studies in smokers, is due to reverse causation. To investigate this, we applied structural equation modeling (SEM), an exploratory approach, and marginal structural modeling (MSM), an approach from the causal inference framework that corrects for reverse causation and time-dependent confounding and estimates causal effects, on data from participants in the European Community Respiratory Health Survey (ECRHS, a multicentre European cohort study initiated in 1991–1993 with ECRHS I, and with two follow-ups: ECRHS II in 1999–2003, and ECRHS III in 2010–2014). 753 subjects who reported current smoking at ECRHS II, with repeated data on lung function at ECRHS I, II and III, physical activity at ECRHS II and III, and potential confounders at ECRHS I and II, were included in the analyses. SEM showed positive associations between physical activity and lung function in both directions. MSM suggested a protective causal effect of physical activity on lung function (overall difference in mean β (95% CI), comparing active versus non-active individuals: 58 mL (21–95) for forced expiratory volume in one second and 83 mL (36–130) for forced vital capacity). Our results suggest bi-directional causation and support a true protective effect of physical activity on lung function in smokers, after accounting for reverse causation and time-dependent confounding. [ABSTRACT FROM AUTHOR]

Purpose: Chronic obstructive pulmonary disease (COPD) is associated with several co-morbidities and non-infectious rhinitis (NIR) has emerged as a new possible co-morbidity. The primary aim of this study is to confirm a previously reported association between NIR and COPD in a multicentre population over time. The secondary aim is to investigate the course over time of such an association through a comparison between early- and late-onset COPD. Methods: This study is part of the European Community Respiratory Health Survey (ECRHS). A random adult population from 25 centres in Europe and one in Australia was examined with spirometry and answered a respiratory questionnaire in 1998–2002 (ECRHS II) and in 2008–2013 (ECRHS III). Symptoms of non-infectious rhinitis, hay fever and asthma, and smoking habits were reported. Subjects reporting asthma were excluded. COPD was defined as a spirometry ratio of FEV1/FVC < 0.7. A total of 5901 subjects were included. Results: Non-infectious rhinitis was significantly more prevalent in subjects with COPD compared with no COPD (48.9% vs 37.1%, p < 0.001) in ECRHS II (mean age 43) but not in ECHRS III (mean age 54). In the multivariable regression model adjusted for COPD, smoking, age, BMI, and gender, non-infectious rhinitis was associated with COPD in both ECRHS II and III. Conclusion: Non-infectious rhinitis was significantly more common in subjects with COPD at a mean age of 43. Ten years later, the association was weaker. The findings indicate that NIR could be associated with the early onset of COPD. [ABSTRACT FROM AUTHOR]

Lung infections play a critical role in cystic fibrosis (CF) pathogenesis. CF respiratory tract is now considered to be a polymicrobial niche and advances in high-throughput sequencing allowed to analyze its microbiota and mycobiota. However, no NGS studies until now have characterized both communities during CF pulmonary exacerbation (CFPE). Thirty-three sputa isolated from patients with and without CFPE were used for metagenomic high-throughput sequencing targeting 16S and ITS2 regions of bacterial and fungal rRNA. We built inter-kingdom network and adapted Phy-Lasso method to highlight correlations in compositional data. The decline in respiratory function was associated with a decrease in bacterial diversity. The inter-kingdom network revealed three main clusters organized around Aspergillus, Candida, and Scedosporium genera. Using Phy-Lasso method, we identified Aspergillus and Malassezia as relevantly associated with CFPE, and Scedosporium plus Pseudomonas with a decline in lung function. We corroborated in vitro the cross-domain interactions between Aspergillus and Streptococcus predicted by the correlation network. For the first time, we included documented mycobiome data into a version of the ecological Climax/Attack model that opens new lines of thoughts about the physiopathology of CF lung disease and future perspectives to improve its therapeutic management. [ABSTRACT FROM AUTHOR]

Objective: Regular physical activity may be associated with improved lung function via reduced systemic inflammation, although studies exploring this mechanism are rare. We evaluated the role of C-reactive protein in blood, which is a common marker of systemic inflammation, on the association of physical activity with forced expiratory volume in one second and forced vital capacity. Methods: Cross-sectional data on spirometry, C-reactive protein levels and self-reported physical activity (yes/no; ≥2 times and ≥1hr per week of vigorous physical activity) were available in the European Community Respiratory Health Survey (N = 2347 adults, 49.3% male, 28–56 years-old). A subsample was also assessed 10 years later using the International Physical Activity Questionnaire, and tertiles of Metabolic Equivalent of Task—minutes per week spent in vigorous, moderate and walking activities were calculated (N = 671, 49.6% male, 40–67 years-old). Adjusted cross-sectional mixed linear regression models and the “mediate” package in “R” were used to assess the presence of mediation. Results: Despite positive significant associations between nearly all physical activity metrics with forced expiratory volume in one second and forced vital capacity, there was no evidence that C-reactive protein levels played a role. An influence of C-reactive protein levels was only apparent in the smaller subsample when comparing the medium to low tertiles of moderate activity (mean difference [95% CIs]: 21.1ml [5.2, 41.9] for forced expiratory volume in one second and 17.3ml [2.6, 38.0] for forced vital capacity). Conclusions: In a population of adults, we found no consistent evidence that the association of physical activity with forced expiratory volume in one second or forced vital capacity is influenced by the level of C-reactive protein in blood. [ABSTRACT FROM AUTHOR]

This longitudinal study investigated whether smoking bans influence passive smoking at work and/or at home in the same subjects. Passive smoking at work and/or at home was investigated in random population samples (European Community Respiratory Health Survey) in 1990‐1995, with follow‐up interviews in 1998‐2003 and 2010‐2014. National smoking bans were classified as partial (restricted to public workplaces) or global (extended to private workplaces). Multivariable analysis was accomplished by three‐level logistic regression models, where level‐1, level‐2, and level‐3 units were, respectively, questionnaire responses, subjects, and centers. Passive smoking at work was reported by 31.9% in 1990‐1995, 17.5% in 1998‐2003, and 2.5% in 2010‐2014. Concurrently, passive smoking at home decreased from 28.9% to 18.2% and 8.8%. When controlling for sex, age, education, smoking status, and ECHRS wave, the odds of passive smoking at work was markedly reduced after global smoking bans (OR = 0.45, 95% CI 0.25‐0.81), particularly among non‐smokers, while the protective effect of global smoking bans on passive smoking at home was only detected in non‐smokers. Smoking bans both in public and private workplaces were effective in reducing passive smoking at work in Europe. However, given the inefficacy of smoking bans in current smokers' dwellings, better strategies are needed to avoid smoking indoors. [ABSTRACT FROM AUTHOR]

Introduction: The fractional exhaled nitric oxide (FENO) is a marker for type 2 inflammation used in diagnostics and management of asthma. In order to use FENO as a reliable biomarker, it is important to investigate factors that influence FENO in healthy individuals. Men have higher levels of FENO than women, but it is unclear whether determinants of FENO differ by sex. Objective: To identify determinants of FENO in men and women without lung diseases. Method: Fractional exhaled nitric oxide was validly measured in 3881 healthy subjects that had answered the main questionnaire of the European Community Respiratory Health Survey III without airways or lung disease. Results: Exhaled NO levels were 21.3% higher in men compared with women P < 0.001. Being in the upper age quartile (60.3‐67.6 years), men had 19.2 ppb (95% CI: 18.3, 20.2) higher FENO than subjects in the lowest age quartile (39.7‐48.3 years) P = 0.02. Women in the two highest age quartiles (54.6‐60.2 and 60.3‐67.6 years) had 15.4 ppb (14.7, 16.2), P = 0.03 and 16.4 ppb (15.6, 17.1), P = <0.001 higher FENO, compared with the lowest age quartile. Height was related to 8% higher FENO level in men (P < 0.001) and 5% higher FENO levels in women (P = 0.008). Men who smoked had 37% lower FENO levels and women had 30% lower levels compared with never‐smokers (P < 0.001 for both). Men and women sensitized to both grass and perennial allergens had higher FENO levels compared with non‐sensitized subjects 26% and 29%, P < 0.001 for both. Conclusion and Clinical Relevance: Fractional exhaled nitric oxide levels were higher in men than women. Similar effects of current smoking, height, and IgE sensitization were found in both sexes. FENO started increasing at lower age in women than in men, suggesting that interpretation of FENO levels in adults aged over 50 years should take into account age and sex. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Hypertensive disorders during pregnancy are one of the leading causes of maternal and offspring mortality and morbidity. Exposure to environmental chemicals is suspected to increase blood pressure (BP) but few studies have investigated the impact of non-persistent chemicals, in particular among pregnant women.Methods: Women included in the study were 152 volunteer participants in the Human Early-Life Exposome (HELIX) project. They provided 3 urine samples daily over one week in two pregnancy trimesters (at around 18 and 32 weeks of gestation) to assess their exposure to phthalates (10 metabolites), phenols (7 compounds) and organophosphate pesticides (4 metabolites). BP was measured at the end of the two collection weeks. Associations between biomarkers of exposure and BP were investigated using generalized estimating equations (GEE) and linear regression, and adjusted for potential confounders.Results: A significant decrease in systolic and/or diastolic BP was observed with exposure to some phthalate metabolites, BPA, and parabens (e.g. β GEE models for systolic BP = -0.91 mmHg (95%CI: -1.65; -0.17) per doubling of BPA concentrations). These associations were more frequently observed in the second trimester of pregnancy and remained statistically significant after correction for multiple testing for BPA only. No associations were observed with organophosphate pesticides.Conclusion: This study investigates the effect of exposure to non-persistent chemicals assessed using multiple biospecimens per subject on BP during pregnancy and suggests that higher exposure to some phthalates and phenols but not pesticides is associated with lower BP during pregnancy. [ABSTRACT FROM AUTHOR]

Objectives: Menopause involves hypoestrogenism, which is associated with numerous detrimental effects, including on respiratory health. Hormone replacement therapy (HRT) is often used to improve symptoms of menopause. The effects of HRT on lung function decline, hence lung ageing, have not yet been investigated despite the recognized effects of HRT on other health outcomes.Study Design: The population-based multi-centre European Community Respiratory Health Survey provided complete data for 275 oral HRT users at two time points, who were matched with 383 nonusers and analysed with a two-level linear mixed effects regression model.Main Outcome Measures: We studied whether HRT use was associated with the annual decline in forced vital capacity (FVC) and forced expiratory volume in one second (FEV1).Results: Lung function of women using oral HRT for more than five years declined less rapidly than that of nonusers. The adjusted difference in FVC decline was 5.6 mL/y (95%CI: 1.8 to 9.3, p = 0.01) for women who had taken HRT for six to ten years and 8.9 mL/y (3.5 to 14.2, p = 0.003) for those who had taken it for more than ten years. The adjusted difference in FEV1 decline was 4.4 mL/y (0.9 to 8.0, p = 0.02) with treatment from six to ten years and 5.3 mL/y (0.4 to 10.2, p = 0.048) with treatment for over ten years.Conclusions: In this longitudinal population-based study, the decline in lung function was less rapid in women who used HRT, following a dose-response pattern, and consistent when adjusting for potential confounding factors. This may signify that female sex hormones are of importance for lung ageing. [ABSTRACT FROM AUTHOR]