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

Abstract 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

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

International audienceContext: 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

Household use of irritants and sprayed cleaning products and asthma endotypes

International audienceCleaning products are often considered as irritants, but those in spray form contain perfumes which may be sensitizers.We aimed to evaluate the hypotheses of non-immunological and immunological mechanisms, by which irritant and sprayed (sensitizer) cleaning products may affect asthma, by assessing their use at home in association with respiratory endotypes.Cross-sectional analyses were conducted on 1,039 adults from the French Epidemiological study on the Genetics and Environment of Asthma (EGEA, mean age: 44 years, 54% women). Household use of cleaning products was self-reported by questionnaire. Five respiratory endotypes were determined by a cluster analysis (https://pubmed.ncbi.nlm.nih.gov/33268339/), 2 in participants without asthma (NA1: asymptomatic; NA2: symptomatic) and 3 in those with current asthma (CA1: adult-onset, poor lung function, neutrophilic inflammation; CA2: middle-age asthma, rhinitis, low Immunoglobulin E level; CA3: allergic childhood-onset). Multinomial logistic regressions adjusted for age, smoking status and gender were performed to estimate associations between the use of irritants/sprays (ref: no weekly use) and endotypes (ref: NA1).A daily use of sprays (13%) was associated with CA2 (OR=1.64[0.97-2.76]). The weekly use of ≥2 sprays (16%) was associated with CA1 (OR=2.60[1.13-5.97]) and CA2 (OR=1.71[1.04-2.80]). No significant association was observed for irritants. An analysis restricted to women showed more pronounced associations for sprays and a daily use of irritants was associated with CA2 (OR=2.48[1.21-5.11]).Weekly use of sprays was associated with two asthma endotypes, but our results did not confirm the hypotheses on the underlying mechanisms

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

International audienceObjective 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

In Utero Exposure to Select Phenols and Phthalates and Respiratory Health in Five-Year-Old Boys: A Prospective Study

the EDEN Mother–Child Cohort Study GroupInternational audienceBackground: Phenols and phthalates may have immunomodulatory and proinflammatory effects and thereby adversely affect respiratory health.Objective: We estimated the associations between gestational exposure to select phthalates and phenols and respiratory health in boys.Methods: Among 587 pregnant women from the EDEN (Etude des Déterminants pré et post natals du développement et de la santé de l’Enfant) cohort who delivered a boy, 9 phenols and 11 phthalates metabolites were quantified in spot pregnancy urine samples. Respiratory outcomes were followed up by questionnaires until age 5, when forced expiratory volume in 1 s (FEV1) was measured by spirometry. Adjusted associations of urinary metabolites log–transformed concentrations with respiratory outcomes and FEV1 in percent predicted (FEV1%) were estimated by survival and linear regression models, respectively.Results: No phenol or phthalate metabolite exhibited clear deleterious associations simultaneously with several respiratory outcomes. Ethyl-paraben was associated with increased asthma rate [hazard rate (HR)=1.10; 95% confidence interval (CI): 1.00, 1.21] and tended to be negatively associated with FEV1% (beta=−0.59; 95% CI: −1.24, 0.05); bisphenol A tended to be associated with increased rates of asthma diagnosis (HR=1.23; 95% CI: 0.97, 1.55) and bronchiolitis/bronchitis (HR=1.13; 95% CI: 0.99, 1.30). Isolated trends for deleterious associations were also observed between 2,5-dichlorophenol and wheezing, and between monocarboxynonyl phthalate, a metabolite of di-isodecyl phthalate (DIDP), and wheezing.Conclusion: Ethyl-paraben, bisphenol A, 2,5-dichlorophenol, and DIDP tended to be associated with altered respiratory health, with ethyl-paraben and bisphenol A exhibiting some consistency across respiratory outcomes. The trends between bisphenol A pregnancy level and increased asthma and bronchiolitis/bronchitis rates in childhood were consistent with a previous cohort study

Additional file 1 of Intra-breath changes in respiratory mechanics are sensitive to history of respiratory illness in preschool children: the SEPAGES cohort

Supplementary Material

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

BACKGROUND: Fine particulate matter (PM 2:5) has been found to be detrimental to respiratory health of children, but few studies have examined the effects of prenatal PM 2:5 oxidative potential (OP) on lung function in infants and preschool children. OBJECTIVES: We estimated the associations of personal exposure to PM 2:5 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 (N 2 MBW) test, performed at 6 wk, and airwave oscillometry (AOS) performed at 3 y. Associations of prenatal PM 2:5 mass and OP with lung function parameters were estimated using multiple linear regressions. RESULTS: In neonates, an interquartile (IQR) increase in OP DTT v (0:89 nmol=min=m 3) was associated with a decrease in functional residual capacity (FRC) measured by N 2 MBW [b = − 2:26 mL; 95% confidence interval (CI): −4:68, 0.15]. Associations with PM 2:5 showed similar patterns in comparison with OP DTT v 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 (Rrs 7-19) from AOS tended to be associated with higher OP DTT

Unravelling sex-specific BPA toxicokinetics in children using a pediatric PBPK model

Bisphenol A (BPA) is a widely known endocrine disruptor (ED) found in many children's products such as toys, feeding utensils, and teething rings. Recent epidemiology association studies have shown postnatal BPA exposure resulted in developing various diseases such as diabetes, obesity, and neurodegeneration, etc., later in their lives. However, little is known about its sex-specific metabolism and consequently internal exposure. The aim of this study was to develop a sex-specific pediatric physiologically based pharmacokinetic model (PBPK) for BPA to compare their toxicokinetic differences. First, the published adult PBPK model was re-validated, and then this model was extended by interpolation to incorporate pediatric sex specific physiological and biochemical parameters. We used both the classical body weight and ontogeny-based scaling approach to interpolate the metabolic process. Then, the pharmacokinetic attributes of the models using the two-scaling approach mentioned above were compared with adult model. Further, a sex-specific PBPK model with an ontogeny scaling approach was preferred to evaluate the pharmacokinetic differences. Moreover, this model was used to reconstruct the BPA exposure from two cohorts (Helix and PBAT Cohort) from 7 EU countries. The half-life of BPA was found to be almost the same in boys and girls at the same exposure levels. Our model estimated BPA children's exposure to be about 1500 times higher than the tolerable daily intake (TDI) recently set by European Food Safety Authority (EFSA) i.e., 0.04 ng/kg BW/day. The model demonstrated feasibility of extending the adult PBPK to sex-specific pediatric, thus investigate a gender-specific health risk assessment.This study was financially supported by Marie Skłodowska-Curie “Neurosome Project” under the grant agreement No. 766251, the European Community funded H2020 HBM4EU project under Grant Agreements no. 733032, and the Instituto de Salud Carlos III (PI17/01194), and the European Community's Seventh Framework Programme (FP7/2007–206) under grant agreement no 308333 (HELIX project). Maribel Casas holds a Miguel Servet fellowship (CP16/00128) funded by Instituto de Salud Carlos III and co-funded by European Social Fund “Investing in your future”. We acknowledge support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. This publication reflects only the authors' views. The Community and other funding organizations are not liable for any use made of the information contained therein. Born in Bradford is only possible because of the enthusiasm and commitment of the children and parents in Born in Bradford. We are grateful to all participants, health professionals and researchers who have made Born in Bradford happen. BiB receives core infrastructure funding from the Wellcome Trust (WT101597MA) and a joint grant from the UK Medical Research Council (MRC) and Economic and Social Science Research Council (ESRC) (MR/N024397/1). This study has received support from European Research Council under the European Union's Seventh Framework Programme (FP7/2007–2013)/ERC grant agreement no 669545 and National Institute for Health Research Applied Research Collaboration Yorkshire and Humber (NIHR200166)

Coupling a human cohort (SEPAGES) and a toxicological experiment to decipher the relations between the Exposome, omics markers and child health

International audienceCharacterization of the Exposome and its effects on children health is warranted. Consistency between human observations and results of toxicological experiments strengths the evidence in environmental health research, but is difficult to identify when epidemiological and toxicological studies are conducted independently. We present an original approach com-bining a cohort with intense exposure monitoring conducted in parallel with an animal experi-ment focused on air pollution effects. Pregnant women are being included in a monocentric couple­child cohort before 18 gestational weeks. Exposure to air pollutants (including NO2, benzene, PM2.5, soot) is assessed every 3 to 6 months by personal monitors in mothers and children. A large biobank is constituted including DNA, RNA for transcriptome assessment, serum, plasma, placenta, repeated pooled urine samples, meconium, child stools, milk and hair. The main health out-comes are respiratory health, fetal and child growth and neurodevelopment. In parallel, pre-gnant rabbits were exposed to diluted filtered diesel exhaust, feto­placental units were col-lected and offspring growth was monitored. To date the cohort includes 260 trios. Maternal median personal exposure is 19.1 µg/m3 (25th­75th centiles, 14.1­24.5) for NO2 and 1.2 µg/m3 (0.7­2.2) for benzene. The rabbit experiment showed transplacental transfer of diesel exhaust nanoparticles and demonstrated effects on placental vascularization and blood flow. Replication will be sought using placenta collected in the cohort. Our cohort constitutes an approach allowing accurate characterization of ear-ly­life exposures to air pollutants. Close collaboration between toxicological and epidemiolo-gical studies is a promising approach that enables cross­talk between both disciplines and ultimately could provide deeper understanding of the interplay between the Exposome, ‘omics markers and child health