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.

Associations between combined urban and lifestyle factors and respiratory health in European children.

INTRODUCTION: Previous studies identified some environmental and lifestyle factors independently associated with children respiratory health, but few focused on exposure mixture effects. This study aimed at identifying, in pregnancy and in childhood, combined urban and lifestyle environment profiles associated with respiratory health in children. METHODS: This study is based on the European Human Early-Life Exposome (HELIX) project, combining six birth cohorts. Associations between profiles of pregnancy (38 exposures) and childhood (84 exposures) urban and lifestyle factors, identified by clustering analysis, and respiratory health were estimated by regression models adjusted for confounders. RESULTS: Among the 1033 included children (mean ± standard-deviation (SD) age: 8.2 ± 1.6 years old, 47% girls) the mean ± SD forced expiratory volume in 1s (FEV1) and forced vital capacity (FVC) were 99 ± 13% and 101 ± 14%, respectively, and 12%, 12% and 24% reported ever-asthma, wheezing and rhinitis, respectively. Four profiles of pregnancy exposures and four profiles of childhood exposures were identified. Compared to the reference childhood exposure profile (low exposures), two exposure profiles were associated with lower levels of FEV1. One profile was characterized by few natural spaces in the surroundings and high exposure to the built environment and road traffic. The second profile was characterized by high exposure to meteorological factors and low levels of all other exposures and was also associated with an increased risk of ever-asthma and wheezing. A pregnancy exposure profile characterized by high exposure levels to all risk factors, but a healthy maternal lifestyle, was associated with a lower risk of wheezing and rhinitis in children, compared to the reference pregnancy profile (low exposures). CONCLUSION: This comprehensive approach revealed pregnancy and childhood profiles of urban and lifestyle exposures associated with lung function and/or respiratory conditions in children. Our findings highlight the need to pursue the study of combined exposures to improve prevention strategies for multifactorial diseases such as asthma.

Beyond the single-outcome approach: A comparison of outcome-wide analysis methods for exposome research.

Outcome-wide analysis can offer several benefits, including increased power to detect weak signals and the ability to identify exposures with multiple effects on health, which may be good targets for preventive measures. Recently, advanced statistical multivariate techniques for outcome-wide analysis have been developed, but they have been rarely applied to exposome analysis. In this work, we provide an overview of a selection of methods that are well-suited for outcome-wide exposome analysis and are implemented in the R statistical software. Our work brings together six different methods presenting innovative solutions for typical problems arising from outcome-wide approaches in the context of the exposome, including dependencies among outcomes, high dimensionality, mixed-type outcomes, missing data records, and confounding effects. The identified methods can be grouped into four main categories: regularized multivariate regression techniques, multi-task learning approaches, dimensionality reduction approaches, and bayesian extensions of the multivariate regression framework. Here, we compare each technique presenting its main rationale, strengths, and limitations, and provide codes and guidelines for their application to exposome data. Additionally, we apply all selected methods to a real exposome dataset from the Human Early-Life Exposome (HELIX) project, demonstrating their suitability for exposome research. Although the choice of the best method will always depend on the challenges to be faced in each application, for an exposome-like analysis we find dimensionality reduction and bayesian methods such as reduced rank regression (RRR) or multivariate bayesian shrinkage priors (MBSP) particularly useful, given their ability to deal with critical issues such as collinearity, high-dimensionality, missing data or quantification of uncertainty.

Statistical Approaches to Study Exposome-Health Associations in the Context of Repeated Exposure Data: A Simulation Study.

The exposome concept aims to consider all environmental stressors simultaneously. The dimension of the data and the correlation that may exist between exposures lead to various statistical challenges. Some methodological studies have provided insight regarding the efficiency of specific modeling approaches in the context of exposome data assessed once for each subject. However, few studies have considered the situation in which environmental exposures are assessed repeatedly. Here, we conduct a simulation study to compare the performance of statistical approaches to assess exposome-health associations in the context of multiple exposure variables. Different scenarios were tested, assuming different types and numbers of exposure-outcome causal relationships. An application study using real data collected within the INMA mother-child cohort (Spain) is also presented. In the simulation experiment, assessed methods showed varying performance across scenarios, making it challenging to recommend a one-size-fits-all strategy. Generally, methods such as sparse partial least-squares and the deletion-substitution-addition algorithm tended to outperform the other tested methods (ExWAS, Elastic-Net, DLNM, or sNPLS). Notably, as the number of true predictors increased, the performance of all methods declined. The absence of a clearly superior approach underscores the additional challenges posed by repeated exposome data, such as the presence of more complex correlation structures and interdependencies between variables, and highlights that careful consideration is essential when selecting the appropriate statistical method. In this regard, we provide recommendations based on the expected scenario. Given the heightened risk of reporting false positive or negative associations when applying these techniques to repeated exposome data, we advise interpreting the results with caution, particularly in compromised contexts such as those with a limited sample size.

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.

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

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

Associations of four biological age markers with child development: A multi-omic analysis in the European HELIX cohort.

Background: While biological age in adults is often understood as representing general health and resilience, the conceptual interpretation of accelerated biological age in children and its relationship to development remains unclear. We aimed to clarify the relationship of accelerated biological age, assessed through two established biological age indicators, telomere length and DNA methylation age, and two novel candidate biological age indicators, to child developmental outcomes, including growth and adiposity, cognition, behavior, lung function and the onset of puberty, among European school-age children participating in the HELIX exposome cohort. Methods: The study population included up to 1173 children, aged between 5 and 12 years, from study centres in the UK, France, Spain, Norway, Lithuania, and Greece. Telomere length was measured through qPCR, blood DNA methylation, and gene expression was measured using microarray, and proteins and metabolites were measured by a range of targeted assays. DNA methylation age was assessed using Horvath's skin and blood clock, while novel blood transcriptome and 'immunometabolic' (based on plasma proteins and urinary and serum metabolites) clocks were derived and tested in a subset of children assessed six months after the main follow-up visit. Associations between biological age indicators with child developmental measures as well as health risk factors were estimated using linear regression, adjusted for chronological age, sex, ethnicity, and study centre. The clock derived markers were expressed as Δ age (i.e. predicted minus chronological age). Results: Transcriptome and immunometabolic clocks predicted chronological age well in the test set (r=0.93 and r=0.84 respectively). Generally, weak correlations were observed, after adjustment for chronological age, between the biological age indicators.Among associations with health risk factors, higher birthweight was associated with greater immunometabolic Δ age, smoke exposure with greater DNA methylation Δ age, and high family affluence with longer telomere length.Among associations with child developmental measures, all biological age markers were associated with greater BMI and fat mass, and all markers except telomere length were associated with greater height, at least at nominal significance (p<0.05). Immunometabolic Δ age was associated with better working memory (p=4 e-3) and reduced inattentiveness (p=4 e-4), while DNA methylation Δ age was associated with greater inattentiveness (p=0.03) and poorer externalizing behaviors (p=0.01). Shorter telomere length was also associated with poorer externalizing behaviors (p=0.03). Conclusions: In children, as in adults, biological aging appears to be a multi-faceted process and adiposity is an important correlate of accelerated biological aging. Patterns of associations suggested that accelerated immunometabolic age may be beneficial for some aspects of child development while accelerated DNA methylation age and telomere attrition may reflect early detrimental aspects of biological aging, apparent even in children. Funding: UK Research and Innovation (MR/S03532X/1); European Commission (grant agreement numbers: 308333; 874583).

Although age is generally measured by the number of years since birth, many factors contribute to the rate at which a person physically ages. In adults, linking these measurements to age gives a measure of overall health and resilience. This 'biological age' offers a better prediction of remaining life and disease risk than the number of years lived. Multiple factors can be used to calculate biological age, such as measuring the length of telomeres ­ protective caps on the end of chromosomes ­ which shorten as people age. The rate at which they shorten can give an indication of how quickly someone is ageing. Researchers can also study epigenetic factors: these mechanisms lead to certain genes being switched on or off, and they can be combined into a 'epigenetic clock' to assess biological age. However, compared with adults, the relationship between biological age and child health and developmental maturity is less well understood. Robinson et al. studied 1,173 school-aged children from six European countries, measuring telomere length, epigenetic factors and other biological indicators related to metabolism and the immune system. The relationships between these factors and an array of child developmental measures such as height, weight, behaviour and the age of onset of puberty were established. The findings showed that biological age indicators are only weakly linked to each other in children. Despite this, biological age was related to greater amount of body fat across all tested indicators ­ which is also associated with biological age in adults and is an important determinant of lifespan. Among several observed effects on development, analysis found that shorter telomere length and older epigenetic age were associated with greater behavioural problems, suggesting they may be detrimental to child development. On the other hand, a greater age due to metabolic and immune related changes was associated with greater cognitive and behavioural maturity. Environmental factors were also linked to biological ageing, with children exposed to smoking in their homes or while their mother was pregnant displaying an older epigenetic age. Robinson et al. showed that biological ageing in children is multifaceted and can have both beneficial and harmful impacts on development. This knowledge is important for identifying early life risk factors that might influence healthy ageing in later life. Future work will help researchers to understand these complex interactions and the long-term consequences for health and well-being.

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.

Exposure to Disinfectants and Cleaning Products and Respiratory Health of Workers and Children in Daycares: The CRESPI Cohort Protocol.

Although cleaning tasks are frequently performed in daycare, no study has focused on exposures in daycares in relation to respiratory health. The CRESPI cohort is an epidemiological study among workers (n~320) and children (n~540) attending daycares. The purpose is to examine the impact of daycare exposures to disinfectants and cleaning products (DCP) on the respiratory health of workers and children. A sample of 108 randomly selected daycares in the region of Paris has been visited to collect settled dust to analyze semi-volatile organic compounds and microbiota, as well as sample indoor air to analyze aldehydes and volatile organic compounds. Innovative tools (smartphone applications) are used to scan DCP barcodes in daycare and inform their use; a database then matches the barcodes with the products' compositions. At baseline, workers/parents completed a standardized questionnaire, collecting information on DCP used at home, respiratory health, and potential confounders. Follow-up regarding children's respiratory health (monthly report through a smartphone application and biannual questionnaires) is ongoing until the end of 2023. Associations between DCP exposures and the respiratory health of workers/children will be evaluated. By identifying specific environments or DCP substances associated with the adverse respiratory health of workers and children, this longitudinal study will contribute to the improvement of preventive measures.

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.

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

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

Association of Prenatal and Postnatal Exposures to Warm or Cold Air Temperatures With Lung Function in Young Infants.

Importance: Little is known about long-term associations of early-life exposure to extreme temperatures with child health and lung function. Objectives: To investigate the association of prenatal and postnatal heat or cold exposure with newborn lung function and identify windows of susceptibility. Design, Setting, and Participants: This population-based cohort study (SEPAGES) recruited pregnant women in France between July 8, 2014, and July 24, 2017. Data on temperature exposure, lung function, and covariates were available from 343 mother-child dyads. Data analysis was performed from January 1, 2021, to December 31, 2021. Exposures: Mean, SD, minimum, and maximum temperatures at the mother-child's residence, estimated using a state-of-the-art spatiotemporally resolved model. Main Outcomes and Measures: Outcome measures were tidal breathing analysis and nitrogen multiple-breath washout test measured at 2 months of age. Adjusted associations between both long-term (35 gestational weeks and first 4 weeks after delivery) and short-term (7 days before lung function test) exposure to ambient temperature and newborn lung function were analyzed using distributed lag nonlinear models. Results: A total of 343 mother-child pairs were included in the analyses (median [IQR] maternal age at conception, 32 [30.0-35.2] years; 183 [53%] male newborns). A total of 246 mothers and/or fathers (72%) held at least a master's degree. Among the 160 female newborns (47%), long-term heat exposure (95th vs 50th percentile of mean temperature) was associated with decreased functional residual capacity (-39.7 mL; 95% CI, -68.6 to -10.7 mL for 24 °C vs 12 °C at gestational weeks 20-35 and weeks 0-4 after delivery) and increased respiratory rate (28.0/min; 95% CI, 4.2-51.9/min for 24 °C vs 12 °C at gestational weeks 14-35 and weeks 0-1 after delivery). Long-term cold exposure (5th vs 50th percentile of mean temperature) was associated with lower functional residual capacity (-21.9 mL; 95% CI, -42.4 to -1.3 mL for 1 °C vs 12 °C at gestational weeks 15-29), lower tidal volume (-23.8 mL; 95% CI, -43.1 to -4.4 mL for 1 °C vs 12 °C at gestational weeks 14-35 and weeks 0-4 after delivery), and increased respiratory rate (45.5/min; 95% CI, 10.1-81.0/min for 1 °C vs 12 °C at gestational weeks 6-35 and weeks 0-1 after delivery) in female newborns as well. No consistent association was observed for male newborns or short-term exposure to cold or heat. Conclusions and Relevance: In this cohort study, long-term heat and cold exposure from the second trimester until 4 weeks after birth was associated with newborn lung volumes, especially among female newborns.

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.

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

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

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.