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While strong evidence supports adverse effects of pre-natal air pollution on child's lung function, previous studies rarely considered fine particulate matter (PM 2.5) or the potential role of offspring sex and no study examined the effects of pre-natal PM 2.5 on the lung function of the newborn. We examined overall and sex-specific associations of personal pre-natal exposure to PM 2.5 and nitrogen (NO 2) with newborn lung function measurements. This study relied on 391 mother-child pairs from the French SEPAGES cohort. PM 2.5 and NO 2 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 (N 2 MBW) 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. Mean exposure to NO 2 and PM 2.5 during pregnancy was 20.2 μg/m3 and 14.3 μg/m3, respectively. A 10 μg/m3 increase in PM 2.5 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 PM 2.5. No association was found between maternal NO 2 exposure and newborns lung function. Personal pre-natal PM 2.5 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 PM 2.5 effects. • Personal exposure measurements to PM 2.5 and NO 2 are conducted repeatedly during pregnancy. • Early measurements of child lung function are performed at 2 months of age. • Personal prenatal PM 2.5 exposure, but not NO 2 , is associated with lower lung volumes in female newborns, but not in males. • Pulmonary effects of air pollution exposure can be initiated in utero. [ABSTRACT FROM AUTHOR]

BACKGROUND: 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. [ABSTRACT FROM AUTHOR]

BACKGROUND: Previous studies aiming at relating exposure to phenols and phthalates with child social behavior characterized exposure using one or a few spot urine samples, resulting in substantial exposure misclassification. Moreover, early infancy exposure was rarely studied. OBJECTIVES: We aimed to examine the associations of phthalates and phenols with child social behavior in a cohort with improved exposure assessment and to a priori identify the chemicals supported by a higher weight of evidence. METHODS: Among 406 mother-child pairs from the French Assessment of Air Pollution exposure during Pregnancy and Effect on Health (SEPAGES) cohort, 25 phenols/phthalate metabolites were measured in within-subject pools of repeated urine samples collected at the second and third pregnancy trimesters (∼21 samples/trimester) and at 2 months and 1-year of age (∼7 samples/period). Social behavior was parent-reported at 3 years of age of the child using the Social Responsiveness Scale (SRS). A structured literature review of the animal and human evidence was performed to prioritize the measured phthalates/phenols based on their likelihood to affect social behavior. Both adjusted linear regression and Bayesian Weighted Quantile Sum (BWQS) regression models were fitted. False discovery rate (FDR) correction was applied only to nonprioritized chemicals. RESULTS: Prioritized compounds included bisphenol A, bisphenol S, triclosan (TCS), diethyl-hexyl phthalate (RDEHP), mono-ethyl phthalate (MEP), mono-n-butyl phthalate (MnBP), and mono-benzyl phthalate (MBzP). With the exception of bisphenols, which showed a mixed pattern of positive and negative associations in pregnant mothers and neonates, few prenatal associations were observed. Most associations were observed with prioritized chemicals measured in 1-y-old infants: Each doubling in urinary TCS (β=0.78; 95% CI: 0.00, 1.55) and MEP (β=0.92; 95% CI: -0.11, 1.96) concentrations were associated with worse total SRS scores, whereas MnBP and RDEHP were associated with worse Social Awareness (β=0.25; 95% CI: 0.01, 0.50) and Social Communication (β=0.43; 95% CI: -0.02, 0.89) scores, respectively. BWQS also suggested worse total SRS [Beta 1=1.38; 95% credible interval (CrI): -0.18, 2.97], Social Awareness (Beta 1=0.37; 95% CrI: 0.06, 0.70), and Social Communication (Beta 1=0.91; 95% CrI: 0.31, 1.53) scores per quartile increase in the mixture of prioritized compounds assessed in 1-y-old infants. The few associations observed with nonprioritized chemicals did not remain after FDR correction, with the exception of benzophenone-3 exposure in 1-y-old infants, which was suggestively associated with worse Social Communication scores (corrected 푝=0.07). DISCUSSION: The literature search allowed us to adapt our statistical analysis according to the weight of evidence and create a corpus of experimental and epidemiological knowledge to better interpret our findings. Early infancy appears to be a sensitive exposure window that should be further investigated. [ABSTRACT FROM AUTHOR]

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 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: 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]

Abstract: Background: Spatially-resolved air pollution models can be developed in large areas. The resulting increased exposure contrasts and population size offer opportunities to better characterize the effect of atmospheric pollutants on respiratory health. However the heterogeneity of these areas may also enhance the potential for confounding. We aimed to discuss some analytical approaches to handle this trade-off. Methods: We modeled NO2 and PM10 concentrations at the home addresses of 1082 pregnant mothers from EDEN cohort living in and around urban areas, using ADMS dispersion model. Simulations were performed to identify the best strategy to limit confounding by unmeasured factors varying with area type. We examined the relation between modeled concentrations and respiratory health in infants using regression models with and without adjustment or interaction terms with area type. Results: Simulations indicated that adjustment for area limited the bias due to unmeasured confounders varying with area at the costs of a slight decrease in statistical power. In our cohort, rural and urban areas differed for air pollution levels and for many factors associated with respiratory health and exposure. Area tended to modify effect measures of air pollution on respiratory health. Conclusions: Increasing the size of the study area also increases the potential for residual confounding. Our simulations suggest that adjusting for type of area is a good option to limit residual confounding due to area-associated factors without restricting the area size. Other statistical approaches developed in the field of spatial epidemiology are an alternative to control for poorly-measured spatially-varying confounders. [Copyright &y& Elsevier]

• 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]

• 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]

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: The associations between exposure to air pollution and asthma control are not well known. The objective of this study was to assess the association between long-term exposure to NO2, O3 and PM10 and asthma control in the follow-up of the Epidemiological study on the Genetics and Environment of Asthma(EGEA2) (2003-2007).Methods: Modelled outdoor NO2, O3 and PM10estimates were linked to each residential address using the 4 km grid air pollutant surface developed by the French Institute of Environment in 2004. Asthma control was assessed in 481 subjects with current asthma using a multidimensional approach following the 2006-2009Global Initiative for Asthma guidelines. Multinomial and ordinal logistic regressions were conducted adjusted for sex, age, body mass index, education, smoking and use of inhaled corticosteroids. The association between air pollution and the three domains of asthma control(symptoms, exacerbations and lung function) was assessed. ORs are reported per IQR.Results: Median concentrations (in micrograms per cubic metre) were 32 (IQR 25-38) for NO2 (n=465), 46(41-52) for O3 and 21 (18-21) for PM10 (n=481). In total, 44%, 29% and 27% had controlled, partly controlled and uncontrolled asthma, respectively. The ordinal ORs for O3 and PM10 with asthma control were1.69 (95% CI 1.22 to 2.34) and 1.35 (95% CI 1.13 to1.64), respectively. When including both pollutants in the same model, both associations persisted. Associations were not modified by sex, smoking status, use of inhaledcorticosteroids, atopy, season of examination or body mass index. Both pollutants were associated with each of the three main domains of control.Conclusions: The results suggest that long-term exposure to PM10 and O3 is associated with uncontrolled asthma in adults, defined by symptoms, exacerbations and lung function. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the additional information provided by pulse transit time (PTT), a noninvasive tool, when using during polysomnography for the diagnosis of sleep breathing disorders in a pediatric population. Main findings: Respiratory and microarousals events were scored twice. The first scoring was performed using nasal pressure, thermistors, thoracic and abdominal movements, and oxygen saturation. The second scoring, blinded to the first scoring, was performed using PTT in combination with all the other signals. Microarousals were scored once visually on the EEG trace (cortical arousals [CAs]) and once using the PTT signal (autonomic arousals [AAs]) blinded to EEG. For the whole group of 16 children studied (mean age, 9.5 years), there was no significant difference between the respiratory disturbance index (RDI) with or without PTT analysis (22.4 ± 13.5/h vs 20.4 ± 14.3/h; not significant [mean ± SD]). Among the children exhibiting a ‘without PTT’ RDI < 30/h, 5 of 12 children (41.66%) showed a clinically significant > 5/h increase in RDI when using PTT. AAs detected by PTT were significantly more frequent than CAs during rapid eye movement (REM) sleep (7.4 ± 3.9/h vs 3.2 ± 2.3/h; p < 0.001) and slow wave sleep (SWS) [6.0 ± 4.3/h vs 0.6 ± 0.5/h; p < 0.0001]. Conclusions: The quantification of respiratory effort using PTT improves the detection of respiratory events in children. The detection of microarousals is improved particularly in REM and SWS. [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]

Background The association between air pollution and rhinitis is not well established. Aim The aim of this longitudinal analysis was to study the association between modeled air pollution at the subjects' home addresses and self-reported incidence of rhinitis. Methods We used data from 1533 adults from two multicentre cohorts' studies (EGEA and ECRHS). Rhinitis incidence was defined as reporting rhinitis at the second follow-up (2011 to 2013) but not at the first follow-up (2000 to 2007). Annual exposure to NO 2 , PM 10 and PM 2.5 at the participants' home addresses was estimated using land-use regression models developed by the ESCAPE project for the 2009–2010 period. Incidence rate ratios (IRR) were computed using Poisson regression. Pooled analysis, analyses by city and meta-regression testing for heterogeneity were carried out. Results No association between long-term air pollution exposure and incidence of rhinitis was found (adjusted IRR (aIRR) for an increase of 10 μg·m −3 of NO 2: 1.00 [0.91–1.09], for an increase of 5 μg·m −3 of PM 2.5 : 0.88 [0.73–1.04]). Similar results were found in the two-pollutant model (aIRR for an increase of 10 μg·m −3 of NO 2: 1.01 [0.87–1.17], for an increase of 5 μg·m −3 of PM 2.5 : 0.87 [0.68–1.08]). Results differed depending on the city, but no regional pattern emerged for any of the pollutants. Conclusions This study did not find any consistent evidence of an association between long-term air pollution and incident rhinitis. [ABSTRACT FROM AUTHOR]

In vitro and toxicological studies have shown that non-persistent environmental chemicals can perturb thyroid hormone homeostasis. Epidemiological studies with improved exposure assessment (i.e., repeated urine samples) are needed to evaluate effects of these compounds, individually or as a mixture, in humans. We studied the associations between prenatal exposure to non-persistent environmental chemicals and neonatal thyroid hormones. The study population consisted of 442 mother–child pairs from the French SEPAGES mother–child cohort recruited between July 2014 and July 2017. For each participant, four parabens, five bisphenols, triclosan, triclocarban, benzophenone-3 as well as metabolites of phthalates and of di(isononyl)cyclohexane-1,2-dicarboxylate were assessed in two pools of repeated urine samples (median: 21 spot urines per pool), collected in the 2nd and 3rd trimesters of pregnancy, respectively. Thyroid stimulating hormone (TSH) and total thyroxine (T4) levels were determined in newborns from a heel-prick blood spot. Maternal iodine and selenium were assessed in urine and serum, respectively. Adjusted linear regression (uni-pollutant model) and Bayesian Kernel Machine Regression (BKMR, mixture model) were applied to study overall and sex-stratified associations between chemicals and hormone concentrations. Interaction with child sex was detected for several compounds. Triclosan, three parabens, and one phthalate metabolite (OH-MPHP) were negatively associated with T4 among girls in the uni-pollutant model. BKMR also suggested a negative association between the mixture and T4 in girls, whereas in boys the association was positive. The mixture was not linked to TSH levels, and for this hormone the uni-pollutant model revealed associations with only a few compounds. Our study, based on repeated urine samples to assess exposure, showed that prenatal exposure to some phenols and phthalates disturb thyroid hormone homeostasis at birth. Furthermore, both uni-pollutant and mixture models, suggested effect modification by child sex, while, to date underlying mechanisms for such sex-differences are not well understood. [ABSTRACT FROM AUTHOR]

Background: During the last decades, a large number of phenotypes and disease classifications of allergic diseases have been proposed. Despite the heterogeneity across studies, no systematic review has been conducted on phenotype classification and the criteria that define allergic diseases. We aimed to identify clinically expressed, population-based phenotypes of allergic diseases and their interrelationships, to explore disease heterogeneity and to evaluate the measurements employed in disease diagnosis. Methods: We conducted a search of MEDLINE up to December 2012, to identify relevant original studies published in the English language that examine at least one objective of this systematic review in subjects aged 0-18 years. The screening of titles and abstracts and the extraction of data were conducted independently by two reviewers. Results: From a total of 13,767 citations, 197 studies met the criteria for inclusion, with 54% being cohort studies. Allergic diseases were studied as a single entity in 55% (109/197) of the studies or in the context of multimorbidity in 45%. Asthma accounted for 81.7% of the studies examining single diseases. Overall, up to 33 different phenotypes of allergic disease were reported. Transient early, late-onset and persistent wheeze were the most frequently reported phenotypes. Most studies (78%) used questionnaires. The skin-prick test was the preferred measurement of sensitization (64%). Spirometry and bronchial hyperresponsiveness were assessed in one third of the studies, peak flow rate in 8.6% and disease severity in 35%. Conclusions: Studies reporting phenotypes of allergic diseases in children are highly heterogeneous and often lack objective phenotypical measures. A concerted effort to standardize methods and terminology is necessary. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Unlabelled: The influence of the generalization of cystic fibrosis newborn screening (CFNBS) in France on sweat test (ST) prescription is unknown. In this French retrospective, descriptive, and multicenter study, we studied the indications, number, methods, and results of STs prescribed by a pediatric pulmonologist in children who had a negative CFNBS and an ST for respiratory symptoms in 2012. We included 502 children with 523 STs, performed with four different methods. The main indication was asthma (71.3 %), then chronic cough (52.4 %), atypical lower airway infections (42.2 %), and bronchiectasis (7 %). Four children had a diagnosis of CF (0.8 %), all presenting with chronic productive cough and recurrent respiratory infections.Conclusion: Asthma is the most frequent indication of ST in our cohort. Because of the systematic CFNBS in France, some prescriptions should be avoided, particularly in case of severe or moderate asthma with no other associated symptom. Moreover, methods of STs often do not follow the guidelines and need standardization.What Is Known: • Newborn screening (NBS) has become the most frequent circumstance of the diagnosis of cystic fibrosis (CF) in France after its generalization. • The prescription of sweat test (ST) in children with respiratory symptoms who already had a negative NBS has not been studied.What Is New: • In children with a negative CF NBS referred to a university hospital for respiratory diseases, despite important variations of ST methods, only 4 children among 502 have been diagnosed as CF. • Despite recommendations, ST prescription should be avoided in children with moderate to severe asthma and no other associated symptom. [ABSTRACT FROM AUTHOR]

Studies of air pollution effects during pregnancy generally only consider exposure in the outdoor air at the home address. We aimed to compare exposure models differing in their ability to account for the spatial resolution of pollutants, space–time activity and indoor air pollution levels. We recruited 40 pregnant women in the Grenoble urban area, France, who carried a Global Positioning System (GPS) during up to 3 weeks; in a subgroup, indoor measurements of fine particles (PM 2.5 ) were conducted at home (n = 9) and personal exposure to nitrogen dioxide (NO 2 ) was assessed using passive air samplers (n = 10). Outdoor concentrations of NO 2 , and PM 2.5 were estimated from a dispersion model with a fine spatial resolution. Women spent on average 16 h per day at home. Considering only outdoor levels, for estimates at the home address, the correlation between the estimate using the nearest background air monitoring station and the estimate from the dispersion model was high (r = 0.93) for PM 2.5 and moderate (r = 0.67) for NO 2 . The model incorporating clean GPS data was less correlated with the estimate relying on raw GPS data (r = 0.77) than the model ignoring space–time activity (r = 0.93). PM 2.5 outdoor levels were not to moderately correlated with estimates from the model incorporating indoor measurements and space–time activity (r = − 0.10 to 0.47), while NO 2 personal levels were not correlated with outdoor levels (r = − 0.42 to 0.03). In this urban area, accounting for space–time activity little influenced exposure estimates; in a subgroup of subjects (n = 9), incorporating indoor pollution levels seemed to strongly modify them. [ABSTRACT FROM AUTHOR]

Background: The classification of rhinitis in adults is missing in epidemiological studies. Objective: To identify phenotypes of adult rhinitis using an unsupervised approach (data-driven) compared with a classical hypothesis-driven approach. Methods: 983 adults of the French Epidemiological Study on the Genetics and Environment of Asthma (EGEA) were studied. Self-reported symptoms related to rhinitis such as nasal symptoms, hay fever, sinusitis, conjunctivitis, and sensitivities to different triggers (dust, animals, hay/flowers, cold air…) were used. Allergic sensitization was defined by at least one positive skin prick test to 12 aeroallergens. Mixture model was used to cluster participants, independently in those without (Asthma-, n = 582) and with asthma (Asthma+, n = 401). Results: Three clusters were identified in both groups: 1) Cluster A (55% in Asthma-, and 22% in Asthma+) mainly characterized by the absence of nasal symptoms, 2) Cluster B (23% in Asthma-, 36% in Asthma+) mainly characterized by nasal symptoms all over the year, sinusitis and a low prevalence of positive skin prick tests, and 3) Cluster C (22% in Asthma-, 42% in Asthma+) mainly characterized by a peak of nasal symptoms during spring, a high prevalence of positive skin prick tests and a high report of hay fever, allergic rhinitis and conjunctivitis. The highest rate of polysensitization (80%) was found in participants with comorbid asthma and allergic rhinitis. Conclusion: This cluster analysis highlighted three clusters of rhinitis with similar characteristics than those known by clinicians but differing according to allergic sensitization, and this whatever the asthma status. These clusters could be easily rebuilt using a small number of variables. [ABSTRACT FROM AUTHOR]

Background Mycobacterium massiliense is closely related to Mycobacterium abscessus and is also a frequent cause of mycobacterial lung disease in patients with cystic fibrosis (CF). There has been no previous investigation of possible differences between M. massiliense and M. abscessus infections in the setting of CF. Methods We studied a prospective cohort of 16 M. massiliense and 27 M. abscessus lung infection cases with CF, with a mean follow-up of 6 years. Results M. massiliense cases were younger than M. abscessus cases (mean age: 12.8 vs 17.1 years; p = 0.02) at the time of the first mycobacterial isolation and also had lower body mass index values (mean: 16.4 vs 19.3 kg/m 2 , p = 0.002). All M. massiliense cases, except one, had negative BMI Z-score values at the time of the first mycobacterial isolation (11/12 vs 16/23 M. abscessus cases, p = 0.04). Clarithromycin-based combination therapies led to mycobacterial eradication in 100% of M. massiliense cases but only in 27% of M. abscessus cases ( p = 0.009). Conclusion Our data show a particular link between M. massiliense and malnutrition specifically in CF patients. Unlike M. abscessus , the bacteriological response of M. massiliense to combination antibiotic therapies containing clarithromycin was excellent. Distinguishing between M. massiliense and M. abscessus has major clinical implications for CF patients. [ABSTRACT FROM AUTHOR]

Background and Aims Catheter venous thrombosis may result in life-threatening embolic complications. Recently, a thrombophilic tendency was described in cystic fibrosis (CF), the significance of which remains unclear. The aims of this study were to (1) document the frequency of catheter venous thrombosis detected by colour-Doppler-ultrasound (Doppler-US), (2) assess genetic and acquired thrombophilia risk factors for catheter venous thrombosis and hypercoagulability status and (3) provide recommendations on laboratory screening when considering insertion of a totally implantable vascular access device (TIVAD) in CF patients. Methods We designed a multicentre prospective study in patients selected at the time of catheter insertion. Doppler-US was scheduled at 1 and 6 months after insertion and before insertion in case of a previous central line. Blood samplings were drawn at insertion and at 1 and 6 months later. Results One-hundred patients received a TIVAD and 90 completed the 6-month study. Prevalence of thrombophilia abnormalities and hypercoagulability was found in 50% of the cohorts. Conversely, catheter venous thrombosis frequency was low (6.6%). Conclusion Our data do not support biological screening at the time of a TIVAD insertion. We emphasise the contribution of a medical history of venous thromboembolism and prospective Doppler-US for identifying asymptomatic catheter venous thrombosis to select patients who may benefit from biological screening and possible anticoagulant therapy. [ABSTRACT FROM AUTHOR]

Background: Increased bronchial responsiveness is characteristic of asthma. Gas cooking, which is a major indoor source of the highly oxidant nitrogen dioxide, has been associated with respiratory symptoms and reduced lung function. However, little is known about the effect of gas cooking on bronchial responsiveness and on how this relationship may be modified by variants in the genes GSTM1, GSTT1 and GSTP1, which influence antioxidant defences. Methods: The study was performed in subjects with forced expiratory volume in one second at least 70% of predicted who took part in the multicentre European Community Respiratory Health Survey, had bronchial responsiveness assessed by methacholine challenge and had been genotyped for GSTM1, GSTT1 and GSTP1- rs1695. Information on the use of gas for cooking was obtained from interviewer-led questionnaires. Effect modification by genotype on the association between the use of gas for cooking and bronchial responsiveness was assessed within each participating country, and estimates combined using meta-analysis. Results: Overall, gas cooking, as compared with cooking with electricity, was not associated with bronchial responsiveness (β=-0.08, 95% CI -0.40 to 0.25, p=0.648). However, GSTM1 significantly modified this effect (β for interaction=-0.75, 95% CI -1.16 to -0.33, p=4×10-4), with GSTM1 null subjects showing more responsiveness if they cooked with gas. No effect modification by GSTT1 or GSTP1-rs1695 genotypes was observed. Conclusions: Increased bronchial responsiveness was associated with gas cooking among subjects with the GSTM1 null genotype. This may reflect the oxidant effects on the bronchi of exposure to nitrogen dioxide. [ABSTRACT FROM AUTHOR]

Abstract: Background: Few studies have suggested the potential role of respiratory viruses in cystic fibrosis (CF) exacerbation, but their real impact is probably underestimated. Method: Sixty-four sputum samples collected from 46 adult patients were included in the study: 33 samples were collected during exacerbation of CF, and 31 during the stable phase. After extraction, nucleic acids were tested for the presence of respiratory viruses. When rhinovirus (HRV) was detected, the 5′UTR and VP4/2 regions were sequenced, and phylogenetically analyzed. The characteristics of patients in exacerbation and stable phase were compared. Results: Viruses were found in 25% of samples. The HRV viruses were the most frequently detected followed by coronaviruses. Only the HRV detection was significantly associated with the occurrence of CF pulmonary exacerbation (p <0.027). Characterization of 5′UTR and VP4/2 regions of the HRV genome specified that HRV-A, -B, -C were detected. All HRV-C were recombinant HRV-Ca. Conclusions: HRV were the most frequently detected viruses; their detection was significantly associated with the occurrence of an exacerbation. The reality of viral recombination between HRV was demonstrated in CF patients for the first time, raising the role of viruses in lung microbiota. Further studies are now warranted to decipher virus impact in CF. [Copyright &y& Elsevier]

Background: Errors in address geocodes may affect estimates of the effects of air pollution on health. Objective: We investigated the impact of four geocoding techniques on the association between urban air pollution estimated with a fine-scale (10 m × 10 m) dispersion model and lung function in adults. Methods: We measured forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC) in 354 adult residents of Grenoble, France, who were participants in two well-characterized studies, the Epidemiological Study on the Genetics and Environment on Asthma (EGEA) and the European Community Respiratory Health Survey (ECRHS). Home addresses were geocoded using individual building matching as the reference approach and three spatial interpolation approaches. We used a dispersion model to estimate mean PM10 and nitrogen dioxide concentrations at each participant's address during the 12 months preceding their lung function measurements. Associations between exposures and lung function parameters were adjusted for individual confounders and same-day exposure to air pollutants. The geocoding techniques were compared with regard to geographical distances between coordinates, exposure estimates, and associations between the estimated exposures and health effects. Results: Median distances between coordinates estimated using the building matching and the three interpolation techniques were 26.4, 27.9, and 35.6 m. Compared with exposure estimates based on building matching, PM10 concentrations based on the three interpolation techniques tended to be overestimated. When building matching was used to estimate exposures, a one-interquartile range increase in PM10 (3.0 µg/m3) was associated with a 3.72-point decrease in FVC% predicted (95% CI: −0.56, −6.88) and a 3.86-point decrease in FEV1% predicted (95% CI: −0.14, −3.24). The magnitude of associations decreased when other geocoding approaches were used [e.g., for FVC% predicted −2.81 (95% CI: −0.26, −5.35) using NavTEQ, or 2.08 (95% CI −4.63, 0.47, p = 0.11) using Google Maps]. Conclusions: Our findings suggest that the choice of geocoding technique may influence estimated health effects when air pollution exposures are estimated using a fine-scale exposure model. [ABSTRACT FROM AUTHOR]

Background: This study is aimed at providing a real-world evaluation of the economic cost of persistent asthma among European adults according to the degree of disease control [as defined by the 2006 Global Initiative for Asthma (GINA) guidelines]. Methods: A prevalence-based cost-of-illness study was carried out on 462 patients aged 30-54 years with persistent asthma (according to the 2002 GINA definition), who were identified in general population samples from 11 European countries and examined in clinical settings in the European Community Respiratory Health Survey II between 1999 and 2002. The cost estimates were computed from the societal perspective following the bottom-up approach on the basis of rates, wages and prices in 2004 (obtained at the national level from official sources), and were then converted to the 2010 values. Results: The mean total cost per patient was EUR 1,583 and was largely driven by indirect costs (i.e. lost working days and days with limited, not work-related activities 62.5%). The expected total cost in the population aged 30-54 years of the 11 European countries was EUR 4.3 billion (EUR 19.3 billion when extended to the whole European population aged from 15 to 64 years). The mean total cost per patient ranged from EUR 509 (controlled asthma) to EUR 2,281 (uncontrolled disease). Chronic cough or phlegm and having a high BMI significantly increased the individual total cost. Conclusions: Among European adults, the cost of persistent asthma drastically increases as disease control decreases. Therefore, substantial cost savings could be obtained through the proper management of adult patients in Europe. [ABSTRACT FROM AUTHOR]

Background: This study is aimed at providing a real-world evaluation of the economic cost of persistent asthma among European adults according to the degree of disease control [as defined by the 2006 Global Initiative for Asthma (GINA) guidelines]. Methods: A prevalence-based cost-of-illness study was carried out on 462 patients aged 30-54 years with persistent asthma (according to the 2002 GINA definition), who were identified in general population samples from 11 European countries and examined in clinical settings in the European Community Respiratory Health Survey II between 1999 and 2002. The cost estimates were computed from the societal perspective following the bottom-up approach on the basis of rates, wages and prices in 2004 (obtained at the national level from official sources), and were then converted to the 2010 values. Results: The mean total cost per patient was EUR 1,583 and was largely driven by indirect costs (i.e. lost working days and days with limited, not work-related activities 62.5%). The expected total cost in the population aged 30-54 years of the 11 European countries was EUR 4.3 billion (EUR 19.3 billion when extended to the whole European population aged from 15 to 64 years). The mean total cost per patient ranged from EUR 509 (controlled asthma) to EUR 2,281 (uncontrolled disease). Chronic cough or phlegm and having a high BMI significantly increased the individual total cost. Conclusions: Among European adults, the cost of persistent asthma drastically increases as disease control decreases. Therefore, substantial cost savings could be obtained through the proper management of adult patients in Europe. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The prevalence rates of smoking in subjects with asthma have frequently been reported as similar to those in the general population; however, available data are not up-to-date. There is only limited and somewhat conflicting information on the long-term effects of smoking on health outcomes among population-based cohorts of subjects with asthma. We aimed to investigate changes in smoking habits and their effects on forced expiratory volume in 1 s (FEV1) in subjects with asthma in comparison with the rest of the population, focusing on the healthy smoker effect. Methods: We studied 9,092 subjects without asthma and 1,045 with asthma at baseline who participated in both the European Community Respiratory Health Survey I (20-44 years old in 1991-1993) and II (1999-2002). Results: At follow-up, smoking was significantly less frequent among subjects with asthma than in the rest of the population (26 vs. 31%; p < 0.001). Subjects with asthma who were already ex-smokers at the beginning of the follow-up in the 1990s had the highest mean asthma score (number of reported asthma-like symptoms, range 0-5), probably as a result of the healthy smoker effect (2.80 vs. 2.44 in never smokers, 2.19 in quitters and 2.24 in smokers; p < 0.001). The influence of smoking on FEV1 decline did not depend on asthma status. Smokers had the highest proportion of subjects with chronic cough/phlegm (p < 0.01). Conclusion: One out of 4 subjects with asthma continues smoking and reports significantly more chronic cough and phlegm than never smokers and ex-smokers. This stresses the importance of smoking cessation in all patients with asthma, even in those with less severe asthma. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The nitric oxide (NO) pathway is involved in asthma, and eosinophils participate in the regulation of the NO pool in pulmonary tissues. We investigated associations between single nucleotide polymorphisms (SNPs) of NO synthase genes (NOS) and biological NO-related phenotypes measured in two compartments (exhaled breath condensate and plasma) and blood eosinophil counts. Methodology: SNPs (N = 121) belonging to NOS1, NOS2 and NOS3 genes were genotyped in 1277 adults from the French Epidemiological study on the Genetics and Environment of Asthma (EGEA). Association analyses were conducted on four quantitative phenotypes: the exhaled fraction of NO (FENO), plasma and exhaled breath condensate (EBC) nitrite-nitrate levels (NO2-NO3) and blood eosinophils in asthmatics and non-asthmatics separately. Genetic heterogeneity of these phenotypes between asthmatics and non-asthmatics was also investigated. Principal Findings: In non-asthmatics, after correction for multiple comparisons, we found significant associations of FeNO levels with three SNPs in NOS3 and NOS2 (P≤0.002), and of EBC NO2-NO3 level with NOS2 (P = 0.002). In asthmatics, a single significant association was detected between FENO levels and one SNP in NOS3 (P = 0.004). Moreover, there was significant heterogeneity of NOS3 SNP effect on FeNO between asthmatics and non-asthmatics (P = 0.0002 to 0.005). No significant association was found between any SNP and NO2-NO3 plasma levels or blood eosinophil counts. Conclusions: Variants in NO synthase genes influence FeNO and EBC NO2-NO3 levels in adults. These genetic determinants differ according to asthma status. Significant associations were only detected for exhaled phenotypes, highlighting the critical relevance to have access to specific phenotypes measured in relevant biological fluid. [ABSTRACT FROM AUTHOR]

Background: Transient receptor potential (TRP) vanilloid and ankyrin cation channels are activated by various noxious chemicals and may play an important role in the pathogenesis of cough. The aim was to study the influence of single nucleotide polymorphisms (SNPs) in TRP genes and irritant exposures on cough. Methods: Nocturnal, usual, and chronic cough, smoking, and job history were obtained by questionnaire in 844 asthmatic and 2046 non-asthmatic adults from the Epidemiological study on the Genetics and Environment of Asthma (EGEA) and the European Community Respiratory Health Survey (ECRHS). Occupational exposures to vapors, gases, dusts, and/or fumes were assessed by a job-exposure matrix. Fifty-eight tagging SNPs in TRPV1, TRPV4, and TRPA1 were tested under an additive model. Results: Statistically significant associations of 6 TRPV1 SNPs with cough symptoms were found in non-asthmatics after correction for multiple comparisons. Results were consistent across the eight countries examined. Haplotype-based association analysis confirmed the single SNP analyses for nocturnal cough (7-SNP haplotype: p-global = 4.8 × 10-6) and usual cough (9-SNP haplotype: p-global = 4.5 × 10-6). Cough symptoms were associated with exposure to irritants such as cigarette smoke and occupational exposures (p < 0.05). Four polymorphisms in TRPV1 further increased the risk of cough symptoms from irritant exposures in asthmatics and non-asthmatics (interaction p < 0.05). Conclusions: TRPV1 SNPs were associated with cough among subjects without asthma from two independent studies in eight European countries. TRPV1 SNPs may enhance susceptibility to cough in current smokers and in subjects with a history of workplace exposures. [ABSTRACT FROM AUTHOR]

Background: Data concerning the effects of prenatal exposures to phthalates and phenols on fetal growth are limited in humans. Previous findings suggest possible effects of some phenols on male birth weight.Objective: Our aim was to assess the relationships between prenatal exposures to phthalates and phenols and fetal growth among male newborns.Methods: We conducted a case-control study on male malformations of the genitalia nested in two French mother-child cohorts with recruitment between 2002 and 2006. We measured, in maternal urinary samples collected between 6 and 30 gestational weeks, the concentrations (micrograms per liter) of 9 phenol (n = 191 pregnant women) and 11 phthalate metabolites (n = 287). Weight, length, and head circumference at birth were collected from maternity records. Statistical analyses were corrected for the oversampling of malformation cases.Results: Adjusted birth weight decreased by 77 g [95% confidence interval (CI): -129, -25] and by 49 g (95% CI: -86, -13) in association with a 1-unit increase in ln-transformed 2,4-dichlorophenol (DCP) and 2,5-DCP urinary concentrations, respectively. Benzophenone-3 (BP3) ln-transformed concentrations were positively associated with weight (26 g; 95% CI: -2, 54) and head circumference at birth (0.1 cm; 95% CI: 0.0, 0.2). Head circumference increased by 0.3 cm (95% CI: 0.0, 0.7) in association with a 1-unit increase in ln-transformed BPA concentration. For phthalate metabolites there was no evidence of monotonic associations with birth weight.Conclusions: Consistent with findings of a previous study, we observed evidence of an inverse association of 2,5-DCP and a positive association of BP3 with male birth weight. [ABSTRACT FROM AUTHOR]

Introduction The French cystic fibrosis (CF) practice recommendations were published at the end of 2002. They advise each patient to be checked up at least once every 3 months in a reference centre for cystic fibrosis. Objective To describe the activity of the four reference centres in the Rhône-Alpes area and the patients' follow-up. Methods All patients with cystic fibrosis consulting one of the four CF centres between 1996 and 2005 were retrospectively included. All outpatient visits were recorded and classified according to (i) patient and year; and (ii) month and year. The two series were assessed graphically to determine a transition threshold, that is, the 2 consecutive years between which practices differed the most. Results A total of 616 patients were included, representing 17 594 outpatient visits. The average number of visits per patient increased from 3.7 in 1996 to 5.0 in 2005, the graphical representation showed a sharp change between 2000 and 2001. Among patients with less than 4 visits in 2000, 88 of them visited a centre 4 times or more in 2001 (44%). The annual number of outpatient visits went from 1035 to 2420. The monthly average number of outpatient visits was 86 in 1996 and 202 in 2005. The graphical representation of activity also showed a sharp change from 2001. Conclusion We showed that the implementation of guidelines occurred the year before its official publication. We also showed that the growth of this implementation was sharp rather than gradual. [ABSTRACT FROM AUTHOR]

Aim: To identify the baseline characteristics associated with suppurative complications in children with community-acquired primary pneumonia. Methods: A retrospective study included all children from 28 days to 15 years old, who presented with community-acquired pneumonia at two French hospitals from 1995 to 2003. Complicated pneumonia was defined by the presence of empyema and/or lung abscess. Results: Of 767 children with community-acquired pneumonia, 90 had suppurative complications: 83 cases of pleural empyema and seven cases of lung abscess. The mean prevalence of complicated pneumonia was 3% during the 1995–1998 period, and then steadily increased following a linear trend to reach 23% in 2003. Children with complicated pneumonia were older and had a longer symptomatic period preceding hospitalization. They were more likely to receive antibiotics, especially aminopenicillins (p < 0.01), and nonsteroidal anti-inflammatory drugs, especially ibuprofen (p < 0.001). In multivariable analysis, ibuprofen was the only preadmission therapy that was independently associated with complicated pneumonia [adjusted OR = 2.57 (1.51–4.35)]. Conclusion: This study confirms an association between the use of prehospital ibruprofen and suppurative pneumonic complications. [ABSTRACT FROM AUTHOR]

Objective: To document the epidemiological, clinical, histological and radiological characteristics of aggressive vascular abnormalities of bone in children. Study design: Correspondents of the French Society of Childhood Malignancies were asked to notify all cases of aggressive vascular abnormalities of bone diagnosed between January 1988 and September 2009. Results: 21 cases were identified; 62% of the patients were boys. No familial cases were observed, and the disease appeared to be sporadic. Mean age at diagnosis was 8.0 years [0.8-16.9 years]. Median follow-up was 3 years [0.3- 17 years]. The main presenting signs were bone fracture (n = 4) and respiratory distress (n = 7), but more indolent onset was observed in 8 cases. Lung involvement, with lymphangiectasies and pleural effusion, was the most frequent form of extraosseous involvement (10/21). Bisphosphonates, alpha interferon and radiotherapy were used as potentially curative treatments. High-dose radiotherapy appeared to be effective on pleural effusion but caused major late sequelae, whereas antiangiogenic drugs like alpha interferon and zoledrenate have had a limited impact on the course of pulmonary complications. The impact of bisphosphonates and alpha interferon on bone lesions was also difficult to assess, owing to insufficient follow-up in most cases, but it was occasionally positive. Six deaths were observed and the overall 10-year mortality rate was about 30%. The prognosis depended mainly on pulmonary and spinal complications. Conclusion: Aggressive vascular abnormalities of bone are extremely rare in childhood but are lifethreatening. The impact of anti-angiogenic drugs on pulmonary complications seems to be limited, but they may improve bone lesions. [ABSTRACT FROM AUTHOR]