Efficacy of a loading dose of IV salbutamol in children with severe acute asthma admitted to a PICU: a randomized controlled trial.

The optimal dose regimen for intravenous (IV) treatment in children with severe acute asthma (SAA) is still a matter of debate. We assessed the efficacy of adding a salbutamol loading dose to continuous infusion with salbutamol in children admitted to a pediatric intensive care unit (PICU) with SAA. This multicentre, placebo-controlled randomized trial in the PICUs of four tertiary care children's hospitals included children (2-18 years) with SAA admitted between 2017 and 2019. Children were randomized to receive either a loading dose IV salbutamol (15 mcg/kg, max. 750 mcg) or normal saline while on continuous salbutamol infusion. The primary outcome was the asthma score (Qureshi) 1 h after the intervention. Analysis of covariance models was used to evaluate sensitivity to change in asthma scores. Serum concentrations of salbutamol were obtained. Fifty-eight children were included (29 in the intervention group). Median baseline asthma score was 12 (IQR 10-13) in the intervention group and 11 (9-12) in the control group (p = 0.032). The asthma score 1 h after the intervention did not differ significantly between the groups (p = 0.508, ß-coefficient = 0.283). The median increase in salbutamol plasma levels 10 min after the intervention was 13 µg/L (IQR 5-24) in the intervention group and 4 µg/L (IQR 0-7) in the control group (p = 0.001). Side effects were comparable between both groups. CONCLUSION: We found no clinical benefit of adding a loading dose IV salbutamol to continuous infusion of salbutamol, in children admitted to the PICU with SAA. Clinically significant side effects from the loading dose were not encountered. WHAT IS KNOWN: • Pediatric asthma guidelines struggle with an evidence-based approach for the treatment of SAA beyond the initial steps of oxygen suppletion, repetitive administration of inhaled ß2-agonists, and systemic steroids. • During an SAA episode, effective delivery of inhaled drugs is unpredictable due to severe airway obstruction. WHAT IS NEW: • This study found no beneficial effect of an additional loading dose IV salbutamol in children admitted to the PICU. • This study found no clinically significant side effects from the loading dose.

Associations of physical condition with lung function and asthma in adolescents from the general population.

BACKGROUND: The relation of physical condition with respiratory outcomes in adolescents is unclear. We examined the hypothesis that adolescents with a lower physical condition represented by a lower cardiorespiratory fitness and physical activity, and a higher screen time have a lower lung function and higher risk of asthma. METHODS: In a population-based prospective cohort study on 4854 children aged 13 years, we assessed cardiorespiratory fitness by using the peak work rate measured by the steep ramp test. Information on physical activity and screen time was obtained by self-reported questionnaires. Lung function was measured by spirometry and current asthma was assessed by a parental-reported questionnaire. RESULTS: Taking sociodemographic, lifestyle, and growth-related confounders and multiple hypothesis testing into account, a 1 SD lower cardiorespiratory fitness was associated with a lower FEV1 , FVC, and FEF75 (Z-score difference (95% CI): -0.31 (-0.35, -0.28), -0.30 (-0.33, -0.26), -0.13 (-0.17, -0.10), respectively), and a higher risk of asthma (Odds Ratio (95% CI) 1.25 (1.06, 1.46)). A 1 SD higher screen time was associated with a lower FVC (Z-score difference (95% CI): -0.06 (-0.10, -0.03)). Physical activity and screen time were not related to asthma. Results did not materially change after additional adjustment for respiratory outcomes at an earlier age. CONCLUSION: Adolescents with a lower cardiorespiratory fitness had a lower lung function and a higher risk of asthma. Those with a higher screen time had a lower FVC. Further studies are needed to explore the effect of improvements in physical condition on long-term respiratory outcomes.

Reducing asthma attacks in children using exhaled nitric oxide (RAACENO) as a biomarker to inform treatment strategy: a multicentre, parallel, randomised, controlled, phase 3 trial.

BACKGROUND: The benefit of fractional exhaled nitric oxide (FeNO) in guiding asthma treatment is uncertain. We evaluated the efficacy of adding FeNO to symptom-guided treatment in children with asthma versus only symptom-guided treatment. METHODS: RAACENO was a multicentre, parallel, randomised, controlled, phase 3 trial done in 35 secondary care centres and 17 primary care recruitment sites (only seven primary care sites managed to recruit patients) in the UK. Patients with a confirmed asthma diagnosis, aged 6-15 years, prescribed inhaled corticosteroids, and who received a course of oral corticosteroids for at least one asthma exacerbation during the 12 months before recruitment were included. Participants were randomly assigned to either FeNO plus symptom-guided treatment (intervention) or symptom-guided treatment alone (standard care) using a 24 h in-house, web-based randomisation system. Participants and the clinical and research teams were not masked to the group allocation. A web-based algorithm gave treatment recommendations based on the Asthma Control Test (ACT) or Childhood ACT (CACT) score; current asthma treatment; adherence to study treatment in the past 3 months; and use of FeNO (in the intervention group). Follow-up occurred at 3-month intervals for 12 months. The primary outcome was any asthma exacerbation treated with oral corticosteroids in the 12 months after randomisation, assessed in the intention-to-treat population. This study is registered with the International Standard Randomised Controlled Trial Registry, ISRCTN67875351. FINDINGS: Between June 22, 2017, and Aug 8, 2019, 535 children were assessed for eligibility, 20 were ineligible and six were excluded post-randomisation. 509 children were recruited and at baseline, the mean age of participants was 10·1 years (SD 2·6), and 308 (60·5%) were male. The median FeNO was 21 ppb (IQR 10-48), mean predicted FEV1 was 89·6% (SD 18·0), and median daily dose of inhaled corticosteroids was 400 µg budesonide equivalent (IQR 400-1000). Asthma was partly or fully controlled in 256 (50·3%) of 509 participants. The primary outcome, which was available for 506 (99%) of 509 participants, occurred in 123 (48·2%) of 255 participants in the intervention group and 129 (51·4%) of 251 in the standard care group, the intention-to-treat adjusted odds ratio (OR) was 0·88 (95% CI 0·61 to 1·27; p=0·49). The adjusted difference in the percentage of participants who received the intervention in whom the primary outcome occurred compared with those who received standard care was -3·1% (-11·9% to 5·6%). In 377 (21·3%) of 1771 assessments, the algorithm recommendation was not followed. Adverse events were reported by 27 (5·3%) of 509 participants (15 in the standard care group and 12 in the intervention group). The most common adverse event was itch after skin prick testing (reported by eight participants in each group). INTERPRETATION: We found that the addition of FeNO to symptom-guided asthma treatment did not lead to reduced exacerbations among children prone to asthma exacerbation. Asthma symptoms remain the only tool for guiding treatment decisions. FUNDING: National Institute for Health Research.

Maternal diet in pregnancy and child's respiratory outcomes: an individual participant data meta-analysis of 18 000 children.

RATIONALE: Severe fetal malnutrition has been related to an increased risk of respiratory diseases later in life, but evidence for the association of a suboptimal diet during pregnancy with respiratory outcomes in childhood is conflicting. We aimed to examine whether a pro-inflammatory or low-quality maternal diet during pregnancy was associated with child's respiratory health. METHODS: We performed an individual participant meta-analysis among 18 326 mother-child pairs from seven European birth cohorts. Maternal pro-inflammatory and low-quality diets were estimated by energy-adjusted Dietary Inflammatory Index (E-DII) and Dietary Approaches to Stop Hypertension (DASH) scores. Preschool wheezing and school-age asthma were measured using questionnaires and lung function by spirometry. RESULTS: After adjustment for lifestyle and sociodemographic factors, we observed that a higher maternal E-DII score (a more pro-inflammatory diet) during pregnancy was associated only with a lower forced vital capacity (FVC) in children (z-score difference -0.05, 95% CI -0.08- -0.02, per interquartile range increase). No linear associations of the maternal E-DII or DASH score with child's wheezing or asthma were observed. In an exploratory examination of the extremes, a very low DASH score (<10th percentile) (a very low dietary quality) was associated with an increased risk of preschool wheezing and a low forced expiratory volume in 1 s/FVC (z-score <-1.64) (OR 1.20, 95% CI 1.06-1.36 and z-score difference 1.40, 95% CI 1.06-1.85, compared to ≥10th percentile), with corresponding population attributable risk fractions of 1.7% and 3.3%, respectively. CONCLUSION: The main results from this individual participant data meta-analysis do not support the hypothesis that maternal pro-inflammatory or low-quality diet in pregnancy are related to respiratory diseases in childhood.

Childhood asthma: pathogenesis and phenotypes.

In the pathogenesis of asthma in children there is a pivotal role for a type 2 inflammatory response to early life exposures or events. Interactions between infections, atopy, genetic susceptibility and environmental exposures (such as farmyard environment, air pollution and tobacco smoke exposure) influence the development of wheezing illness and the risk of progression to asthma. The immune system, lung function and the microbiome in gut and airways develop in parallel, and dysbiosis of the microbiome may be a critical factor in asthma development. Increased infant weight gain and preterm birth are other risk factors for development of asthma and reduced lung function. The complex interplay between these factors explains the heterogeneity of asthma in children. Subgroups of patients can be identified as phenotypes, based on clinical parameters, or endotypes, based on a specific pathophysiological mechanism. Paediatric asthma phenotypes and endotypes may ultimately help to improve diagnosis of asthma, prediction of asthma development and treatment of individual children, based on clinical, temporal, developmental or inflammatory characteristics. Unbiased, data-driven clustering, using a multidimensional or systems biology approach may be needed to better define phenotypes. The present knowledge on inflammatory phenotypes of childhood asthma has now been successfully applied in the treatment with biologicals of children with severe therapy-resistant asthma, and it is to be expected that more personalised treatment options may become available.

A population-based study on associations of stool microbiota with atopic diseases in school-age children.

BACKGROUND: Infants with less diverse gut microbiota seem to have higher risks of atopic diseases in early life, but any associations at school age are unclear. OBJECTIVES: This study sought to examine the associations of diversity, relative abundance, and functional pathways of stool microbiota with atopic diseases in school-age children. METHODS: We performed a cross-sectional study within an existing population-based prospective cohort among 1440 children 10 years of age. On stool samples, 16S ribosomal RNA gene sequencing was performed, and taxonomic and functional tables were produced. Physician-diagnosed eczema, allergy, and asthma were measured by questionnaires, allergic sensitization by skin prick tests, and lung function by spirometry. RESULTS: The α-diversity of stool microbiota was associated with a decreased risk of eczema (odds ratio [OR], 0.98; 95% CI, 0.97, 1.00), and ß-diversity was associated with physician-diagnosed inhalant allergy (R2 = 0.001; P = .047). Lachnospiraceae, Ruminococcaceae_UCG-005, and Christensenellaceae_R-7_group species were associated with decreased risks of eczema, inhalant allergic sensitization, and physician-diagnosed inhalant allergy (OR range, 0.88-0.94; 95% CI range, 0.79-0.96 to 0.88-0.98), while Agathobacter species were associated with an increased risk of physician-diagnosed inhalant allergy (OR, 1.23; 95% CI, 1.08-1.42). Functional pathways related to heme and terpenoid biosynthesis were associated with decreased risks of physician-diagnosed inhalant allergy and asthma (OR range, 0.89-0.86; 95% CI range, 0.80-0.99 to 0.73-1.02). No associations of stool microbiota with lung function were observed. CONCLUSIONS: The diversity, relative abundance and functional pathways of stool microbiota were most consistently associated with physician-diagnosed inhalant allergy in school-age children and less consistently with other atopic diseases.

Cardio-metabolic risk factors during childhood in relation to lung function and asthma.

BACKGROUND: Cardio-metabolic risk factors might have an adverse effect on respiratory outcomes, but associations in children are unknown. We aimed to study the longitudinal associations of cardio-metabolic risk factors with lung function and asthma at school age. We also examined whether any association was explained by child's body mass index (BMI). METHODS: In a population-based cohort study among 4988 children, cardio-metabolic risk factors were measured at 6 and 10 years and included blood pressure, cholesterol, triglycerides, insulin, and C-reactive protein (CRP) concentrations. At age 10 years, lung function was measured by spirometry and current physician-diagnosed asthma was assessed by questionnaire. RESULTS: After adjustment for confounders, child's BMI, and multiple testing, we observed that a higher diastolic blood pressure at the age of 6 years was associated with a higher forced vital capacity (FVC) at the age of 10 years (Z-score difference (95% CI): 0.05 (0.01, 0.08), per SDS increase in diastolic blood pressure). Also, child's CRP concentrations above the 75th percentile at both ages 6 and 10 years were related to a lower FVC as compared to CRP concentrations below the 75th percentile at both ages (Z-score difference (95% CI) -0.21 (-0.36, -0.06)). No consistent associations of other cardio-metabolic risk factors with respiratory outcomes were observed. CONCLUSION: Blood pressure and CRP, but not lipids and insulin, were associated with lower lung function but not with asthma. The underlying mechanisms and long-term effects of these associations require further investigation.

Association between nasal and nasopharyngeal bacterial colonization in early life and eczema phenotypes.

BACKGROUND: An association has been reported between early life Staphylococcus aureus nasal carriage and higher risk of childhood eczema, but it is unclear whether this relationship is causal and associations with other bacterial species are unclear. OBJECTIVE: To examine the associations of early life nasal and nasopharyngeal bacterial carriage with eczema phenotypes, and the direction of any associations identified. METHODS: Among 996 subjects of a population-based prospective cohort study, nasal swabs for Staphylococcus  aureus, and nasopharyngeal swabs for Streptococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenzae were collected and cultured from age 6 weeks to 6 years. Never, early, mid-, late transient and persistent eczema phenotypes were identified from parental-reported physician-diagnosed eczema from age 6 months until 10 years. Multinomial regression models and cross-lagged models were applied. RESULTS: Staphylococcus aureus nasal carriage at 6 months was associated with an increased risk of early transient and persistent eczema (OR (95% CI): 2.69 (1.34, 5.39) and 4.17 (1.12, 15.51)). The associations between Staphylococcus aureus nasal carriage and eczema were mostly cross-sectional, and not longitudinal. No associations of Staphylococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenza nasopharyngeal bacterial carriage with eczema and eczema phenotypes were observed (OR range (95% CI): 0.71 (0.35, 1.44) to 1.77 (0.84, 3.73)). CONCLUSIONS: Early life Staphylococcus aureus nasal carriage, but not Staphylococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenza nasopharyngeal carriage, was associated with early transient and persistent eczema. Staphylococcus aureus nasal carriage and eczema were mostly cross-sectionally associated, and not longitudinally, making a causal relationship in either direction unlikely.

Increased Th22 cell numbers in a general pediatric population with filaggrin haploinsufficiency: The Generation R Study.

BACKGROUND: Mutations in the filaggrin gene (FLG) affect epidermal barrier function and increase the risk of atopic dermatitis (AD). We hypothesized that FLG mutations affect immune cell composition in a general pediatric population. Therefore, we investigated whether school-aged children with and without FLG mutations have differences in T- and B-cell subsets. METHODS: This study was embedded in a population-based prospective cohort study, the Generation R Study, and included 523 children of European genetic ancestry aged 10 years. The most common FLG mutations in the European population (R501X, S1085CfsX36, R2447X, and S3247X) were genotyped. Additionally, 11-color flow cytometry was performed on peripheral blood samples to determine helper T (Th), regulatory T (Treg), and CD27+ and CD27- memory B cells. Subset analysis was performed in 358 non-AD and 102 AD cases, assessed by parental questionnaires. RESULTS: FLG mutations were observed in 8.4% of the total population and in 15.7% of the AD cases. Children with any FLG mutation had higher Th22 cell numbers compared to FLG wild-type children in the general and non-AD population. Children with and without FLG mutations had no difference in Th1, Th2, Th17, Treg, or memory B-cell numbers. Furthermore, in children with AD, FLG mutation carriership was not associated with differences in T- and B-cell subsets. CONCLUSIONS: School-aged children of a general population with FLG mutations have higher Th22 cell numbers, which reflects the immunological response to the skin barrier dysfunction. FLG mutations did not otherwise affect the composition of the adaptive immunity in this general pediatric population.

Parental psychological distress during pregnancy and the risk of childhood lower lung function and asthma: a population-based prospective cohort study.

BACKGROUND: Although maternal psychological distress during pregnancy is associated with increased risks of respiratory morbidity in preschool children, it is unknown whether this association persists into later childhood. OBJECTIVE: To examine the association between parental psychological distress during pregnancy and lung function and asthma in children of school age. METHODS: This study of 4231 children was embedded in a population-based prospective cohort. Parental psychological distress was assessed by the Brief Symptom Inventory during and 3 years after pregnancy, and in mothers also at 2 and 6 months after pregnancy. At age 10 years, lung function was obtained by spirometry and asthma by questionnaire. RESULTS: The prevalence of asthma was 5.9%. Maternal overall psychological distress during pregnancy was associated with a lower forced vital capacity (FVC) (z-score difference -0.10 (95% CI -0.20 to -0.01) per 1-unit increase), maternal depressive symptoms during pregnancy with a lower forced expiratory volume in the first second (FEV1) and FVC (-0.13 (95% CI -0.24 to -0.01) and -0.13 (95% CI -0.24 to -0.02) when using clinical cut-offs) in their children. All maternal psychological distress measures during pregnancy were associated with an increased risk of asthma (range OR: 1.46 (95% CI 1.12 to 1.90) to 1.91 (95% CI 1.26 to 2.91)). Additional adjustment for paternal psychological distress during pregnancy and parental psychological distress after pregnancy did not materially change the associations. Paternal psychological distress during pregnancy was not associated with childhood respiratory morbidity. CONCLUSION: Maternal, but not paternal, psychological distress during pregnancy is associated with an increased risk of asthma and partly lower lung function in children. This suggests intrauterine programming for the risk of later-life respiratory disease.

Associations of Plasma Fatty Acid Patterns during Pregnancy with Respiratory and Allergy Outcomes at School Age.

Fatty acids might play a role in asthma and allergy development as they can modulate immune responses. We examined among 4260 mother-child pairs participating in a population-based cohort the associations of maternal plasma fatty acid patterns during pregnancy with a child's respiratory and allergy outcomes at school-age. In mid-pregnancy, 22 individual fatty acids were measured from maternal blood. Three patterns were previously identified by principal component analysis: A 'high n-6 polyunsaturated fatty acid (PUFA)', a 'monounsaturated and saturated fatty acid', and a 'high n-3 PUFA' pattern. At the age of 10 years, a child's lung function was assessed by spirometry, current asthma and physician-diagnosed inhalant allergy by questionnaire, and inhalant allergic sensitization by skin prick tests. A higher 'high n-6 PUFA' pattern was associated with a higher forced expiratory volume in 1 s/forced vital capacity and forced expiratory flow after exhaling 75% of forced vital capacity (Z-score difference (95% CI) 0.04 (0, 0.07) and 0.04 (0.01, 0.07), respectively, per SD increase in the fatty acid pattern). We observed no associations of maternal fatty acid patterns with a child's asthma or allergy outcomes. Our results showed limited associations of maternal patterns of high n-6 PUFA concentrations in pregnancy with a better lung function in school-aged children.

Risk factors for intensive care admission in children with severe acute asthma in the Netherlands: a prospective multicentre study.

RATIONALE: Severe acute asthma (SAA) can be fatal, but is often preventable. We previously observed in a retrospective cohort study, a three-fold increase in SAA paediatric intensive care (PICU) admissions between 2003 and 2013 in the Netherlands, with a significant increase during those years of numbers of children without treatment of inhaled corticosteroids (ICS). OBJECTIVES: To determine whether steroid-naïve children are at higher risk of PICU admission among those hospitalised for SAA. Furthermore, we included the secondary risk factors tobacco smoke exposure, allergic sensitisation, previous admissions and viral infections. METHODS: A prospective, nationwide multicentre study of children with SAA (2-18 years) admitted to all Dutch PICUs and four general wards between 2016 and 2018. Potential risk factors for PICU admission were assessed using logistic regression analyses. MEASUREMENTS AND MAIN RESULTS: 110 PICU and 111 general ward patients were included. The proportion of steroid-naïve children did not differ significantly between PICU and ward patients. PICU children were significantly older and more exposed to tobacco smoke, with symptoms >1 week prior to admission. Viral susceptibility was not a significant risk factor for PICU admission. CONCLUSIONS: Children with SAA admitted to a PICU were comparable to those admitted to a general ward with respect to ICS treatment prior to admission. Preventable risk factors for PICU admission were >7 days of symptoms without adjustment of therapy and exposure to tobacco smoke. Physicians who treat children with asthma must be aware of these risk factors.

Quality of life and psychosocial outcomes in children with severe acute asthma and their parents.

OBJECTIVES: To prospectively evaluate quality of life (QoL) and psychosocial outcomes in children with severe acute asthma (SAA) after pediatric intensive care (PICU) admission compared to children with SAA who were admitted to a general ward (GW). In addition, we assessed post-traumatic stress (PTS) and asthma-related QoL in the parents. METHODS: A preplanned follow-up of 3-9 months of our nationwide prospective multicenter study, in which children with SAA admitted to a Dutch PICU (n=110) or GW (n=111) were enrolled between 2016-2018. Asthma-related QoL, PTS symptoms, emotional and behavioral problems, and social impact in children and/or parents were assessed with validated web-based questionnaires. RESULTS: We included 100 children after PICU and 103 after GW admission, with a response rate of 50% for the questionnaires. Median time to follow-up was 5 months (range 1-12 months). Time to reach full schooldays after admission was significantly longer in the PICU group (mean of 10 vs 4 days, p=0.001). Parents in the PICU group reported more PTS symptoms (intrusion p=0.01, avoidance p=0.01, arousal p=0.02) compared to the GW group. CONCLUSION: No significant differences were found between PICU and GW children on self-reported outcome domains, except for the time to reach full schooldays. PICU parents reported PTS symptoms more often than the GW group. Therefore, monitoring asthma symptoms and psychosocial screening of children and parents after PICU admission should both be part of standard care after SAA. This should identify those who are at risk for developing PTSD, in order to timely provide appropriate interventions. This article is protected by copyright. All rights reserved.

C hlamydia trachomatis during pregnancy and childhood asthma-related morbidity: a population-based prospective cohort.

INTRODUCTION: Chlamydia trachomatis is the most commonly reported sexually transmitted disease and although infection during pregnancy is associated with neonatal complications, long-term respiratory consequences are unknown. We aimed to determine whether C. trachomatis infection during pregnancy is associated with asthma-related symptoms across childhood METHODS: This study among 2475 children and their mothers was embedded in a population-based prospective cohort study. Maternal urine samples were tested for C. trachomatis infection during pregnancy. Questionnaires provided information on childhood physician-attended lower respiratory tract infections and wheezing, and current asthma at age 10 years. Lung function was measured by spirometry at age 10 years. RESULTS: The prevalence of C. trachomatis infection during pregnancy was 3.2% (78 out of 2475). C. trachomatis infection during pregnancy was not associated with lower respiratory tract infections until age 6 years, but was associated with a higher odds of wheezing in children until age 10 years (OR 1.50 (95% CI 1.10-2.03)). C. trachomatis infection during pregnancy was associated with an increased odds of asthma (OR 2.29 (95% CI 1.02-5.13)), and with a lower forced expiratory volume in 1 s/forced vital capacity and forced expiratory flow at 75% of forced vital capacity (z-score difference -0.28 (95% CI -0.52- -0.04) and -0.24 (95% CI -0.46- -0.01), respectively) in children at age 10 years. The observed associations were only partly explained by mode of delivery, gestational age at birth or birthweight. CONCLUSIONS: C. trachomatis infection during pregnancy is associated with increased odds of wheezing, asthma and impaired lung function. The causality of the observed associations and potential underlying mechanisms need to be explored.

Correction: Pharmacogenomic associations of adverse drug reactions in asthma: systematic review and research prioritization.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Airway bacterial carriage and childhood respiratory health: A population-based prospective cohort study.

BACKGROUND: Airway bacterial carriage might play a role in respiratory disease. We hypothesize that nasal carriage with Staphylococcus aureus or nasopharyngeal carriage with Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae predisposes individuals to adverse respiratory health. OBJECTIVE: To examine the association of early-life airway bacterial carriage with respiratory tract infections and vice versa, and of early-life airway bacterial carriage with wheezing, lung function, and asthma in later childhood. METHODS: We collected upper airway swabs for bacterial culturing for S aureus, H influenzae, M catarrhalis, and H influenzae at six timepoints between the ages of 6 weeks and 6 years among 945 children participating in a population-based prospective cohort study. Information on respiratory tract infections and wheezing until age 6 years, and asthma at age 10 years was obtained by questionnaires. Lung function at age 10 years was measured by spirometry. We tested possible bidirectional associations between airway bacterial carriage and respiratory tract infections by cross-lagged models, and associations of repeatedly measured airway bacterial carriage with wheezing, lung function, and asthma by generalized estimating equations models and regression models. RESULTS: Cross-lagged modeling showed that early-life airway bacterial carriage was not consistently associated with upper and lower respiratory tract infections or vice versa. Nasopharyngeal carriage with any bacteria in infancy was associated with an increased risk of wheezing (OR [95% CI]: 1.66 [1.31, 2.10]). Airway bacterial carriage was not consistently associated with school-age lung function or asthma. CONCLUSION: Nasopharyngeal carriage with any bacteria is associated with wheezing, but not respiratory tract infections, asthma, or lung function.

Sociodemographic factors, current asthma and lung function in an urban child population.

BACKGROUND: We aimed to assess which sociodemographic factors are associated with current asthma and indicators of lung function in 10-year-old children. METHODS: We analysed data of 5237 children (Mean age: 9.7, SD: 0.3) from the Generation R Study (2012-2016), a population-based cohort study in the Netherlands. Indicators of sociodemographic factors included parental educational level, net household income, financial difficulties, parental employment status and child ethnic background. Current asthma (yes/no) was defined as ever doctor-diagnosed-asthma combined with wheezing symptoms or asthma-medication use in the past 12 months. Lung function was measured by spirometry and included forced expiratory volume in 1 second (FEV1 ), forced vital capacity (FVC), FEV1 /FVC, and forced expiratory flow after exhaling 75% of FVC (FEF75 ). Within-study sex-, height- and age-adjusted lung function measurements' z-scores were converted. RESULTS: After adjustment for all sociodemographic factors, an independent association was observed between ethnic background with current asthma and lung function. Compared with children with a Dutch background, children with a nonwestern ethnic background had a higher odds of having current asthma (OR: 1.61, 95% CI: 1.02, 2.53), lower FVC z-score (-0.25, 95% CI: -0.35, -0.14), higher FEV1 /FVC z-score (0.26, 95% CI: 0.14, 0.37) and higher FEF75% z-score (0.15, 95% CI: 0.04, 0.25). CONCLUSIONS: Among 10-year-old children, ethnic background was associated with current asthma and lung function after adjusting for a wide range of sociodemographic factors. No associations were found between socioeconomic status indicators and current asthma. Explanations for these associations such as language barriers, suboptimal care or pathophysiological differences require further investigation.

Timing- and Dose-Specific Associations of Prenatal Smoke Exposure With Newborn DNA Methylation.

INTRODUCTION: Fetal changes in DNA methylation may underlie associations of maternal smoking during pregnancy with adverse outcomes in children. We examined critical periods and doses of maternal smoking during pregnancy in relation to newborn DNA methylation, and associations of paternal smoking with newborn DNA methylation. AIMS AND METHODS: This study was embedded in the Generation R Study, a population-based prospective cohort study from early pregnancy onwards. We assessed parental smoking during pregnancy using questionnaires. We analyzed associations of prenatal smoke exposure with newborn DNA methylation at 5915 known maternal smoking-related cytosine-phosphate-guanine sites (CpGs) in 1261 newborns using linear regression. Associations with false discovery rate-corrected p-values < .05 were taken forward. RESULTS: Sustained maternal smoking was associated with newborn DNA methylation at 1391 CpGs, compared with never smoking. Neither quitting smoking early in pregnancy nor former smoking was associated with DNA methylation, compared with never smoking. Among sustained smokers, smoking ≥5, compared with <5, cigarettes/d was associated with DNA methylation at seven CpGs. Paternal smoking was not associated with DNA methylation, independent of maternal smoking status. CONCLUSIONS: Our results suggest that CpGs associated with sustained maternal smoking are not associated with maternal smoking earlier in pregnancy or with paternal smoking. Some of these CpGs show dose-response relationships with sustained maternal smoking. The third trimester may comprise a critical period for associations of smoking with newborn DNA methylation, or sustained smoking may reflect higher cumulative doses. Alternatively, maternal smoking limited to early pregnancy and paternal smoking may be associated with DNA methylation at specific other CpGs not studied here. IMPLICATIONS: Our results suggest that quitting maternal smoking before the third trimester of pregnancy, and possibly lowering smoking dose, may prevent differential DNA methylation in the newborns at CpGs associated with sustained smoking. If the relevance of DNA methylation for clinical outcomes is established, these results may help in counseling parents-to-be about quitting smoking.

Does treatment guided by exhaled nitric oxide fraction improve outcomes in subgroups of children with asthma?

INTRODUCTION: Exhaled nitric oxide fraction (F ENO), a biomarker of eosinophilic airway inflammation, may be useful to guide asthma treatment. F ENO-guided treatment may be more effective in certain subgroups for improving asthma outcomes compared to standard treatment. METHODS: An individual patient data analysis was performed using data from seven randomised clinical trials (RCTs) which used F ENO to guide asthma treatment. The incidence of an asthma exacerbation and loss of control, and the time to first exacerbation and loss of control were described between five subgroups of RCT participants. RESULTS: Data were available in 1112 RCT participants. Among those not treated with leukotriene receptor antagonists (LTRA), but not among those who were treated with LTRA, F ENO-guided treatment was associated with reduced exacerbation risk (OR 0.68, 95% CI 0.49-0.94), longer time to first exacerbation (hazard ratio (HR) 0.76, 95% CI 0.57-0.99) and borderline reduced risk for loss of control (OR 0.70, 95% CI 0.49-1.00). Nonobese children, compared to obese children, were less likely to lose asthma control when treatment was guided by F ENO (OR 0.69, 95% CI 0.48-0.99) and time to loss of control was longer (HR 0.77, 95% CI 0.61-0.99). CONCLUSIONS: Asthma treatment guided by F ENO may be more effective in achieving better asthma outcomes for patients who are not treated with LTRA and who are not obese, compared to standard practice.

Eczema phenotypes and risk of allergic and respiratory conditions in school age children.

BACKGROUND: Eczema phenotypes based on eczema onset and persistence might better identify groups prone to allergic and respiratory conditions than a binary definition of eczema. We examined the associations of childhood eczema phenotypes with allergic sensitization, allergy, asthma and lung function at school age. METHODS: This study among 4277 children was embedded in a multi-ethnic population-based prospective cohort study. Five eczema phenotypes (never, early transient, mid-transient, late transient, persistent) based on parental-reported physician-diagnosed eczema from age 6 months until 10 years were identified. At age 10 years, allergic sensitization was measured by skin prick tests, physician-diagnosed allergy and asthma by parent-reported questionnaires, and lung function by spirometry. Adjusted linear, logistic and multinomial regression models were applied. RESULTS: Compared with never eczema, all eczema phenotypes were associated with increased risks of asthma (odds ratios (OR) range (95% confidence interval): 2.68 (1.58, 4.57) to 11.53 (6.65, 20.01)), food and inhalant allergic sensitization (1.72 (1.25, 2.36) to 12.64 (7.20, 22.18)), and physician-diagnosed inhalant allergy (1.92 (1.34, 2.74) to 11.91 (7.52, 18.86)). Strongest effect estimates were observed of early and persistent eczema with the risk of physician-diagnosed food allergy (OR 6.95 (3.76, 12.84) and 35.05 (18.33, 70.00), respectively) and combined asthma and physician-diagnosed allergy (7.11 (4.33, 11.67) and 29.03 (15.27, 55.22), respectively). Eczema phenotypes were not associated with lung function measures. CONCLUSION: Eczema phenotypes were differentially associated with risks of respiratory and allergic conditions in school-aged children. Children with early transient and persistent eczema might benefit from more intense follow-up for early identification and treatment of asthma and allergies.