Deep phenotyping of the unselected COPSAC2010 birth cohort study

BACKGROUND: We hypothesize that perinatal exposures, in particular the human microbiome and maternal nutrition during pregnancy, interact with the genetic predisposition to cause an abnormal immune modulation in early life towards a trajectory to chronic inflammatory diseases such as asthma and others. OBJECTIVE: The aim of this study is to explore these interactions by conducting a longitudinal study in an unselected cohort of pregnant women and their offspring with emphasis on deep clinical phenotyping, exposure assessment, and biobanking. Exposure assessments focus on the human microbiome. Nutritional intervention during pregnancy in randomized controlled trials are included in the study to prevent disease and to be able to establish causal relationships. METHODS: Pregnant women from eastern Denmark were invited during 2008–2010 to a novel unselected ‘COPSAC(2010)’ cohort. The women visited the clinic during pregnancy weeks 24 and 36. Their children were followed at the clinic with deep phenotyping and collection of biological samples at nine regular visits until the age of 3 and at acute symptoms. Randomized controlled trials of high‐dose vitamin D and fish oil supplements were conducted during pregnancy, and a trial of azithromycin for acute lung symptoms was conducted in the children with recurrent wheeze. RESULTS: Seven hundred and thirty‐eight mothers were recruited from week 24 of gestation, and 700 of their children were included in the birth cohort. The cohort has an over‐representation of atopic parents. The participant satisfaction was high and the adherence equally high with 685 children (98%) attending the 1 year clinic visit and 667 children (95%) attending the 2 year clinic visit. CONCLUSIONS: The COPSAC(2010) birth cohort study provides longitudinal clinical follow‐up with highly specific end‐points, exposure assessments, and biobanking. The cohort has a high adherence rate promising strong data to elucidate the interaction between genomics and the exposome in perinatal life leading to lifestyle‐related chronic inflammatory disorders such as asthma

Fish Oil-Derived Fatty Acids in Pregnancy and Wheeze and Asthma in Offspring

© 2016 Massachusetts Medical Society. Bisgaard, H., Stokholm, J., Chawes, B. L., Vissing, N. H., Bjarnadóttir, E., Schoos, A.-M. M., … Bønnelykke, K. (2016). Fish Oil–Derived Fatty Acids in Pregnancy and Wheeze and Asthma in Offspring. New England Journal of Medicine, 375(26), 2530–2539. https://doi.org/10.1056/NEJMoa1503734BACKGROUND Reduced intake of n-3 long-chain polyunsaturated fatty acids (LCPUFAs) may be a contributing factor to the increasing prevalence of wheezing disorders. We assessed the effect of supplementation with n-3 LCPUFAs in pregnant women on the risk of persistent wheeze and asthma in their offspring. METHODS We randomly assigned 736 pregnant women at 24 weeks of gestation to receive 2.4 g of n-3 LCPUFA (fish oil) or placebo (olive oil) per day. Their children formed the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC 2010) cohort and were followed prospectively with extensive clinical phenotyping. Neither the investigators nor the participants were aware of group assignments during follow-up for the first 3 years of the children's lives, after which there was a 2-year follow-up period during which only the investigators were unaware of group assignments. The primary end point was persistent wheeze or asthma, and the secondary end points included lower respiratory tract infections, asthma exacerbations, eczema, and allergic sensitization. RESULTS A total of 695 children were included in the trial, and 95.5% completed the 3-year, double-blind follow-up period. The risk of persistent wheeze or asthma in the treatment group was 16.9%, versus 23.7% in the control group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.97; P=0.035), corresponding to a relative reduction of 30.7%. Prespecified subgroup analyses suggested that the effect was strongest in the children of women whose blood levels of eicosapentaenoic acid and docosahexaenoic acid were in the lowest third of the trial population at randomization: 17.5% versus 34.1% (hazard ratio, 0.46; 95% CI, 0.25 to 0.83; P=0.011). Analyses of secondary end points showed that supplementation with n-3 LCPUFA was associated with a reduced risk of infections of the lower respiratory tract (31.7% vs. 39.1%; hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.033), but there was no statistically significant association between supplementation and asthma exacerbations, eczema, or allergic sensitization. CONCLUSIONS Supplementation with n-3 LCPUFA in the third trimester of pregnancy reduced the absolute risk of persistent wheeze or asthma and infections of the lower respiratory tract in offspring by approximately 7 percentage points, or one third. (Funded by the Lund-beck Foundation and others; ClinicalTrials.gov number, NCT00798226.)Lundbeck Foundatio

Screen Time Is Associated With Cardiometabolic and Cardiovascular Disease Risk in Childhood and Adolescence

BackgroundScreen time in children and adolescents may be linked to cardiometabolic and cardiovascular risk. METHODS: We analyzed data from &gt;1000 participants in the COPSAC2010 and COPSAC2000 (Copenhagen Prospective Studies on Asthma in Childhood) mother-child 2000 and 2010 cohorts. Discretionary screen time, reported by parents or self, was assessed in relation to a composite cardiometabolic risk score based on Z scores of waist circumference, systolic blood pressure, high-density lipoprotein cholesterol, triglycerides, and glucose. Secondary outcomes included insulin resistance, inflammation, lipoproteins, and anthropometry. A predicted cardiovascular risk score, derived from Cox models trained on UK Biobank data, was also assessed as an outcome. We evaluated whether lifestyle factors (sleep, physical activity, diet, puberty) moderated these associations. Blood nuclear magnetic resonance metabolomics were modeled using supervised machine learning to identify a metabolic screen-time signature. ResultsEach additional hour of screen time was associated with higher cardiometabolic risk in both children (β=0.08 [0.01-0.14], P=0.021) and adolescents (β=0.13 [0.07-0.20], P=0.001). Sleep duration significantly moderated this association in both cohorts (childhood: P=0.029; adolescence: P=0.012), with higher risk among those with shorter sleep. Screen time was also associated with higher predicted cardiovascular risk in adolescence (β=0.07 [0.01-0.13], P=0.017). A screen time-associated metabolomic signature identified in childhood was validated in adolescence (β=0.14 [0.03-0.26], P=0.014). ConclusionsScreen time was positively associated with cardiometabolic and cardiovascular risk, and these associations were stronger among children and adolescents with shorter sleep duration. These findings highlight the importance of jointly considering screen time and sleep patterns in the assessment of early-life risk factors for cardiometabolic and cardiovascular health.</p

Neonatal Urine Metabolic Profiling and Development of Childhood Asthma

none9Urine metabolomics case-control studies of childhood asthma have demonstrated a discriminative ability. Here, we investigated whether urine metabolic profiles from healthy neonates were associated with the development of asthma in childhood. Untargeted metabolomics by liquid chromatography-mass spectrometry was applied to urine samples collected at age 4 weeks in 171 and 161 healthy neonates born from mothers with asthma from the COPSAC2000 and COPSAC2010 cohorts, respectively, where persistent wheeze/asthma was prospectively diagnosed using a symptom-based algorithm. Univariate and multivariate analyses were applied to investigate differences in metabolic profiles between children who developed asthma and healthy children. Univariate analysis showed 63 and 87 metabolites (q-value 0.60. Database search enabled annotation of three discriminative features: a glucoronidated compound (steroid), 3-hydroxytetradecanedioic acid (fatty acid), and taurochenodeoxycholate-3-sulfate (bile acid). The urine metabolomics profiles from healthy neonates were associated with the development of childhood asthma, but further research is needed to understand underlying metabolic pathways.noneChawes, Bo L; Giordano, Giuseppe; Pirillo, Paola; Rago, Daniela; Rasmussen, Morten A; Stokholm, Jakob; Bønnelykke, Klaus; Bisgaard, Hans; Baraldi, EugenioChawes, Bo L; Giordano, Giuseppe; Pirillo, Paola; Rago, Daniela; Rasmussen, Morten A; Stokholm, Jakob; Bønnelykke, Klaus; Bisgaard, Hans; Baraldi, Eugeni

Lung function testing and inflammation markers for wheezing preschool children : A systematic review for the EAACI Clinical Practice Recommendations on Diagnostics of Preschool Wheeze

AbstractBackground: Preschool wheeze is highly prevalent; 30%–50% of children have wheezed at least once before age six. Wheezing is not a disorder; it is a symptom of obstruction in the airways, and it is essential to identify the correct diagnosis behind this symptom. An increasing number of studies provide evidence for novel diagnostic tools for monitoring and predicting asthma in the pediatric population. Several techniques are available to measure airway obstruction and airway inflammation, including spirometry, impulse oscillometry, whole‐body plethysmography, bronchial hyperresponsiveness test, multiple breath washout test, measurements of exhaled NO, and analyses of various other biomarkers.Methods: We systematically reviewed all the existing techniques available for measuring lung function and airway inflammation in preschool children to assess their potential and clinical value in the routine diagnostics and monitoring of airway obstruction.Results: f applicable, measuring FEV1 using spirometry is considered useful. For those unable to perform spirometry, whole‐body plethysmography and IOS may be useful. Bronchial reversibility to beta2‐agonist and hyperresponsiveness test with running exercise challenge may improve the sensitivity of these tests.Conclusions: The difficulty of measuring lung function and the lack of large randomized controlled trials makes it difficult to establish guidelines for monitoring asthma in preschool children.Abstract Background: Preschool wheeze is highly prevalent; 30%–50% of children have wheezed at least once before age six. Wheezing is not a disorder; it is a symptom of obstruction in the airways, and it is essential to identify the correct diagnosis behind this symptom. An increasing number of studies provide evidence for novel diagnostic tools for monitoring and predicting asthma in the pediatric population. Several techniques are available to measure airway obstruction and airway inflammation, including spirometry, impulse oscillometry, whole‐body plethysmography, bronchial hyperresponsiveness test, multiple breath washout test, measurements of exhaled NO, and analyses of various other biomarkers. Methods: We systematically reviewed all the existing techniques available for measuring lung function and airway inflammation in preschool children to assess their potential and clinical value in the routine diagnostics and monitoring of airway obstruction. Results: f applicable, measuring FEV1 using spirometry is considered useful. For those unable to perform spirometry, whole‐body plethysmography and IOS may be useful. Bronchial reversibility to beta2‐agonist and hyperresponsiveness test with running exercise challenge may improve the sensitivity of these tests. Conclusions: The difficulty of measuring lung function and the lack of large randomized controlled trials makes it difficult to establish guidelines for monitoring asthma in preschool children

Outcomes reported in randomized controlled trials for mixed and non‐IgE‐mediated food allergy: Systematic review

Background Mixed and non‐IgE‐mediated food allergy is a subset of immune‐mediated adverse food reactions that can impose a major burden on the quality of life of affected patients and their families. Clinical trials to study these diseases are reliant upon consistent and valid outcome measures that are relevant to both patients and clinicians, but the degree to which such stringent outcome reporting takes place is poorly studied. Objective As part of the Core Outcome Measures for Food Allergy (COMFA) project, we identified outcomes reported in randomized clinical trials (RCT) of treatments for mixed or non‐IgE‐mediated food allergy. Design In this systematic review, we searched the Ovid, MEDLINE and Embase databases for RCTs in children or adults investigating treatments for food protein‐induced enterocolitis syndrome, food protein‐induced allergic proctocolitis, food protein‐induced enteropathy and eosinophilic gastrointestinal disorders including eosinophilic esophagitis [EoE], eosinophilic gastritis and eosinophilic colitis published until 14 October 2022. Results Twenty‐six eligible studies were identified, with 23 focused on EoE (88%). Most interventions were corticosteroids or monoclonal antibodies. All EoE studies assessed patient‐reported dysphagia, usually using a non‐validated questionnaire. Twenty‐two of 23 EoE studies used peak tissue eosinophil count as the primary outcome, usually using a non‐validated assessment method, and other immunological markers were only exploratory. Thirteen (57%) EoE studies reported endoscopic outcomes of which six used a validated scoring tool recently recommended as a core outcome for EoE trials. Funding source was not obviously associated with likelihood of an RCT reporting mechanistic versus patient‐reported outcomes. Only 3 (12%) RCTs concerned forms of food allergy other than EoE, and they reported on fecal immunological markers and patient‐reported outcomes.ConclusionsOutcomes measured in clinical trials of EoE and non‐IgE‐mediated food allergy are heterogeneous and largely non‐validated. Core outcomes for EoE have been developed and need to be used in future trials. For other forms of mixed or non‐IgE‐mediated food allergies, core outcome development is needed to support the development of effective treatments