Oropharyngeal Microbiota Clusters in Children with Asthma or Wheeze Associate with Allergy, Blood Transcriptomic Immune Pathways, and Exacerbation Risk.

Rationale: Children with preschool wheezing or school-age asthma are reported to have airway microbial imbalances. Objectives: To identify clusters in children with asthma or wheezing using oropharyngeal microbiota profiles. Methods: Oropharyngeal swabs from the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) pediatric asthma or wheezing cohort were characterized using 16S ribosomal RNA gene sequencing, and unsupervised hierarchical clustering was performed on the Bray-Curtis ß-diversity. Enrichment scores of the Molecular Signatures Database hallmark gene sets were computed from the blood transcriptome using gene set variation analysis. Children with severe asthma or severe wheezing were followed up for 12-18 months, with assessment of the frequency of exacerbations. Measurements and Main Results: Oropharyngeal samples from 241 children (age range, 1-17 years; 40% female) revealed four taxa-driven clusters dominated by Streptococcus, Veillonella, Rothia, and Haemophilus. The clusters showed significant differences in atopic dermatitis, grass pollen sensitization, FEV1% predicted after salbutamol, and annual asthma exacerbation frequency during follow-up. The Veillonella cluster was the most allergic and included the highest percentage of children with two or more exacerbations per year during follow-up. The oropharyngeal clusters were different in the enrichment scores of TGF-ß (transforming growth factor-ß) (highest in the Veillonella cluster) and Wnt/ß-catenin signaling (highest in the Haemophilus cluster) transcriptomic pathways in blood (all q values <0.05). Conclusions: Analysis of the oropharyngeal microbiota of children with asthma or wheezing identified four clusters with distinct clinical characteristics (phenotypes) that associate with risk for exacerbation and transcriptomic pathways involved in airway remodeling. This suggests that further exploration of the oropharyngeal microbiota may lead to novel pathophysiologic insights and potentially new treatment approaches.

Distinct clinical parameters were associated with shorter spontaneous resolution in children with non-tuberculous mycobacterial lymphadenitis.

AIM: Non-tuberculous mycobacteria (NTM) lymphadenitis typically resolves spontaneously, yet factors influencing the duration remain explored. We aimed to identify clinical parameters associated with shorter spontaneous resolution. METHODS: This cohort study included children with NTM lymphadenitis from 1 January 2015 to 1 March 2021 at Copenhagen University Hospital. Time-to-event analysis assessed clinical parameters associated with the duration of NTM lymphadenitis. RESULTS: Sixty children (57% boys) with a median age of 24 months (range 11-84) were included; 13 (22%) received primary surgery, 13 (22%) underwent surgery after a wait-and-see period and 34 (57%) received no intervention. In children without intervention, the median duration was 10 months (range 2-25). Faster resolution was associated with parental-reported lymph node enlargement within 2 weeks (HR 2.3, 95% CI 1.0-5.0; p = 0.044), abscess on ultrasound examination (HR 3.3, 95% CI 1.5-7.3; p = 0.003) and skin discoloration and/or perforation within 3 months of onset (HR 4.3, 95% CI 1.3-14.4; p = 0.017 and HR 3.7, 95% CI 1.5-9.1; p = 0.005). CONCLUSION: Knowledge of predictors for shorter spontaneous resolution of NTM lymphadenitis, such as rapid initial lymph node enlargement, abscess on ultrasound examination, and skin discoloration and/or perforation within 3 months of disease onset, may guide clinical management decisions concerning surgery versus a conservative approach.

Host RNA Expression Signatures in Young Infants with Urinary Tract Infection: A Prospective Study.

Early diagnosis of infections in young infants remains a clinical challenge. Young infants are particularly vulnerable to infection, and it is often difficult to clinically distinguish between bacterial and viral infections. Urinary tract infection (UTI) is the most common bacterial infection in young infants, and the incidence of associated bacteremia has decreased in the recent decades. Host RNA expression signatures have shown great promise for distinguishing bacterial from viral infections in young infants. This prospective study included 121 young infants admitted to four pediatric emergency care departments in the capital region of Denmark due to symptoms of infection. We collected whole blood samples and performed differential gene expression analysis. Further, we tested the classification performance of a two-gene host RNA expression signature approaching clinical implementation. Several genes were differentially expressed between young infants with UTI without bacteremia and viral infection. However, limited immunological response was detected in UTI without bacteremia compared to a more pronounced response in viral infection. The performance of the two-gene signature was limited, especially in cases of UTI without bloodstream involvement. Our results indicate a need for further investigation and consideration of UTI in young infants before implementing host RNA expression signatures in clinical practice.

CNS infection in children with brain tumors: adding ventriculostomy to brain tumor resection increases risk more than 20-fold.

PURPOSE: To investigate the risk of central nervous system (CNS) infections in children undergoing neurosurgery for brain tumors. METHODS: Single-center retrospective cohort study including all children with brain tumors undergoing neurosurgical treatment over an 11-year period. RESULTS: A total of 274 patients undergoing 733 neurosurgical procedures were included. Overall, 12.8% of patients were diagnosed with a CNS infection during their course of treatment. CNS infections were more frequent among children treated with CSF diversion (p < 0.001) and independently associated with low age (OR/y 0.9 (CI 95% 0.769-0.941), intraventricular (OR 2.8, CI 95% 1.2-6.5), and high-grade tumors (OR 2.7, CI 95% 1.1-6.5). The majority of CNS infections occurred within 30 days of surgery, resulting in a postoperative CNS infection rate of 5.3%. Postoperative CNS infections were significantly more frequent following adjunct EVD placement during tumor resection compared to a stand-alone craniotomy (30.4% vs. 1.5%, RR 20.6, CI 95% 5.7-72.2). CONCLUSION: CNS infections affect at least 12% of children with brain tumors and are associated with age, tumor location, and grade. Adding EVD to tumor surgery increases the risk of postoperative CNS infection, and reconsidering routine adjunct EVD placement is therefore advocated.

Lactate as a Screening Tool for Critical Illness in a Pediatric Emergency Department.

OBJECTIVES: Lactate has in some pediatric emergency departments (PEDs) gained acceptance as a screening tool for critical illness, with cut-off values of 2.0 to 2.5 mmol/L. We aimed to investigate if lactate could predict the need of acute resuscitation in patients in a PED. PATIENTS AND METHODS: This retrospective observational cohort study included patients aged 0 to 17 years admitted to the PED at Copenhagen University Hospital in Denmark from January 1, 2019 to January 1, 2021. Patients were included if they had lactate measured as part of their routine blood sampling because of acute PED evaluation. Area under the receiver operating characteristic (ROC) curve (AUC) was calculated to assess the ability of lactate to predict the need of acute resuscitation. In patients without need of acute resuscitation, we calculated the lactate upper limit as the 95th percentile, and significant predictors were included in a multiple linear regression model. RESULTS: A total of 1355 children were included. Fourteen (1%) children with a need of acute resuscitation had a median lactate of 1.7 mmol/L (interquartile range, 1.4-2.3) versus 1.6 mmol/L (interquartile range, 1.3-2.1) in children without need of resuscitation ( P > 0.05). The AUC for lactate to predict acute resuscitation was 0.56 (95% confidence interval, 0.54-0.59). In children without need of acute resuscitation, the 95th percentile of lactate was 3.2 mmol/L, and 392 (29.8%) had lactate greater than 2.0 mmol/L. Increasing age and venous sampling were associated with lower lactate. Lactate was not associated with sex, pediatric early warning score, or duration of hospital admission. The 95th percentile of lactate after inhaled beta-2-agonists was 5.0 mmol/L. CONCLUSIONS: In children evaluated in a PED, lactate achieved a low AUC, suggesting a poor ability of predicting acute resuscitation. In children without need of acute resuscitation, the 95th percentile for lactate was 3.2 mmol/L, higher than the generally accepted cut-off values. This is important to recognize to avoid concern in otherwise clinically stable children. Our data did not support the use of lactate as a screening tool for early recognition of critical illness in a PED.

A Protocol for Low-Input RNA-Sequencing of Patients with Febrile Neutropenia Captures Relevant Immunological Information.

Improved methods are needed for diagnosing infectious diseases in children with cancer. Most children have fever for other reasons than bacterial infection and are exposed to unnecessary antibiotics and hospital admission. Recent research has shown that host whole blood RNA transcriptomic signatures can distinguish bacterial infection from other causes of fever. Implementation of this method in clinics could change the diagnostic approach for children with cancer and suspected infection. However, extracting sufficient mRNA to perform transcriptome profiling by standard methods is challenging due to the patient's low white blood cell (WBC) counts. In this prospective cohort study, we succeeded in sequencing 95% of samples from children with leukaemia and suspected infection by using a low-input protocol. This could be a solution to the issue of obtaining sufficient RNA for sequencing from patients with low white blood cell counts. Further studies are required to determine whether the captured immune gene signatures are clinically valid and thus useful to clinicians as a diagnostic tool for patients with cancer and suspected infection.

Unexplained fever in children-Benefits and challenges of FDG-PET/CT.

AIM: To explore [fluorine-18]-fluoro-2-deoxy-d-glucose positron-emission-tomography/computed tomography (18 FDG-PET/CT) in patients where standard investigations were non-diagnostic. METHODS: We reviewed medical records of previously healthy children who had 18 FDG-PET/CT performed at Copenhagen University Hospital in 2015-2020 due to unexplained fever. RESULTS: Thirty-five of 819 paediatric 18 FDG-PET/CT were performed due to unexplained fever. The final diagnoses were malignancy (11%), infections (23%), inflammatory diseases (43%) and miscellaneous (26%). 18 FDG-PET/CT was diagnostic in six cases with Takayasu's arteritis, tuberculosis, Langerhans cell histiocytosis and Ewing sarcoma. Sixteen cases had focal 18 FDG-uptake, but 18 FDG-PET/CT could only differentiate malignancy, infection and inflammation in three cases. In six cases with inflammatory diseases and no focal signs, PET/CT was normal except increased non-specific 18 FDG-uptake in bone marrow and spleen in five cases. One case was false positive (suspicion of appendicitis) and two false negative (leukaemia and inflammatory disease). CONCLUSION: 18 FDG-PET/CT was diagnostic, or contributed to the diagnosis, in several children with unexplained fever referred to a tertiary centre. Challenges comprised (i) only increased non-specific 18 FDG-uptake in bone marrow and spleen in half of cases with inflammatory diseases, (ii) no differentiation between complicated infections, malignancy and inflammation in most cases with focal processes and (iii) a small risk of false positive and false negative results.

Meropenem to Children With Febrile Neutropenia Induces Monoresistant Pseudomonas aeruginosa.

Antimicrobial resistance in Pseudomonas aeruginosa is a threat to children with cancer. We explored the association between P. aeruginosa resistance and previous antibiotic exposure. All children with cancer and P. aeruginosa bacteremia in 2007 to 2016 in Denmark, a country with an overall resistance rate of ∼3%, were included. Twenty percent (10/49) of isolates from children previously exposed to meropenem were meropenem nonsusceptible. The only significant risk factor of meropenem nonsusceptibility was previous meropenem therapy (P=0.03). On the basis of these results, we suggest that meropenem should be reserved as a last resort for children with febrile neutropenia in countries with low antimicrobial resistance.

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

BACKGROUND: 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 Childhood2010 (COPSAC2010) 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 Lundbeck Foundation and others; ClinicalTrials.gov number, NCT00798226 .).

Cadherin-related Family Member 3 Genetics and Rhinovirus C Respiratory Illnesses.

RATIONALE: Experimental evidence suggests that CDHR3 (cadherin-related family member 3) is a receptor for rhinovirus (RV)-C, and a missense variant in this gene (rs6967330) is associated with childhood asthma with severe exacerbations. OBJECTIVES: To determine whether rs6967330 influences RV-C infections and illnesses in early childhood. METHODS: We studied associations between rs6967330 and respiratory infections and illnesses in the COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood 2010) and COAST (Childhood Origins of Asthma Birth Cohort Study) birth cohorts, where respiratory infections were monitored prospectively for the first 3 years of life. Nasal samples were collected during acute infections in both cohorts and during asymptomatic periods in COAST and analyzed for RV-A, RV-B, and RV-C, and other common respiratory viruses. MEASUREMENTS AND MAIN RESULTS: The CDHR3 asthma risk allele (rs6967330-A) was associated with increased risk of respiratory tract illnesses (incidence risk ratio [IRR] = 1.14 [95% confidence interval, 1.05-1.23]; P = 0.003). In particular, this variant was associated with risk of respiratory episodes with detection of RV-C in COPSAC2010 (IRR = 1.89 [1.14-3.05]; P = 0.01) and in COAST (IRR = 1.37 [1.02-1.82]; P = 0.03) children, and in a combined meta-analysis (IRR = 1.51 [1.13-2.02]; P = 0.006). In contrast, the variant was not associated with illnesses related to other viruses (IRR = 1.07 [0.92-1.25]; P = 0.37). Consistent with these observations, the CDHR3 variant was associated with increased detection of RV-C, but not of other viruses during scheduled visits at specific ages. CONCLUSIONS: The CDHR3 asthma risk allele is associated specifically with RV-C illnesses in two birth cohorts. This clinical evidence supports earlier molecular evidence indicating that CDHR3 functions as an RV-C receptor, and raises the possibility of preventing RV-C infections by targeting CDHR3.

Cat exposure in early life decreases asthma risk from the 17q21 high-risk variant.

BACKGROUND: Early-life exposure to cats and dogs has shown diverging associations with childhood asthma risk, and gene-environment interaction is one possible explanation. OBJECTIVES: We investigated interactions between cat and dog exposure and single nucleotide polymorphism rs7216389 variants in the chromosome 17q21 locus, the strongest known genetic risk factor for childhood asthma. METHODS: Genotyping was performed in 377 children from the at-risk Copenhagen Prospective Studies on Asthma in Childhood2000. The primary end point was the development of asthma until age 12 years. The secondary end point was the number of episodes with pneumonia and bronchiolitis from 0 to 3 years of age. Exposures included cat and dog ownership from birth and cat and dog allergen levels in bedding at age 1 year. Replication was performed in the unselected COPSAC2010 cohort with follow-up until 5 years of age. RESULTS: Cat and/or dog exposure from birth was associated with a lower prevalence of asthma among children with the rs7216389 high-risk TT genotype (adjusted hazard ratio, 0.16; 95% CI, 0.04-0.71; P = .015), with no effect in those with the CC/CT genotype (adjusted P = .283), demonstrating interaction between cat and dog exposure and the rs7216389 genotype (adjusted P = .044). Cat allergen levels were inversely associated with asthma development in children with the TT genotype (adjusted hazard ratio, 0.83; 95% CI, 0.71-0.97; P = .022), supporting the cat-rs7216389 genotype interaction (adjusted P = .008). Dog allergen exposure did not show such interaction. Furthermore, the TT genotype was associated with higher risk of pneumonia and bronchiolitis, and this increased risk was likewise decreased in children exposed to cat. Replication showed similar effects on asthma risk. CONCLUSION: The observed gene-environment interaction suggests a role of early-life exposure, especially to cat, for attenuating the risk of childhood asthma, pneumonia, and bronchiolitis in genetically susceptible subjects.

A genome-wide association meta-analysis of diarrhoeal disease in young children identifies FUT2 locus and provides plausible biological pathways.

More than a million childhood diarrhoeal episodes occur worldwide each year, and in developed countries a considerable part of them are caused by viral infections. In this study, we aimed to search for genetic variants associated with diarrhoeal disease in young children by meta-analyzing genome-wide association studies, and to elucidate plausible biological mechanisms. The study was conducted in the context of the Early Genetics and Lifecourse Epidemiology (EAGLE) consortium. Data about diarrhoeal disease in two time windows (around 1 year of age and around 2 years of age) was obtained via parental questionnaires, doctor interviews or medical records. Standard quality control and statistical tests were applied to the 1000 Genomes imputed genotypic data. The meta-analysis (N = 5758) followed by replication (N = 3784) identified a genome-wide significant association between rs8111874 and diarrhoea at age 1 year. Conditional analysis suggested that the causal variant could be rs601338 (W154X) in the FUT2 gene. Children with the A allele, which results in a truncated FUT2 protein, had lower risk of diarrhoea. FUT2 participates in the production of histo-blood group antigens and has previously been implicated in the susceptibility to infections, including Rotavirus and Norovirus Gene-set enrichment analysis suggested pathways related to the histo-blood group antigen production, and the regulation of ion transport and blood pressure. Among others, the gastrointestinal tract, and the immune and neuro-secretory systems were detected as relevant organs. In summary, this genome-wide association meta-analysis suggests the implication of the FUT2 gene in diarrhoeal disease in young children from the general population.

NKG2D gene variation and susceptibility to viral bronchiolitis in childhood.

BACKGROUND: Genetic factors associated with bronchiolitis are inadequately characterized. We therefore inspected a selected subpopulation of our previous genome-wide association study (GWAS) of bronchiolitis for overlap with known quantitative trait loci (QTLs) to identify susceptibility loci that potentially affect mRNA and protein levels. METHODS: GWAS included a Finnish-Swedish case-control population (n = 187), matched for age and site. We integrated GWAS variants (p < 10-4) with QTL data. We subsequently verified allele-specific expression of identified QTLs by flow cytometry. Association of the resulting candidate loci with bronchiolitis was tested in three additional cohorts from Finland and Denmark (n = 1201). RESULTS: Bronchiolitis-susceptibility variant rs10772271 resided within QTLs previously associated with NKG2D (NK group 2, member D) mRNA and protein levels. Flow cytometric analysis confirmed the association with protein level in NK cells. The GWAS susceptibility allele (A) of rs10772271 (odds ratio [OR] = 2.34) corresponded with decreased NKG2D expression. The allele was nominally associated with bronchiolitis in one Finnish replicate (OR = 1.50), and the other showed directional consistency (OR = 1.43). No association was detected in Danish population CONCLUSIONS: The bronchiolitis GWAS susceptibility allele was linked to decreased NKG2D expression in the QTL data and in our expression analysis. We propose that reduced NKG2D expression predisposes infants to severe bronchiolitis.

Association between respiratory infections in early life and later asthma is independent of virus type.

BACKGROUND: Lower respiratory tract infections in the first years of life are associated with later asthma, and this observation has led to a focus on the potential causal role of specific respiratory viruses, such as rhinoviruses and respiratory syncytial virus, in asthma development. However, many respiratory viruses and bacteria trigger similar respiratory symptoms and it is possible that the important risk factors for asthma are the underlying susceptibility to infection and the exaggerated reaction to such triggers rather than the particular triggering agent. OBJECTIVE: We sought to study the association between specific infections in early life and development of asthma later in childhood. METHODS: Three hundred thirteen children were followed prospectively in the Copenhagen Prospective Studies of Asthma in Childhood2000 high-risk birth cohort. Nine respiratory virus types (respiratory syncytial virus, rhinoviruses, other picornaviruses, coronaviruses 229E and OC43, parainfluenza viruses 1-3, influenza viruses AH1, AH3, and B, human metapneumovirus, adenoviruses, and bocavirus) and 3 pathogenic airway bacteria (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis) were identified in airway secretions sampled during episodes of troublesome lung symptoms in the first 3 years of life. Asthma was determined by age 7 years. RESULTS: In unadjusted analyses, all viruses and pathogenic bacteria identified during episodes of troublesome lung symptoms were associated with increased risk of asthma by age 7 years with similar odds ratios for all viruses and pathogenic bacteria. After adjustment for the frequency of respiratory episodes, the particular triggers were no longer associated with asthma. CONCLUSION: The number of respiratory episodes in the first years of life, but not the particular viral trigger, was associated with later asthma development. This suggests that future research should focus on the susceptibility and exaggerated response to lower respiratory tract infections in general rather than on the specific triggering agent.

Duration of wheezy episodes in early childhood is independent of the microbial trigger.

BACKGROUND: Wheezy episodes in young children are often triggered by viral and bacterial respiratory tract infections, but there is little evidence supporting the hypothesis that symptom duration depends on the specific microbial trigger. OBJECTIVE: We sought to investigate whether the duration of wheezy episodes in young children depends on the microbial trigger. METHODS: Two hundred eighty-three children from the Copenhagen Prospective Study on Asthma in Childhood2000 at-risk birth cohort were prospectively examined for common airway pathogenic bacteria and viruses during acute wheezy episodes in the first 3 years of life. Findings were related to symptomatic duration of episodes, as monitored in daily diary cards from birth. RESULTS: Eight hundred thirty-seven samples were investigated for viruses, bacteria, or both. Both viruses and bacteria were identified in 55% of episodes, bacteria were identified exclusively in 31% of episodes, and viruses were identified exclusively in 10% of episodes. The median duration of acute symptoms was 9 days (interquartile range, 5-16 days), and duration was independent of bacterial or viral species. CONCLUSIONS: The duration of wheezy episodes was independent of pathogenic airway bacterial or viral species. This suggests that symptom burden from infections is dependent on other factors, such as environmental exposures or host factors. The common term viral wheeze seems inappropriate in view of the finding of pathogenic bacteria in 86% of wheezy episodes.

Effect of Vitamin D3 Supplementation During Pregnancy on Risk of Persistent Wheeze in the Offspring: A Randomized Clinical Trial.

IMPORTANCE: Observational studies have suggested that increased dietary vitamin D intake during pregnancy may protect against wheezing in the offspring, but the preventive effect of vitamin D supplementation to pregnant women is unknown. OBJECTIVE: To determine whether supplementation of vitamin D3 during the third trimester of pregnancy reduces the risk of persistent wheeze in the offspring. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, single-center, randomized clinical trial conducted within the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort. Enrollment began March 2009 with a goal of 708 participants, but due to delayed ethical approval, only 623 women were recruited at 24 weeks of pregnancy. Follow-up of the children (N = 581) was completed when the youngest child reached age 3 years in March 2014. INTERVENTIONS: Vitamin D3 (2400 IU/d; n = 315) or matching placebo tablets (n = 308) from pregnancy week 24 to 1 week postpartum. All women received 400 IU/d of vitamin D3 as part of usual pregnancy care. MAIN OUTCOMES AND MEASURES: Age at onset of persistent wheeze in the first 3 years of life. Secondary outcomes included number of episodes of troublesome lung symptoms, asthma, respiratory tract infections, and neonatal airway immunology. Adverse events were assessed. RESULTS: Of the 581 children, persistent wheeze was diagnosed during the first 3 years of life in 47 children (16%) in the vitamin D3 group and 57 children (20%) in the control group. Vitamin D3 supplementation was not associated with the risk of persistent wheeze, but the number of episodes of troublesome lung symptoms was reduced, and the airway immune profile was up-regulated (principal component analysis, P = .04). There was no effect on additional end points. Intrauterine death was observed in 1 fetus (<1%) in the vitamin D3 group vs 3 fetuses (1%) in the control group and congenital malformations in 17 neonates (5%) in the vitamin D3 group vs 23 neonates (8%) in the control group. [table: see text]. CONCLUSIONS AND RELEVANCE: The use of 2800 IU/d of vitamin D3 during the third trimester of pregnancy compared with 400 IU/d did not result in a statistically significant reduced risk of persistent wheeze in the offspring through age 3 years. However, interpretation of the study is limited by a wide CI that includes a clinically important protective effect. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00856947.

The burden of severe asthma in childhood and adolescence: results from the paediatric U-BIOPRED cohorts.

U-BIOPRED aims to characterise paediatric and adult severe asthma using conventional and innovative systems biology approaches. A total of 99 school-age children with severe asthma and 81 preschoolers with severe wheeze were compared with 49 school-age children with mild/moderate asthma and 53 preschoolers with mild/moderate wheeze in a cross-sectional study. Despite high-dose treatment, the severe cohorts had more severe exacerbations compared with the mild/moderate ones (annual medians: school-aged 3.0 versus 1.1, preschool 3.9 versus 1.8; p<0.001). Exhaled tobacco exposure was common in the severe wheeze cohort. Almost all participants in each cohort were atopic and had a normal body mass index. Asthma-related quality of life, as assessed by the Paediatric Asthma Quality of Life Questionnaire (PAQLQ) and the Paediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ), was worse in the severe cohorts (mean±se school-age PAQLQ: 4.77±0.15 versus 5.80±0.19; preschool PACQLQ: 4.27±0.18 versus 6.04±0.18; both p≤0.001); however, mild/moderate cohorts also had significant morbidity. Impaired quality of life was associated with poor control and airway obstruction. Otherwise, the severe and mild/moderate cohorts were clinically very similar. Children with severe preschool wheeze or severe asthma are usually atopic and have impaired quality of life that is associated with poor control and airflow limitation: a very different phenotype from adult severe asthma. In-depth phenotyping of these children, integrating clinical data with high-dimensional biomarkers, may help to improve and tailor their clinical management.

Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort.

U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach.This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements.Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12 months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids.Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of "omic" datasets that are at the core of this systems medicine approach.