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To investigate the risk of central nervous system (CNS) infections in children undergoing neurosurgery for brain tumors.Single-center retrospective cohort study including all children with brain tumors undergoing neurosurgical treatment over an 11-year period.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).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.

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.

Aim: To explore [fluorine-18]-fluoro-2-deoxy-d-glucose positron-emission-tomography/computed tomography (18FDG-PET/CT) in patients where standard investigations were non-diagnostic. Methods: We reviewed medical records of previously healthy children who had 18FDG-PET/CT performed at Copenhagen University Hospital in 2015–2020 due to unexplained fever. Results: Thirty-five of 819 paediatric 18FDG-PET/CT were performed due to unexplained fever. The final diagnoses were malignancy (11%), infections (23%), inflammatory diseases (43%) and miscellaneous (26%). 18FDG-PET/CT was diagnostic in six cases with Takayasu's arteritis, tuberculosis, Langerhans cell histiocytosis and Ewing sarcoma. Sixteen cases had focal 18FDG-uptake, but 18FDG-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 18FDG-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: 18FDG-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 18FDG-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.

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.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.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 (P0.05). 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.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.

Background: Although estimates of suboptimal adherence to oral corticosteroids in asthma range from 30% to 50%, no ideal method for measurement exists; the impact of poor adherence in severe asthma is likely to be particularly high. Research Questions: What is the prevalence of suboptimal adherence detected by self-reporting and direct measures? Is suboptimal adherence associated with disease activity? Study Design and Methods: Data were included from individuals with severe asthma taking part in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) study and prescribed daily oral corticosteroids. Participants completed the Medication Adherence Report Scale, a five-item questionnaire used to grade adherence on a scale from 1 to 5, and provided a urine sample for analysis of prednisolone and metabolites by liquid chromatography-mass spectrometry. Results: Data from 166 participants were included in this study: mean (SD) age, 54.2 (± 11.9) years; FEV 1, 65.1% (± 20.5%) predicted; female, 58%; 37% completing the Medication Adherence Report Scale reported suboptimal adherence; and 43% with urinary corticosteroid data did not have detectable prednisolone or metabolites in their urine. Good adherence by both methods was detected in 49 of the 142 (35%) of participants in whom both methods were performed; adherence detection did not match between methods in 53%. Self-reported high adherers had better asthma control and quality of life, whereas directly measured high adherers had lower blood eosinophil levels. Interpretation: Low adherence is a common problem in severe asthma, whether measured directly or self-reported. We report poor agreement between the two methods, suggesting some disassociation between self-assessment of medication adherence and regular oral corticosteroid use, which suggests that each approach may provide complementary information in clinical practice.

Multisystem inflammatory syndrome in children (MIS-C) is a novel disease that is associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1 Until now, only one study has attempted to estimate the incidence of MIS-C among SARS-CoV-2-infected children and adolescents.2 This study from the New York State has reported an incidence of MIS-C of 2 per 100,000 persons younger than 21 years of age between 1 March and 10 May 2020. In the same period and population, the incidence of laboratory-confirmed SARS-CoV-2 infection was 322 per 100,000, equivalent to an incidence of MIS-C of one in 161 of SARS-CoV-2-infected individuals.2 However, at this very early stage during the pandemic, access to SARS-CoV-2 PCR testing was very limited, particularly among asymptomatic children and adolescents. Thus, the estimated incidence from the New York State may have been overestimated. Based on seropositive individuals in Denmark, we aimed to estimate the incidence of MIS-C among SARS-CoV-2-infected children and adolescents during the first year of the pandemic.The study was a prospective nationwide cohort study of MIS-C using data from all 18 Danish paediatric departments, which serve 1,153,049 children and adolescents below 18 years of age. The study was carried out from 1 March 2020 to 28 February 2021. Each paediatric department had identified a principal investigator on 12 March 2020 as part of a nationwide paediatric COVID-19 research study. This study was approved by the Ethics Committee of Capital Region of Denmark (H-20028631) and the Danish Data Protection Agency (P-2019–29). Informed parental consent was provided before participation.We found that 23 patients had been diagnosed with MIS-C, based on the criteria devised by the World Health Organization and American Centers for Disease Control and Prevention. This equated to a yearly incidence of two per 100,000 individuals under 18. The patients had a median age of eight (range 2–17) years, nine patients were aged 12–17 and median hospitalisation was eight (3–24) days. We found that 13/23 (57%) had hypotension, five (22%) received vasopressor support, 12 (52%) were admitted to intensive care units. Twenty-one patients (91%) received intravenous immunoglobulin, 17 (74%) had steroids, and three (13%) were given anakinra while two cases were self-limiting. All the children survived. All cases had confirmed SARS-CoV-2 infection determined by either positive SARS-CoV-2 polymerase chain reaction prior to the diagnose of MIS-C (20 of 23 cases; 87%) (tested due exposure or symptoms) and/or positive SARS-CoV-2 serology (15 of 18 cases; 83%).The cumulative incidence of Danish children with SARS-CoV-2 was estimated from a nationwide seroprevalence surveillance study by the Statens Serum Institut of randomly selected individuals in March 2021.3 In this study, seroprevalence of SARS-CoV-2 in the Danish population was determined since August 2020 in the non-vaccinated population after personal invitation to persons above 12 years of age. These data were representative for all regions in Denmark with equal distribution. Detection of total antibodies to SARS-CoV-2 was determined by an enzyme-linked immunosorbent assay in serum (WANTAI Ab ELISA®). The study found that 43/530 (8.1%) individuals aged 12–17 years had positive SARS-CoV-2 immunoglobulin G in March 2021 (personal communication Laura Espenhain) and 7.0% (CI 6.6–7.4) of 10,631 adolescents and adults.3 This suggests an incidence of MIS-C of one in 3,700 in paediatrics patient aged above 12 years, based on nine MIS-C patients out of 33,183 positive for SARS-CoV-2. When we assumed the same seroprevalence for patients below 12 years of age, the overall incidence of MIS-C in children and adolescents was one in 4,100, based on 23 MIS-C patients out of 93,397 infected with SARS-CoV-2.This study provides an estimate of the risk of MIS-C after SARS-CoV-2 infection. MIS-C cases were determined by prospective nationwide data from all Danish paediatric departments, and we assume our case series was complete for several reasons. First, all cases underwent in-depth investigations for differential diagnoses. Second, all cases had either positive polymerase chain reaction (PCR) prior to MIS-C and/or positive SARS-CoV-2 serology. Third, children hospitalised with unexplained severe systemic inflammation in March and April 2020, before we became aware of MIS-C, were subsequently investigated with SARS-CoV-2 serology. However, as no unequivocal diagnostic criteria exist, milder self-limiting cases could have gone undiagnosed. In addition, hyperinflammatory conditions unrelated to SARS-CoV-2, but occurring in patients with previous SARS-CoV-2 infection, could have been diagnosed as MIS-C. Another limitation of this study was the relatively few MIS-C cases which probably was due to the relatively low SARS-CoV-2 infection rate in Denmark.With respect to Danish children and adolescents infected with SARS-CoV-2, we used nationwide seroprevalence data from children aged 12–17 years.3 These surveillance data included relatively few individuals encumbering the total number of SARS-CoV-2-infected children and adolescents with some uncertainty. The data were extrapolated to children below 12 years, as a previous nationwide Danish study in the same settings showed that the SARS-CoV-2 seroprevalence was equal across all childhood age groups.4 However, a Swiss population-based study found a lower seroprevalence in children below 10 years of age.5 Thus, the one in 4,100 risk of MIS-C may have been underestimated in younger children. On the contrary, the risk could also have been overestimated as antibodies may wane. A strength of our study was the serology-based estimate of the SARS-CoV-2 incidence, as this was more reliable than using PCR-positive cases. The calculated number of infected individuals, determined by serology (93,397), was more than twice the number of PCR-positive children (38,877), according to national PCR-surveillance data from 1 March 2020 to 28 February 2021. Hence, the incidence was calculated to be as high as one in 1,700 individuals, versus one in 4,100, if counting to PCR-positive children only. This reflected the fact that PCR test capacity was limited in Denmark during the first wave and the possibility that a significant proportion of children were not tested due to no, or just mild, symptoms. Accordingly, the previous estimate of the incidence of MIS-C among SARS-CoV-2-infected individuals from the New York State in spring 2020 was based on PCR-positive cases and found a 25-fold higher incidence than the incidence estimated in our study (one in 161 versus one in 4,100 in our population).2 Thus, it may also reflect that asymptomatic children and adolescents may not have undergone PCR testing in the New York State at this early stage of the pandemic.SARS-CoV-2 was initially regarded as a mild infection in children, but the emergence of MIS-C means that it is now recognised as an infection with a significant risk for serious complications.1 We have previously reported that the risk of hospital admission due to acute COVID-19 was one in 1,250 SARS-CoV-2-infected children and that they were hospitalised for a median of only two days, without intensive care.6 In contrast, the children with MIS-C in this study were hospitalised for a median of eight days and more than half required intensive care.In conclusion, despite this population-based prospective study is encumbered with several uncertainties, it confirms that MIS-C is a rare but serious complication of SARS-CoV-2 infection, which occurred in one in 4,100 infected children.

Background: Paediatric central nervous system (CNS) tuberculosis (TB) imposes a high risk of death and neurologic sequelae, particularly if the diagnosis is delayed. Children from non-TB endemic countries are particularly at risk of delayed or missed diagnosis. We aimed to investigate CNS TB in Denmark, a TB low-endemic country and where Bacillus Calmette–Guerin (BCG) vaccination is not a part of the vaccination schedule. Methods: A nationwide retrospective case survey of all children with CNS TB in 2000–2015 identified through the National Danish TB Notification Register. We assessed epidemiology, clinical and paraclinical features, diagnostic criteria, treatment and outcome. Results: Nine ethnic Danes and 12 children from TB-endemic countries with CNS TB were identified. Clinical features, C-reactive protein, chest X-ray and indirect TB screening assays all had low sensitivity (19–75%). All (18/18) patients had elevated cerebrospinal fluid (CSF) white blood cells and 15 of 17 (88%) had a combination of at least two characteristic CSF findings (lymphocyte predominance, elevated protein and/or hypoglycorrhachia). Cerebral computed tomography and magnetic resonance imaging were abnormal in 10 of 16 (63%) and 12 of 14 (86%), respectively. Treatment was initiated after a median of 3 days in children from TB-endemic countries, and after 10 days in ethnic Danish children. One patient died (5%): A native Danish girl who died before the diagnosis was established. Conclusions: Children from non-TB endemic countries may be at risk of delayed diagnosis and poorer prognosis compared to high-risk children. Cerebral magnetic resonance imaging and characteristic CSF findings had high diagnostic sensitivity.

Liposomal amphotericin-B (L-AmB) prophylaxis is used in children with leukemia when azoles are contraindicated, but its effect is debated. We reviewed cases of invasive aspergillosis despite L-AmB 2.5 mg/kg twice weekly in children with high-risk leukemia during 2012-2019. Ten (16%) of 62 children had proven or probable aspergillosis. Thus, L-AmB prophylaxis offered insufficient protection for Aspergillus, in particular for Aspergillus flavus.

Relapse of neonatal meningitis is most commonly caused by Escherichia coli. Management to prevent relapse varies and evidence is limited. We present four cases of relapsing neonatal E. coli meningitis in Denmark in 2016–2017 and review the current literature on this subject. During the primary episodes, our patients received cephalosporin for 3 weeks and gentamicin for the first 3 days. The only identified risk factor was delayed CSF sterilization in three of four cases and no repeated lumbar puncture. Relapse occurred after 2–28 days; one case with ventriculitis and one with empyema. Relapses were treated for 6–14 weeks with monotherapy. No children had an underlying disease predisposing to E. coli meningitis. There is generally a trend towards reducing invasive procedures, e.g., lumbar puncture and the length of intravenous antibiotics in pediatric infectious diseases, but our cases highlight a condition where the opposite might be needed.

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.

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. GWAS included a Finnish–Swedish case–control population (n = 187), matched for age and site. We integrated GWAS variants (p

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 COPSAC 2010 (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 COPSAC 2010 (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.

Listeria monocytogenes meningitis in Danish children 1 month to 17 years from 2000 to 2017 was identified and patient files reviewed. There were 5 cases, equaling an annual incidence of 0.024 per 100,000 children or 0.014 when excluding 2 immunodeficient children. Even in a country with a high general incidence of listeriosis, Listeria meningitis is a rare event in healthy children.

Background Asthma prevalence is 339 million globally. ‘Severe asthma’ (SA) comprises subjects with uncontrolled asthma despite proper management. Objectives To compare asthma from diverse ethnicities and environments. Methods A cross-sectional analysis of two adult cohorts, a Brazilian (ProAR) and a European (U-BIOPRED). U-BIOPRED comprised of 311 non-smoking with Severe Asthma (SAn), 110 smokers or ex-smokers with SA (SAs) and 88 mild to moderate asthmatics (MMA) while ProAR included 544 SA and 452 MMA. Although these projects were independent, there were similarities in objectives and methodology, with ProAR adopting operating procedures of U-BIOPRED. Results Among SA subjects, age, weight, proportion of former smokers and FEV1 pre-bronchodilator were similar. The proportion of SA with a positive skin prick tests (SPT) to aeroallergens, the scores of sino-nasal symptoms and quality of life were comparable. In addition, blood eosinophil counts (EOS) and the % of subjects with EOS > 300 cells/μl were not different. The Europeans with SA however, were more severe with a greater proportion of continuous oral corticosteroids (OCS), worse symptoms and more frequent exacerbations. FEV1/FVC pre- and post-bronchodilator were lower among the Europeans. The MMA cohorts were less comparable in control and treatment, but similar in the proportion of allergic rhinitis, gastroesophageal reflux disease and EOS >3%. Conclusions ProAR and U-BIOPRED cohorts, with varying severity, ethnicity and environment have similarities, which provide the basis for global external validation of asthma phenotypes. This should stimulate collaboration between asthma consortia with the aim of understanding SA, which will lead to better management.

We systematically retested children with borderline-positive quantiferon (0.35-0.99 IU/mL) during the period 2015-2019. Among 647 tests, 27 (4%) were positive (>0.35 IU/mL). Borderline-positive quantiferon accounted for 10 of 27 (37%) positive tests. When retested, 9 of 10 (90%) were negative. Children younger than 5 years had negative tuberculin skin tests. Thus, we found high test variability in the borderline range and, in some children, high suspicion of false positive tests.

Background While the etiopathogenesis of atopic dermatitis is complex and poorly understood, neonatal exposures are important for disease occurrence. However, the effect of dog exposure on the risk of atopic dermatitis is unresolved. Objective We investigated whether domestic dog exposure affected the risk of atopic dermatitis in children during the first 3 years of life. Methods Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) are ongoing prospective clinical birth cohort studies. Data from 411 children born to mothers with asthma (COPSAC2000) and 700 unselected children (COPSAC2010) were analyzed following the same protocols at the same research site. Atopic dermatitis was diagnosed prospectively according to the Hanifin–Rajka criteria. Parental history of asthma, eczema, or rhinitis was defined by self-reported physician diagnosis. In the COPSAC2000, maternal specific serum IgE against eight inhalant allergens was sampled after the children's birth and at pregnancy week 24 in the COPSAC2010 cohort. Associations between dog exposure and atopic dermatitis were analyzed by Cox proportional hazard regression models and adjusted for lifestyle confounders. Results In the COPSAC2000 and COPSAC2010 cohorts, the risk of atopic dermatitis was significantly lower in children with domestic dog exposure (adjustedHR = 0.46 [0.25–0.87], P = 0.02; and adjustedHR = 0.58 [0.36–0.93], P = 0.03, respectively). The risk of atopic dermatitis decreased in a dose-dependent manner with increasing number of dogs (adjustedHR = 0.58 [0.38–0.89], P = 0.01) in the COPSAC2010. The protective effect was restricted to children born to mothers with atopic disease in the unselected COPSAC2010 cohort (adjustedHR = 0.39 [0.19–0.82], P = 0.01), as no effect was observed in children born to mothers without atopic disease (adjustedHR = 0.92 [0.49–1.73], P = 0.79). Paternal atopic status did not affect the risk of atopic dermatitis. We found no significant interaction between the CD14 T/T genotype and domestic dog exposure in either cohort (COPSAC2000, P = 0.36; and COPSAC2010 cohort, P = 0.42). Conclusion Neonatal domestic dog exposure was associated with a strongly reduced risk of atopic dermatitis in two independent birth cohorts and in a dose-dependent manner. While the mechanisms involved are unclear, our findings raise the question of whether in utero exposures may affect the risk of atopic dermatitis and emphasize the importance of the early environment for disease trajectory.

Rationale: Paediatric severe asthma is a heterogeneous disease suggesting that there may be discrete underlying clinical phenotypes. Objective: To generate and validate unbiased paediatric clusters in U-BIOPRED. Methods: Cross-sectional analysis of baseline data from the European U-BIOPRED study. Demography, medical history, medication, environmental risk factors, asthma control and quality of life data were collected. External validation utilised a Dutch community paediatric-asthma cohort (PACMAN). Clinical variables were first condensed by factor analysis, followed by subsampled (10000x, proportion: 90%) partition-around-medoid clustering and stability testing by consensus distributions and Calinski & Harabasz index. Finally Classification and Regression Tree Analysis (CART) was applied to generate a prediction model. Results: 250 patients (147 male, 7.9 ±4.8 yrs) with a complete data set of 34 clinical variables were included generating 7 stable clusters (figure) with unique clinical characteristics. Clustering of the PACMAN cohort using the same variables and application of CART-model delivered 3 phenotypes, in agreement with the U-BIOPRED less severe phenotypes (P2,P3,P6). Conclusion: Unsupervised analysis based on clinical parameters revealed 7 stable clusters of paediatric asthma. Part of these clusters could be replicated in an external cohort, suggesting broad pathophysiological and clinical relevance.

BACKGROUND:There is a large, unexplained variation in the frequency of childhood infections. We described incidence and risk factors of infections in early childhood.METHODS:Simple infections were captured during the first 3 years of life in the Copenhagen Prospective Studies on Asthma in Childhood 2000 birth cohort. Environmental exposures were analyzed by quasi-Poisson regression and sparse principal component analysis.RESULTS:The 334 children experienced a median of 14 (range 2–43) infectious episodes at ages 0 to 3 years. The overall rate of infections was associated with the number of children in the day care (adjusted incidence rate ratio [aIRR] 1.09 [1.2–1.16]) and the m2 per child in the day care (aIRR 0.96 [0.92–0.99]). Upper respiratory infections were also associated with the number of children in the day care (aIRR 1.11 [1.03–1.20]) and the m2 per child in the day care (aIRR 0.95 [0.91–0.99]), whereas lower respiratory infections were associated with caesarean section (aIRR 1.49 [1.12–1.99]), maternal smoking (aIRR 1.66 [1.18–2.33]), older siblings (aIRR 1.54 [1.19–2.01]), and the age at entry to day care (aIRR 0.77 [0.65–0.91]). The sparse principal component analysis revealed a risk factor profile driven by tobacco exposure, social circumstances, and domestic pets, but could only be used to explain 8.4% of the infection burden.CONCLUSIONS:Children experienced around 14 infections during the first 3 years of life, but incidences varied greatly. Environmental exposures only explained a small fraction of the variation, suggesting host factors as major determinants of infectious burden.

BACKGROUND: Bacteria and viruses are equally associated with the risk of acute episodes of asthma-like symptoms in young children, suggesting antibiotics as a potential treatment for such episodes. We aimed to assess the effect of azithromycin on the duration of respiratory episodes in young children with recurrent asthma-like symptoms, hypothesising that it reduces the duration of the symptomatic period.METHODS: In this randomised, double-blind, placebo-controlled trial, we recruited children aged 1-3 years, who were diagnosed with recurrent asthma-like symptoms from the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort; a birth cohort consisting of the general Danish population of Zealand, including Copenhagen. Exclusion criteria were macrolide allergy, heart, liver, neurological, and kidney disease, and, before each treatment, one or more clinical signs of pneumonia (respiratory frequency of ≥50 breaths per min; fever of ≥39°C; C-reactive protein concentration of ≥476·20 nmol/L [≥50 mg/L]). Each episode of asthma-like symptoms lasting at least 3 days was randomly allocated to a 3-day course of azithromycin oral solution of 10 mg/kg per day or placebo after thorough examination by a study physician at the Copenhagen Prospective Studies on Asthma research unit. Each episode was randomly allocated independently of previous treatment from a computer-generated list of random numbers in blocks of ten (generated at the Pharmacy of Glostrup). Investigators and children were masked until the youngest child turned 3 years of age and throughout the data validation and analysis phases. The primary outcome was duration of the respiratory episode after treatment, verified by prospective daily diaries and analysed with Poisson regression. Analyses were per protocol (excluding those without a primary outcome measure or who did not receive treatment). This trial is registered with ClinicalTrials.gov, number NCT01233297.FINDINGS: Between Nov 17, 2010, and Jan 28, 2014, we randomly allocated 158 asthma-like episodes in 72 children (79 [50%] to azithromycin and 79 [50%] to placebo). The mean duration of the episode after treatment was 3·4 days for children receiving azithromycin compared with 7·7 days for children receiving placebo. Azithromycin caused a significant shortening of the episode of 63·3% (95% CI 56·0-69·3; pINTERPRETATION: Azithromycin reduced the duration of episodes of asthma-like symptoms in young children, suggesting that this drug could have a role in acute management of exacerbations. Further research is needed to disentangle the inflammatory versus antimicrobial aspects of this relation.FUNDING: Lundbeck Foundation, Danish Ministry of Health, Danish Council for Strategic Research, Capital Region Research Foundation.

Streszczenie Wprowadzenie Infekcje dolnego odcinka drog oddechowych w pierwszych latach zycia wiązą sie z wystąpieniem astmy w poźniejszym okresie. Obserwacja ta doprowadzila do badan nad potencjalną rolą przyczynową w rozwoju astmy specyficznych wirusow odpowiedzialnych za infekcje drog oddechowych, takich jak rinowirusy i wirus RSV. Poniewaz jednak liczne wirusy i bakterie wywolują podobne objawy ze strony ukladu oddechowego, to mozliwe, ze istotnymi czynnikami rozwoju astmy są istniejąca wrazliwośc na infekcje oraz nadmierna reakcja na taki bodziec, a nie sam czynnik wywolujący infekcje. Cele Celem byla ocena związkow miedzy określonymi infekcjami w pierwszych latach zycia a rozwojem astmy w poźniejszym dziecinstwie. Metody Badaniem prospektywnym objeto trzysta trzynaścioro dzieci z kohorty urodzeniowej prowadzonej w ramach Kopenhaskiego Badania nad Astmą u Dzieci ( Copenhagen Prospective Studies of Asthma in Childohood 2000 ). W probkach wydzieliny z drog oddechowych uzyskiwanej w momencie wystąpienia epizodow objawow plucnych w pierwszych 3 latach zycia zidentyfikowano dziewiec wirusow wywolujących choroby drog oddechowych (wirus RSV, rinowirusy, inne pikornawirusy, koronawirus 229E i OC43, wirusy paragrypy 1–3, wirusy grypy AH1, AH3 i B, ludzki metapneumowirus, adenowirusy i ludzki bokawirus) oraz 3 bakterie patogeniczne dla ukladu oddechowego ( Streptococcus pneumoniae , Haemophilus influenzae i Moraxella catarrhalis ). Obecnośc astmy określano w 7. roku zycia. Wyniki W nieskorygowanych analizach wszystkie wirusy i patogenne bakterie wykryte w czasie epizodow objawow z drog oddechowych wiązaly sie ze zwiekszonym ryzykiem rozwoju astmy w 7. roku zycia z podobnymi ilorazami szans dla wszystkich wirusow i bakterii patogennych. Po uwzglednianiu czestości epizodow infekcji powiązanie miedzy poszczegolnymi patogenami a astmą zanikalo. Wnioski Liczba infekcji drog oddechowych w pierwszych latach zycia, ale nie konkretny patogen wirusowy, wiąze sie z rozwojem astmy w poźniejszym dziecinstwie. To sugeruje, ze dalsze badania powinny sie skupic ogolnie na podatności i nadmiernej reakcji na infekcje dolnych drog oddechowych, a nie na badaniach konkretnych patogenow.

Meningococcal disease is a rapidly progressing infection, which continues to cause deaths among children and adolescents. In this review, clinical signs and initial treatment of acute childhood meningococcal disease is described. Operational flow charts have been developed for assessment of non-blanching rash and initial treatment of meningococcal disease.

Summary Aim Prescription of inhaled corticosteroids to children with asthma is recommended at half the nominal dose of adults in order to reduce the risk of systemic side effects. However, there is a lack of pharmacokinetic trials supporting such dose reduction regimens. Therefore, we aimed to compare the systemic exposure to the active ingredients of a fixed dose combination of beclometasone-dipropionate (BDP) and formoterol after dry powder inhaler (DPI) administration in children, adolescents and adults. Methods The pharmacokinetic profiles of formoterol and beclometasone-17-monopropionate (B17MP; active metabolite of BDP) were evaluated over 8 h from two independent studies comprising children (6–11yrs, n = 27), adolescents (12–17 yrs, n = 28) and adults (≥18 yrs, n = 30) receiving a single, fixed dose of BDP/formoterol (children: 200 μg/24 μg, adolescents and adults: 400 μg/24 μg) via DPI. Results The systemic exposure (AUC) for children versus adults was almost doubled for formoterol and similar for B17MP despite the halved BDP dose administered in children. In adolescents the AUC for formoterol and B17MP were approximately one third higher than in adults for both compounds. Upon normalization for the BDP/formoterol dose in the three populations the AUC and peak concentration ( C max ) correlated inversely with age and body surface area of the patients ( r ≤ −0.53; p Conclusion The systemic exposure to the active ingredients of BDP/formoterol administered as DPI correlates inversely with age and body size suggesting that dry powder dosage regimens should be adjusted for age and body size to avoid high systemic drug levels in children.

Aim The fixed combination of beclomethasone (BDP) and formoterol pressurized metered dose inhaler (pMDI) (Foster®, Chiesi Farmaceutici) is being developed in the lower strength (BDP/formoterol: 50/6 μg) to provide an appropriate dosage for children with asthma. The aim of this work was to investigate the systemic bioavailability of beclomethasone-17-monoproprionate (B17MP, the active metabolite of BDP) and formoterol after single inhalation of Foster® pMDI 50/6 μg vs. the free combination of BDP and formoterol pMDIs in asthmatic children.

BACKGROUND: Asthma is a heterogeneous disease in which there is a differential response to asthma treatments. This heterogeneity needs to be evaluated so that a personalised management approach can be provided.OBJECTIVES: We stratified patients with moderate-to-severe asthma based on clinico-physiological parameters and performed an -omics analysis of sputum.METHODS: Partition-around-medoid clustering was applied to a training set of 266 asthma participants from the European U-BIOPRED adult cohort using 8 pre-specified clinic-physiological variables. This was repeated in a separate validation set of 152 asthmatics. The clusters were compared based on sputum proteomic and transcriptomic data.RESULTS: Four reproducible and stable clusters of asthmatics were identified. The training set cluster T1 consists of well-controlled moderate-to-severe asthmatics, while cluster T2 is a group of late-onset severe asthmatics with history of smoking and chronic airflow obstruction. Cluster T3 is similar to cluster T2 in terms of chronic airflow obstruction but is composed of non-smokers. Cluster T4 is predominantly composed of obese female uncontrolled severe asthmatics with increased exacerbations, but with normal lung function. The validation set exhibited similar clusters, demonstrating reproducibility of the classification. There were significant differences in sputum proteomics and transcriptomics between the clusters. The severe asthma clusters, T2, T3 and T4, had higher sputum eosinophilia than T1 with no differences in sputum neutrophil counts, exhaled nitric oxide and serum IgE levels.CONCLUSION: Clustering based on clinico-physiological parameters yielded 4 stable and reproducible clusters that associate with different pathobiological pathways.CLINICAL IMPLICATIONS: The definition of four distinct clusters of asthma linked to different pathobiological pathways provides a better template for the phenotyping and personalised treatment of severe asthma, where high unmet needs remain.CAPSULE SUMMARY: Unsupervised clustering of asthma on clinical features alone has led to the definition of four phenotypes. Sputum 'omics' analysis has revealed different biological pathways pointing towards potential new treatments.

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.

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 Childhood 2000 . 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 COPSAC 2010 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.

Inhaled corticosteroids and long-acting β2-agonists are medications taken daily on a long-term basis to keep asthma under clinical control. Studies have shown that delivering this therapy in a combination inhaler is as effective as giving each drug separately, but fixed combination inhalers are more convenient for adolescents with asthma, increasing treatment adherence and ensuring that long-acting β2-agonists are always accompanied by inhaled corticosteroids [1,2]. An extrafine fixed combination of beclometasone dipropionate (BDP) and formoterol fumarate (FF) is marketed both as a pressurized metered dose inhaler (pMDI) and as a dry powder inhaler (DPI), as Foster® and Foster® Nexthaler® (Chiesi Farmaceutici S.p.A., Parma, Italy) [3], respectively, at the dose strength of 100/6 μg for patients with asthma ≥18 years of age. The same dose strength is currently being developed in asthmatic adolescents aged 12–17 years. The purpose of this study was to investigate the systemic availability of B17MP (active metabolite of BDP) and formoterol after inhalation of an extrafine fixed combination of BDP/FF 100/6 μg via the NEXThaler® DPI in comparison to the free combination of BDP (Clenil® Pulvinal® 100 μg) and FF (Foradil® Aerolizer® 12 μg) DPIs (Novartis Pharmaceuticals Ltd, Frimley, UK) at a total single dose of 400/24 μg in asthmatic adolescents. Adolescents aged 12–17 years with mild-to-moderate asthma in a stable state participated in this randomized, crossover, single-dose study with two active treatment periods conducted at the Children's Asthma Clinic, Copenhagen, Denmark (ClinicalTrials.gov Identifier: NCT01191424). On each treatment day, blood was sampled for pharmacokinetic and pharmacodynamic assessments before and 5, 15 and 30 min and 1, 2, 4, 6 and 8 h after actuation of the DPIs [4]. Lung function [forced expiratory volume in 1 s (FEV1)] and heart rate were assessed concomitantly and adverse events recorded (see Appendix S1 for details). Pharmacokinetic end-points were as follows: area under the plasma drug concentration–time curve (AUC0–t), maximal plasma concentration (Cmax) and terminal half-life (t1/2) for B17MP and formoterol. The AUC0–t for B17MP was the primary end-point. Pharmacodynamic end-points were as follows: plasma potassium and plasma cortisol minimum plasma concentration (Cmin) and AUC0–t, plasma glucose Cmax and AUC0–2h, time-averaged FEV1 (AUC0–8h/8h) and heart rate (AUC0–8h/8h). All variables were log-transformed and treatment comparisons made using ANOVA models estimating the ratio of the adjusted geometric means test/reference (fixed/free combination) with the corresponding 90% confidence interval (CI) for the pharmacokinetic variables and 95% CI for the pharmacodynamic variables. Bioequivalence for the variables between treatments was demonstrated if the CIs were within the 0.8–1.25 acceptance region [5]. The study design had 90% power to reject the null hypothesis that the upper limit of the 90% CI for the ratio of test/reference means above 1.25 for B17MP AUC0–t. Twenty-seven adolescents [55% males; mean age (SD), 14 years (1.7)] completed the study. The B17MP AUC0–t was slightly higher following BDP/FF NEXThaler® vs. BDP and FF DPIs: test/reference ratio 1.14 (90% CI, 1.03–1.28; Table 1). The plasma cortisol test/reference ratio lower 90% CI bound was just below 0.8 [AUC0–t ratio, 0.92 (0.79–1.06)], but no plasma cortisol levels were below the lower clinical normal limit (5 ng ml−1) in either treatment group. Formoterol AUC0–t was higher following test vs. reference treatment [ratio, 1.46 (1.36–1.56)] and Cmax significantly increased [ratio, 2.83 (2.56–3.13)], but time to Cmax was the same for both treatments (median, 0.08 h). The plasma potassium [AUC0–t test/reference ratio, 0.98 (0.95–1.00)], plasma glucose [AUC0–2h ratio, 1.02 (0.99–1.05)] and heart rate [AUC0–8h/8h ratio, 1.05 (1.01–1.09)] were all within the predefined bioequivalence limit. The treatment effects on FEV1 were similar, and no notable differences in adverse events were observed (see Appendix S1). Table 1 Pharmacokinetic and pharmacodynamic comparison of BDP/FF 400/24 μg inhaled from the fixed BDP/FF 100/6 μg NEXThaler® DPI vs. BDP (Clenil® Pulvinal® 100 μg) and FF ... In adolescents with asthma, the systemic exposure to B17MP following four actuations of BDP/FF 100/6 μg NEXThaler® DPI compared with four actuations of BDP (Clenil® Pulvinal® 100 μg) and two actuations of FF (Foradil® Aerolizer® 12 μg) DPIs was slightly above the 125% bioequivalence limit, with a minor suppression of plasma cortisol levels. The clinical relevance of such suppression should be assessed after repeated administration according to European Medicines Agency guidelines [5]. Formoterol exposure was higher after administration of the fixed vs. free combination, but with comparable systemic effect in terms of heart rate, plasma glucose and plasma potassium. The FEV1 and safety profiles were also comparable. Potassium AUC0–t and Cmin were not affected by the increased formoterol exposure, which may be due to the transient formoterol peak concentration and the time delay between concentration and response or, alternatively, assay insensitivity. We speculate that the increased systemic exposure to formoterol and the slightly increased exposure to B17MP following the fixed BDP/FF NEXThaler® is caused by device-dependent different lung deposition. The BDP/FF NEXThaler® is an extrafine particle DPI with a low minimal inhalation flow threshold [6] in comparison to the Foradil® Aerolizer®, which requires a flow >60 l min−1, below which deagglomeration may be inefficient, resulting in a reduced emitted dose with larger particles and reduced lung deposition. In conclusion, inhalation from BDP/FF 100/6 μg NEXThaler® DPI resulted in a very similar exposure to B17MP but a greater exposure to formoterol compared with the licensed free combination in asthmatic adolescents. However, the greater bioavailability of formoterol following dosing with NEXThaler® had no systemic impact and did not affect the safety profile. For conduction of future bioequivalence trials, we highly recommend usage of devices with comparable lung deposition characteristics, because systemic absorption in adolescents seems to differ according to the device, which may have safety implications.

Background Neonatal colonization of the airways with respiratory pathogens is associated with increased risk of lower respiratory infections (LRI) in early childhood. Therefore, we hypothesized that children developing LRI have an aberrant immune response to pathogenic bacteria in infancy. The objective was to characterize in vitro the early life systemic immune response to pathogenic bacteria and study the possible association with incidence of LRI during the first 3 years of life. Methods The Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) is a clinical birth cohort study of 411 children born of mothers with asthma. LRI incidence was prospectively captured from 6-monthly planned visits and visits at acute respiratory episodes. The in vitro systemic immune response to Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae was characterized by the production of TNF-α, IFN-γ, IL-2, IL-5, IL-10, IL-13 and IL-17 in peripheral blood mononuclear cells isolated at age 6 months from 291 infants. Data were analyzed by Poisson regression against incidence of LRI in infancy. Results A multivariable model including all cytokine responses from the 3 different bacterial stimulations significantly identified children at risk of LRI (P = 0.006). The immune response pattern associated with LRI was characterized by perturbed production of several cytokines rather than production of one specific cytokine, and was independent of concurrent asthma. TNF-α and IL-5 were key drivers but did not explain the entire variation in LRI susceptibility. Conclusions Children at risk of future LRI present a perturbed systemic immune response upon exposure to common airway pathogens in early life.

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 (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 (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.

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 .).

Pathological features of the airway in young children with severe recurrent wheeze suggest an association between bacterial colonization and the initiating events of early asthma. We conducted a study to investigate a possible association between bacterial colonization of the hypopharynx in asymptomatic neonates and later development of recurrent wheeze, asthma, and allergy during the first 5 years of life.The subjects were children from the Copenhagen Prospective Study on Asthma in Childhood birth cohort who were born to mothers with asthma. Aspirates from the hypopharyngeal region of asymptomatic 1-month-old infants were cultured for Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus. Wheeze was monitored prospectively on diary cards during the first 5 years of life. Blood eosinophil count and total IgE and specific IgE were measured at 4 years of age. Lung function was measured and asthma was diagnosed at 5 years of age.Hypopharyngeal samples were cultured from 321 neonates at 1 month of age. Twenty-one percent of the infants were colonized with S. pneumoniae, M. catarrhalis, H. influenzae, or a combination of these organisms; colonization with one or more of these organisms, but not colonization with S. aureus, was significantly associated with persistent wheeze (hazard ratio, 2.40; 95% confidence interval [CI], 1.45 to 3.99), acute severe exacerbation of wheeze (hazard ratio, 2.99; 95% CI, 1.66 to 5.39), and hospitalization for wheeze (hazard ratio, 3.85; 95% CI, 1.90 to 7.79). Blood eosinophil counts and total IgE at 4 years of age were significantly increased in children colonized neonatally with S. pneumoniae, M. catarrhalis, H. influenzae, or a combination of these organisms, but specific IgE was not significantly affected. The prevalence of asthma and the reversibility of airway resistance after beta2-agonist administration at 5 years of age were significantly increased in the children colonized neonatally with these organisms as compared with the children without such colonization (33% vs. 10% and 23% vs. 18%, respectively).Neonates colonized in the hypopharyngeal region with S. pneumoniae, H. influenzae, or M. catarrhalis, or with a combination of these organisms, are at increased risk for recurrent wheeze and asthma early in life.

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; pse 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.

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 Childhood 2000 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.

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; pversus 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.

Background: It is recommended to vaccinate pregnant women against influenza. A possible impact on the immune expression of the fetus has never been studied. We aim to study the immune signature in the upper airways and the incidence of infections in neonates born to mothers receiving Influenza A(H1N1) pnd09 vaccination during pregnancy. Methods: One hundred and fifty-six women from the unselected Copenhagen Prospective Study on Asthma in Childhood (COPSAC 2010) received Influenza A(H1N1) pnd09-vaccination during the 2009 pandemic. Fifty-one mothers received the vaccine during pregnancy and 105 after pregnancy; 332 neonates of nonvaccinated mothers were included as secondary controls. Nasal mucosal lining fluid was sampled in 488 neonates and assessed for interleukin (IL)-12p70, IP-10, interferon-gamma (IFN)-gamma, tumor necrosis factor-alpha (TNF)-alpha, MIP-1 beta, MCP-1, MCP-4, IL-4, IL-5, IL-13, eotaxin-1, eotaxin-3, TARC, MDC, IL-17, IL-1 beta, IL-8, transforming growth factor beta (TGF)-beta 1, IL-10 and IL-2. Infections were monitored the first year of life by daily diary cards and clinical controls. Results: Neonates of mothers vaccinated during pregnancy had significant up-regulation of TGF-beta 1 [ratio = 1.52 (1.22-1.90), P = 0.0002], and corresponding down-regulation (P

BackgroundVascular endothelial growth factor (VEGF) is implicated in airway remodelling and asthma development. We studied VEGFA gene variants and plasma levels and the development of lung function, bronchial hyperresponsiveness and asthma in childhood.MethodsWe analysed 13 SNPs in the VEGFA gene in 411 children from the COPSAC2000 high-risk birth cohort. Asthma was diagnosed prospectively, and lung function measurements were obtained at birth and 6years of age. Plasma VEGF levels were measured at 18months of age. We used a Bonferroni adjusted significance level. Findings were replicated in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort at age 8.ResultsAt age six, three SNPs from the same linkage block were associated with FEV1 (rs699947, P=1.31E-05), independent of asthma, and there were suggestive associations between FEV1/FVC ratio and rs833052 and maximal mid-expiratory flow and rs6900017. Replication in the PIAMA cohort showed borderline association between FEV1 and rs699947 and significant meta-analysis result. SNPs upstream and nearby rs699947 were nominally associated with VEGF plasma levels. VEGF levels were not associated with asthmatic symptoms or lung function measures.Conclusions and Clinical RelevanceVEGF gene variants are associated with lung function at school age, but not at birth, suggesting a role of VEGF in post-natal lung function development.

The frequency of pneumonia and bronchiolitis exhibits considerable variation in otherwise healthy children, and suspected risk factors explain only a minor proportion of the variation. We hypothesized that alterations in the airway microbiome in early life may be associated with susceptibility to pneumonia and bronchiolitis in young children.To investigate the relation between neonatal airway colonization and pneumonia and bronchiolitis during the first 3 years of life.Participants comprised children of the Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) cohort, a prospective birth cohort study of 411 children born to mothers with asthma. Aspirates from the hypopharynx at age 4 weeks were cultured for Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus. Clinical information on pneumonia and bronchiolitis within the first 3 years of life was prospectively collected by the research physicians at the center. Analyses were adjusted for covariates associated with pneumonia and bronchiolitis and bacterial airway colonization.Hypopharyngeal aspirates and full clinical follow-up until 3 years of age were available for 265 children. Of these, 56 (21%) neonates were colonized with S. pneumoniae, H. influenzae, and/or M. catarrhalis at 4 weeks of age. Colonization with at least one of these microorganisms (but not S. aureus) was significantly associated with increased incidence of pneumonia and bronchiolitis (adjusted incidence rate ratio, 1.79 [1.29-2.48]; P0.005) independently of concurrent or later asthma.Neonatal airway colonization with S. pneumoniae, H. influenzae, or M. catarrhalis is associated with increased risk of pneumonia and bronchiolitis in early life independently of asthma. This suggests a role of pathogenic bacterial colonization of the airways in neonates for subsequent susceptibly to pneumonia and bronchiolitis.

We report two cases of chronic infantile neurological, cutaneous, and articular (CINCA) syndrome. It is a rare congenital multisystemic inflammatory disease characterised by early onset of urticarial skin rash, central nervous system involvement and articular signs. Our two cases were first diagnosed at 13 and 14 years of age, respectively. From birth they presented with typical symptoms of CINCA syndrome, however isolated each symptom was non-specific. After the syndrome was recognised and treatment with anakinra was initiated, most symptoms disappeared.

Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood1. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits2. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism. Major funding for the research in this paper is provided by the Academy of Finland (project grants 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), 41071 (Skidi), 209072, 129255, 104781, 120315, 129269, 1114194, 206374, 251360, 139900/24300796, Center of Excellence in Complex Disease Genetics and SALVE) and Biocentrum Helsinki; Arthritis Research UK; the Augustinus Foundation; the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL); the Biomedical Research Council, Singapore (BMRC 06/1/21/19/466); BIF: Boehringer Ingelheim Fonds (travel grant to A.T.); the British Heart Foundation; the C.G. Sundell Foundation; the Canadian Institutes of Health Research (grant MOP-82893); Cancer Research UK; the Chief Scientist Office of the Scottish Government; the Children’s Hospital of Philadelphia (Institute Development Award); Conselleria de Sanitat Generalitat Valenciana; the Copenhagen Graduate School of Health Sciences; the Cotswold Foundation (Research Development Award); the Curtin University and Women and Infants Research Foundation; the Danish Health Insurance Societies (Health Fund); the Danish Medical Research Council; the Danish National Research Foundation; the Danish Pediatric Asthma Centre; the Danish Pharmacists’ Fund; the Danish Strategic Research Council; the Darlington Trust; the Department of Health and Social Services in Northern Ireland; Deutsche Forschungsgemeinschaft (DFG); Diabetes Hilfs- und Forschungsfonds Deutschland (DHFD; travel grant to M. Stumvoll); Diabetes UK (grants RD08/0003704 and RD08/0003692); the Dunhill Medical Trust; the Dutch Asthma Foundation (grants 3.4.01.26, 3.2.06.022, 3.4.09.081 and 3.2.10.085CO); the Dutch Ministry of the Environment (EFRE): Europäische Fonds für Regionale Entwicklung (LIFE Child Obesity); the Egmont Foundation; the Else Kröner-Fresenius Foundation; the Emil Aaltonen Foundation (T.L.); the ENGAGE project and grant agreement HEALTH-F4-2007-201413; the Erasmus Medical Center; Erasmus University, Rotterdam; the European Commission (EURO-BLCS, Beta-JUDO, Framework 5 award QLG1-CT-2000-01643, GABRIEL (Integrated Program LSH-2004-1.2.5-1 contract 018996), framework programme 6 EUROSPAN project (contract LSHG-CT-2006-018947), Sixth Research, Technological Development (RTD) Framework Programme (Contract FOOD-CT-2005-007034) and Seventh Framework Programme (FP7/2007-2013)); the European Research Council (ERC Advanced; 230374); the European Science Foundation (ESF; EU/QLRT-2001-01254); the Exeter NHS Research and Development; Faculty of Biology and Medicine of Lausanne; the Finnish Foundation of Cardiovascular Research; the Finnish Cultural Foundation; the Finnish Innovation Fund Sitra; the Finnish Ministry of Education and Culture; the Finnish Ministry of Social Affairs and Health; the Finnish Social Insurance Institution; the Foundation for Paediatric Research; Fundació La Marató de TV3; Fundación Roger Torné; Generalitat de Catalunya–Interminesterial Council for Research and Technological Innovation (CIRIT; 1999SGR) 00241; the German Diabetes Association (A.T.); the German Bundesministerium fuer Forschung und Technology (grants 01 AK 803 A-H and 01 IG 07015 G); the German Research Foundation for the Clinical Research Group Atherobesity KFO 152 (KO3512/1 to A.K.); GlaxoSmithKline; the Hagedorn Research Institute; Instituto de Salud Carlos III (CB06/02/0041, FIS PI041436, PI081151, PI041705 and PS09/00432 and FIS-FEDER 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314 and 09/02647); the Interdisciplinary Centre for Clinical Research at the University of Leipzig (B27 to A.T. and M. Stumvoll); the Integrated Research and Treatment Centre (IFB) Adiposity Diseases; the Jackstädt-Foundation; the Juho Vainio Foundation; the Juvenile Diabetes Research Foundation International (JDRF); Kuopio, Tampere and Turku University Hospital Medical Funds (grant 5031343 to T.A. Lakka and grant 9M048 to T.L.); The Lundbeck Foundation; the Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction, Prevention and Care (LuCAMP); the March of Dimes Birth Defects Foundation (6-FY09-507); the MRC, UK (grants 74882, G0000934, G0601653, G0500539, G0600705, G0601261, G0600331, PrevMetSyn/SALVE PS0476 and MC-A760-5QX00); the Munich Center of Health Sciences (MC Health); the National Health and Medical Research Council of Australia (grants 403981 and 003209); the US National Human Genome Research Institute; the US National Institute of Allergy and Infectious Diseases; the US National Institute of Child Health and Human Development; the US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); the US National Institutes of Health (grants U01DK062418, U01HG004423, U01HG004446, U01HG004438, R01DK075787, 1R01HD056465-01A, R01D0042157-01A, DK078150, TW05596, HL085144, HD054501, RR20649, ES10126, DK56350 and Biomedical Research Centers funding); the Netherlands Bioinformatics Centre (NBIC) BioAssist (RK/2008.024); a National Heart, Lung, and Blood Institute (NHLBI) grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01); the NIH Genetic Association Information Network (GAIN); the NIH/National Institute of Mental Health (NIMH) (5R01MH63706:02 and MH081802); the Rutgers University Cell and DNA Repository cooperative agreement (NIMH U24 MH068457-06); the Novo Nordisk Foundation Center for Basic Metabolic Research; the Center for Medical Systems Biology (CMSB; NWO Genomics); the Netherlands Organization for Scientific Research (NWO: Social Sciences (MaGW) and the Netherlands Organization for Health Research and Development (ZonMw) (Middelgroot-911-09-032, Spinozapremie 56-464-14192, 904-61-090, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, 985-10-002, 40-0056-98-9032 and 912-03-031); the Paavo Nurmi Foundation; the Peninsula NIHR Clinical Research Facility; the Pharmacy Foundation of 1991; the PhD School of Molecular Metabolism University of Southern Denmark; the Raine Medical Research Foundation; the Royal Society; the Sigrid Juselius Foundation; South West NHS Research and Development; the Spanish Ministry of Science and Innovation (SAF2008-00357), Turku University Hospital; the Swiss National Science Foundation (33CSCO-122661); the Tampere Tuberculosis Foundation; the Telethon Institute for Child Health Research; the Turku University Foundation; the US Centers for Disease Control and Prevention; University Hospital Oulu, Biocenter, the University of Oulu (75617); the University of Bristol; the University of Potsdam; the University of Southampton; the University of Western Australia (UWA); the VU Institute for Health and Care Research (EMGO+) and the Neuroscience Campus Amsterdam (NCA); the Wellcome Trust (grants GR069224, WT088806, 068545/Z/02, 076467, 085301, 090532, 083270, 083948, 085541/Z/08/Z, WT089549 and WT083431MA); and the Yrjö Jahnsson Foundation.