BURDEN AND SUBTYPES OF EARLY-LIFE INFECTIONS INCREASE THE RISK OF ASTHMA.

BACKGROUND: Early-life respiratory tract infections have been linked to the development of asthma, but studies on burden and subtypes of common infections in asthma development are sparse. OBJECTIVE: The study aimed to examine the association between burden of early-life infections, including subtypes, with risk of asthma from ages 3-10 years and lung function at age 10 years. METHODS: We included 662 children from the COPSAC2010 birth cohort, where infections, i.e., colds, acute tonsillitis, acute otitis media (AOM), pneumonia, gastroenteritis, and fever were registered prospectively in daily diaries at age 0-3 years, and asthma was diagnosed longitudinally from ages 3-10 years. The association between infection burden and subtypes and risk of asthma was analysed by generalized estimating equations. RESULTS: The children experienced a median of 16 [IQR=12-23] infections age 0-3 years. Children with a high burden of infections (above median) had an increased risk of asthma age 3-10: aOR=3.61 (2.39-5.45), p<0.001, which was driven by colds, pneumonia, gastroenteritis, and fever episodes (p-values<0.05), but not by AOM and tonsillitis. Lower lung function measures age 10 were associated with burden of pneumonia, but not the overall infection burden. The association between colds and risk of asthma was significantly higher in children with allergic rhinitis at age 6 (p-interaction=0.032). CONCLUSION: High burden of early-life infections in terms of colds, pneumonia, gastroenteritis, and fever is associated with increased risk of developing asthma, particularly in children with respiratory allergy. Strategies to diminish these early-life infections could potentially offer a path for primary prevention of childhood asthma.

Core Outcome Set for IgE-mediated food allergy clinical trials and observational studies of interventions: International Delphi consensus study 'COMFA'.

BACKGROUND: IgE-mediated food allergy (FA) is a global health concern with substantial individual and societal implications. While diverse intervention strategies have been researched, inconsistencies in reported outcomes limit evaluations of FA treatments. To streamline evaluations and promote consistent reporting, the Core Outcome Measures for Food Allergy (COMFA) initiative aimed to establish a Core Outcome Set (COS) for FA clinical trials and observational studies of interventions. METHODS: The project involved a review of published clinical trials, trial protocols and qualitative literature. Outcomes found as a result of review were categorized and classified, informing a two-round online-modified Delphi process followed by hybrid consensus meeting to finalize the COS. RESULTS: The literature review, taxonomy mapping and iterative discussions with diverse COMFA group yielded an initial list of 39 outcomes. The iterative online and in-person meetings reduced the list to 13 outcomes for voting in the formal Delphi process. One more outcome was added based on participant suggestions after the first Delphi round. A total of 778 participants from 52 countries participated, with 442 participating in both Delphi rounds. No outcome met a priori criteria for inclusion, and one was excluded as a result of the Delphi. Thirteen outcomes were brought to the hybrid consensus meeting as a result of Delphi and two outcomes, 'allergic symptoms' and 'quality of life' achieved consensus for inclusion as 'core' outcomes. CONCLUSION: In addition to the mandatory reporting of adverse events for FA clinical trials or observational studies of interventions, allergic symptoms and quality of life should be measured as core outcomes. Future work by COMFA will define how best to measure these core outcomes.

Normal saline for children with bronchiolitis: study protocol for a randomised controlled non-inferiority trial.

INTRODUCTION: Bronchiolitis is one of the most common reasons for hospital admissions in early childhood. As supportive treatment, some treatment guidelines suggest using nasal irrigation with normal saline (NS) to facilitate clearance of mucus from the airways. In addition, most paediatric departments in Denmark use nebulised NS for the same purpose, which can mainly be administered as inpatient care. However, no studies have ever directly tested the effect of saline in children with bronchiolitis. METHODS AND ANALYSIS: The study is an investigator-initiated, multicentre, open-label, randomised, controlled non-inferiority trial and will be performed at six paediatric departments in eastern Denmark. We plan to include 300 children aged 0-12 months admitted to hospital with bronchiolitis. Participating children are randomised 1:1:1 to nebulised NS, nasal irrigation with NS or no saline therapy. All other treatment will be given according to standard guidelines.The primary outcome is duration of hospitalisation, analysed according to intention-to-treat analysis using linear regression and Cox regression analysis. By including at least 249 children, we can prove non-inferiority with a limit of 12 hours admission, alpha 2.5% and a power of 80%. Secondary outcomes are need for respiratory support with nasal continuous positive airway pressure or high-flow oxygen therapy and requirement of fluid supplements (either by nasogastric tube or intravenous). ETHICS AND DISSEMINATION: This study may inform current practice for supportive treatment of children with bronchiolitis. First, if NS is found to be helpful, it may be implemented into global guidelines. If no effect of NS is found, we can stop spending resources on an ineffective treatment. Second, if NS is effective, but nasal irrigation is non-inferior to nebulisation, it may reduce the workload of nurses, and possible duration of hospitalisation because the treatment can be delivered by the parents at home. TRIAL REGISTRATION NUMBER: NCT05902702.

Key risk factors of asthma-like symptoms are mediated through infection burden in early childhood.

BACKGROUND: Risk factors of asthma-like symptoms in childhood may act through an increased infection burden because infections often trigger these symptoms. OBJECTIVE: We sought to investigate whether the effect of established risk factors of asthma-like episodes in early childhood is mediated through burden and subtypes of common infections. METHODS: The study included 662 children from the Copenhagen Prospective Studies on Asthma in Childhood 2010 mother-child cohort, in which infections were registered prospectively in daily diaries from age 0 to 3 years. The association between established risk factors of asthma-like episodes and infection burden was analyzed by quasi-Poisson regressions, and mediation analyses were performed for significant risk factors. RESULTS: In the first 3 years of life, the children experienced a median of 16 (interquartile range, 12-23) infectious episodes. We found that the infection burden significantly (PACME < .05) mediated the association of maternal asthma (36.6% mediated), antibiotics during pregnancy (47.3%), siblings at birth (57.7%), an asthma exacerbation polygenic risk score (30.6%), and a bacterial airway immune score (80.2%) with number of asthma-like episodes, whereas the higher number of episodes from male sex, low birth weight, low gestational age, and maternal antibiotic use after birth was not mediated through an increased infection burden. Subtypes of infections driving the mediation were primarily colds, pneumonia, gastroenteritis, and fever, but not acute otitis media or acute tonsillitis. CONCLUSIONS: Several risk factors of asthma-like symptoms in early childhood act through an increased infection burden in the first 3 years of life. Prevention of infectious episodes may therefore be beneficial to reduce the burden of asthma-like symptoms in early childhood.

Bacterial colonisation of the airway in neonates and risk of asthma and allergy until age 18†years.

BACKGROUND: We previously showed an association between neonatal bacterial airway colonisation and increased risk of persistent wheeze/asthma until age 5 years. Here, we study the association with persistent wheeze/asthma and allergy-related traits until age 18 years. METHODS: We investigated the association between airway colonisation with Streptococcus pneumoniae, Moraxella catarrhalis and/or Haemophilus influenzae in 1-month-old neonates from the COPSAC2000 mother-child cohort and the development of persistent wheeze/asthma and allergy-related traits longitudinally until age 18 years using generalised estimating equations. Replication was sought in the similarly designed COPSAC2010 cohort of 700 children. RESULTS: Neonatal airway colonisation was present in 66 (21%) out of 319 children and was associated with a 4-fold increased risk of persistent wheeze/asthma (adjusted OR 4.01 (95% CI 1.76-9.12); p<0.001) until age 7 years, but not from age 7 to 18 years. Replication in the COPSAC2010 cohort showed similar results using 16S data. Colonisation was associated with an increased number of exacerbations (adjusted incidence rate ratio 3.20 (95% CI 1.38-7.44); p<0.01) until age 7 years, but not from age 7 to 18 years. Colonisation was associated with increased levels of blood eosinophils (adjusted geometric mean ratio 1.24 (95% CI 1.06-1.44); p<0.01) and tumour necrosis factor (TNF)-α (adjusted geometric mean ratio 1.09 (95% CI 1.02-1.16); p=0.01) until age 12 years. There were no associations with lung function, bronchial reactivity, fractional exhaled nitric oxide, allergic sensitisation, total IgE or atopic dermatitis up to age 18 years. CONCLUSIONS: Neonatal airway colonisation was associated with early-onset persistent wheeze/asthma, exacerbations, elevated blood eosinophils and elevated TNF-α in blood, most prominent in early childhood, thereafter diminishing and no longer evident by age 18 years.

Exhaled nitric oxide is only an asthma-relevant biomarker among children with allergic sensitization.

BACKGROUND: Fraction of exhaled nitric oxide (FeNO) is used for diagnosing and monitoring asthma in children, but the influence of allergic sensitization is still poorly understood. Here, we investigate how asthma and allergic sensitization influence FeNO levels during childhood. METHODS: We investigated the associations between asthma, aeroallergen sensitization, and FeNO measured from age 5-18 years in the COPSAC2000 birth cohort of 411 children using repeated measurement mixed models adjusted for gestational age, sex, concurrent airway infection, inhaled corticosteroids, and tobacco exposure. Replication was sought in the similarly designed COPSAC2010 cohort of 700 children. RESULTS: In the COPSAC2000 cohort, 133 had asthma between age 5 and 18 years, and in the COPSAC2010 cohort, 112 had asthma between age 5 and 10 years. In the COPSAC2000 cohort, asthma and aeroallergen sensitization were both associated with higher FeNO from age 5 to 18 years: adjusted geometric mean ratio (aGMR), 1.22 (1.08-1.35), p < .01, and 1.41 (1.21-1.65), p < 0.001, respectively. However, asthma was associated with increased FeNO among children with aeroallergen sensitization: 1.44 (1.23-1.69), p < .0001, whereas asthma was associated with decreased FeNO among nonsensitized children: 0.80 (0.65-0.99), p = .05 (p-interaction<.0001 for asthma x sensitization). Replication in the COPSAC2010 cohort showed similar results (p-interaction <.01). Further, blood eosinophil count, total-IgE, bronchodilator response, and bronchial hyperreactivity were all associated with increased FeNO among children sensitized to aeroallergens, but not among nonsensitized children. CONCLUSION: Fraction of exhaled nitric oxide is elevated through childhood in children with asthma and is correlated with asthma-associated traits depending on the presence of aeroallergen sensitization. These findings indicate that FeNO is only a valid asthma biomarker in children with concurrent aeroallergen sensitization, which is important for guideline recommendations on the clinical use of FeNO.

Asthma medication and risk of dental diseases in children - A prospective cohort study.

BACKGROUND: Dental caries and enamel defects are the main causes of poor dental health in children, with a substantial impact on their well-being. Use of inhaled asthma medication is a suspected risk factor, but there is a lack of prospective studies investigating this and other prenatal and early life risk factors. METHODS: Copenhagen Prospective Studies on Asthma in Childhood 2010 mother-child cohort (COPSAC2010 ) consists of 700 women who were recruited at 24 weeks of pregnancy. 588 of their children participated in a dental examination at 6 years of age (84%) at the COPSAC2010 research unit. Caries was defined as decayed, missing, or filled surfaces. Enamel defect was defined as demarcated opacity, post-eruptive enamel breakdown, and/or atypical restoration on at least one molar. Caries and enamel defects were assessed in both deciduous and permanent dentitions. RESULTS: We found no associations between inhaled corticosteroids or ß2 -agonists or asthma symptoms in early childhood and the risk of caries or enamel defects by 6 years of age. Furthermore, we found no strong pre-, peri-, or postnatal risk factors for dental diseases at 6 years, except from nominally significant associations between antibiotic use in pregnancy (OR = 1.25, [1.01-1.54]), maternal education level (OR = 1.57, [1.01-2.45]), having a dog at home (OR = 0.50, [0.27-0.93]), and risk of enamel defects. CONCLUSIONS: Use of inhaled corticosteroids, ß2 -agonists, or asthma symptoms in the first 6 years of life were not associated with the development of caries or enamel defects. This finding is reassuring for parents and physicians prescribing asthma medication for young children.

Atopic and non-atopic effects of fish oil supplementation during pregnancy.

BACKGROUND: We recently conducted a double-blinded randomised controlled trial showing that fish-oil supplementation during pregnancy reduced the risk of persistent wheeze or asthma in the child by 30%. Here, we explore the mechanisms of the intervention. METHODS: 736 pregnant women were given either placebo or n-3 long-chain polyunsaturated fatty acids (LCPUFAs) in the third trimester in a randomised controlled trial. Deep clinical follow-up of the 695 children in the trial was done at 12 visits until age 6 years, including assessment of genotype at the fatty acid desaturase (FADS) locus, plasma fatty acids, airway DNA methylation, gene expression, microbiome and metabolomics. RESULTS: Supplementation with n-3 LCPUFA reduced the overall risk of non-atopic asthma by 73% at age 6 (relative risk (RR) 0.27 (95% CI 0.06 to 0.85), p=0.042). In contrast, there was no overall effect on asthma with atopic traits (RR 1.42 (95% CI 0.63 to 3.38), p=0.40), but this was significantly modified by maternal FADS genotype and LCPUFA blood levels (interaction p<0.05), and supplementation did reduce the risk of atopic asthma in the subgroup of mothers with FADS risk variants and/or low blood levels of n-3 LCPUFA before the intervention (RR 0.31 (95% CI 0.11 to 0.75), p=0.016). Furthermore, n-3 LCPUFA significantly reduced the number of infections (croup, gastroenteritis, tonsillitis, otitis media and pneumonia) by 16% (incidence rate ratio 0.84 (95% CI 0.74 to 0.96), p=0.009). CONCLUSIONS: n-3 LCPUFA supplementation in pregnancy showed protective effects on non-atopic asthma and infections. Protective effects on atopic asthma depended on maternal FADS genotype and n-3 LCPUFA levels. This indicates that the fatty acid pathway is involved in multiple mechanisms affecting the risk of asthma subtypes and infections. TRIAL REGISTRATION NUMBER: NCT00798226.

Exposures to perfluoroalkyl substances and asthma phenotypes in childhood: an investigation of the COPSAC2010 cohort.

BACKGROUND: Exposure to perfluoroalkyl substances may affect offspring immune development and thereby increase risk of childhood asthma, but the underlying mechanisms and asthma phenotype affected by such exposure is unknown. METHODS: In the Danish COPSAC2010 cohort of 738 unselected pregnant women and their children plasma PFOS and PFOA concentrations were semi-quantified by untargeted metabolomics analyses and calibrated using a targeted pipeline in mothers (gestation week 24 and 1 week postpartum) and children (age ½, 1½ and 6 years). We examined associations between pregnancy and childhood PFOS and PFOA exposure and childhood infections, asthma, allergic sensitization, atopic dermatitis, and lung function measures, and studied potential mechanisms by integrating data on systemic low-grade inflammation (hs-CRP), functional immune responses, and epigenetics. FINDINGS: Higher maternal PFOS and PFOA exposure during pregnancy showed association with a non-atopic asthma phenotype by age 6, a protection against sensitization, and no association with atopic asthma or lung function, or atopic dermatitis. The effect was primarily driven by prenatal exposure. There was no association with infection proneness, low-grade inflammation, altered immune responses or epigenetic changes. INTERPRETATIONS: Prenatal exposure to PFOS and PFOA, but not childhood exposure, specifically increased the risk of low prevalent non-atopic asthma, whereas there was no effect on atopic asthma, lung function, or atopic dermatitis. FUNDING: All funding received by COPSAC are listed on www.copsac.com. The Lundbeck Foundation (Grant no R16-A1694); The Novo Nordic Foundation (Grant nos NNF20OC0061029, NNF170C0025014, NNF180C0031764); The Ministry of Health (Grant no 903516); Danish Council for Strategic Research (Grant no 0603-00280B); and The Capital Region Research Foundation have provided core support to the COPSAC research center. COPSAC acknowledges the National Facility for Exposomics (SciLifeLab, Sweden) for supporting calibration of the untargeted metabolomics PFAS data. BC and AS has received funding for this project from the European Union's Horizon 2020 research and innovation programme (BC: grant agreement No. 946228 DEFEND; AS: grant agreement No. 864764 HEDIMED).

25 Years of translational research in the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC).

The Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) mother-child cohorts have provided a foundation of 25 years of research on the origins, prevention, and natural history of childhood asthma and related disorders. COPSAC's approach is characterized by clinical translational research with longitudinal deep phenotyping and exposure assessments from pregnancy, in combination with multi-omic data layers and embedded randomized controlled trials. One trial showed that fish oil supplementation during pregnancy prevented childhood asthma and identified pregnant women with the highest benefits from supplementation, thereby creating the potential for personalized prevention. COPSAC revealed that airway colonization with pathogenic bacteria in early life is associated with an increased risk of asthma. Further, airway bacteria were shown to be a trigger of acute asthma-like symptoms, with benefit from antibiotic treatment. COPSAC identified an immature gut microbiome in early life as a risk factor for asthma and allergy and further demonstrated that asthma can be predicted by infant lung function. At a molecular level, COPSAC has identified novel susceptibility genes, early immune deviations, and metabolomic alterations associated with childhood asthma. Thus, the COPSAC research program has enhanced our understanding of the processes causing childhood asthma and has suggested means of personalized prevention and treatment.

Supplementation With Fish Oil in Pregnancy Reduces Gastroenteritis in Early Childhood.

BACKGROUND: We hypothesized that insufficient intake of fish oil-derived omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs) during pregnancy is a contributing factor to gastroenteritis in early childhood. We examined the effect of n-3 LCPUFA supplementation on gastroenteritis symptoms in the offspring's first 3 years of life. METHODS: This was a double-blinded, randomized controlled trial whereby 736 mothers were administered n-3 LCPUFA or control from pregnancy week 24 until 1 week after birth. We measured the number of days with gastroenteritis, number of episodes with gastroenteritis, and the risk of having a gastroenteritis episode in the first 3 years of life. RESULTS: A median reduction of 2.5 days with gastroenteritis (P = .018) was shown, corresponding to a 14% reduction in the n-3 LCPUFA group compared with controls in the first 3 years of life (P = .037). A reduction in the number of gastroenteritis episodes (P = .027) and a reduced risk of having an episode (hazard ratio, 0.80 [95% confidence interval, .66-.97]; P = .023) were also shown. CONCLUSIONS: Fish oil supplementation from the 24th week of pregnancy led to a reduction in the number of days and episodes with gastroenteritis symptoms in the first 3 years of life. The findings suggest n-3 LCPUFA supplementation as a preventive measure against gastrointestinal infections in early childhood. CLINICAL TRIALS REGISTRATION: NCT00798226.

[Spontaneous pneumomediastinum initially interpreted as anaphylaxis in a boy].

Spontaneous pneumomediastinum is a rare but maybe also underdiagnosed condition in the paediatric population. Symptoms are often mild, and the disease course is often benign, but more serious differential diagnosis must be excluded. This case report is about a four-year-old boy admitted to the children's department with a suspected allergic reaction because off swelling of his chin after taking NSAID. He had pain from the throat and neck and crepitation on the left side of his thorax. X-ray showed pneumomediastinum and subcutaneous emphysema.

Persistent Asthma in Childhood.

Asthma is the most common chronic disease in children and a cause of great distress for both the children and their families [...].

Increasing severity of early-onset atopic dermatitis, but not late-onset, associates with development of aeroallergen sensitization and allergic rhinitis in childhood.

BACKGROUND: Early exposure to allergens through a defect skin barrier has been proposed as a mechanism for inducing sensitization and development of allergic diseases. We hypothesized that early-onset, severe atopic dermatitis (AD) is associated with development of aeroallergen sensitization and allergic rhinitis. METHODS: We included 368 children from the Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000 ) at-risk mother-child cohort. AD was diagnosed prospectively based on Hanifin&Rajka's criteria and severity assessed using the Scoring Atopic Dermatitis (SCORAD) index. Early-onset AD was defined as debut ≤1 year, late-onset as debut from 1-6 years. Aeroallergen sensitization and allergic rhinitis were diagnosed at ages 6-7 and 12 years. Associations between early-onset and late-onset AD and allergy endpoints were calculated using general estimating equations (GEE) models to compute the overall odds ratios (OR) for both time points. RESULTS: Early-onset AD (yes/no) and severity (SCORAD) were associated with development of aeroallergen sensitization during childhood; GEE OR = 1.68 [1.08; 2.62], p = .02 and 1.08 [1.03; 1.12], p < .001, whereas late-onset AD showed a borderline significant association and late-onset severity showed no association; GEE OR = 1.65 [0.92; 2.94], p = .08 and 1.01 [0.97; 1.06], p = .55. The same trend was seen for allergic rhinitis with significant association between early-onset AD and allergic rhinitis; GEE OR = 1.56 [1.01; 2.41], p = .04 and severity; GEE OR = 1.09 [1.05; 1.13], p < .001, whereas late-onset AD showed no association. The effects on sensitization and rhinitis of early-onset versus late-onset AD severity were significantly different: p-interactionsensitization  = .03 and p-interactionrhinitis  < .01. CONCLUSION: Increasing severity of early-onset AD, but not late-onset AD, associates with aeroallergen sensitization and allergic rhinitis later in childhood.

Immunological Outcomes of Allergen-Specific Immunotherapy in Food Allergy.

IgE-mediated food allergies are caused by adverse immunologic responses to food proteins. Allergic reactions may present locally in different tissues such as skin, gastrointestinal and respiratory tract and may result is systemic life-threatening reactions. During the last decades, the prevalence of food allergies has significantly increased throughout the world, and considerable efforts have been made to develop curative therapies. Food allergen immunotherapy is a promising therapeutic approach for food allergies that is based on the administration of increasing doses of culprit food extracts, or purified, and sometime modified food allergens. Different routes of administration for food allergen immunotherapy including oral, sublingual, epicutaneous and subcutaneous regimens are being evaluated. Although a wealth of data from clinical food allergen immunotherapy trials has been obtained, a lack of consistency in assessed clinical and immunological outcome measures presents a major hurdle for evaluating these new treatments. Coordinated efforts are needed to establish standardized outcome measures to be applied in food allergy immunotherapy studies, allowing for better harmonization of data and setting the standards for the future research. Several immunological parameters have been measured in food allergen immunotherapy, including allergen-specific immunoglobulin levels, basophil activation, cytokines, and other soluble biomarkers, T cell and B cell responses and skin prick tests. In this review we discuss different immunological parameters and assess their applicability as potential outcome measures for food allergen immunotherapy that may be included in such a standardized set of outcome measures.

Parent-specific effects on risk of developing allergic sensitization and asthma in childhood.

BACKGROUND: Parent's history of atopic traits increases the risk of the same traits in their children, but mother's history may confer an increased risk compared to father's history. OBJECTIVE: To investigate parent-specific effects on risk of developing allergic sensitization and asthma in childhood. METHODS: We included 685 parent-child trios from the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) cohort. Parent's asthma was assessed by structured interviews and child's asthma was diagnosed prospectively at regular visits to the COPSAC clinic until age 6. Specific IgE and total IgE levels were measured in parents and children by age 0.5, 1.5 and 6 years. Associations between parent and child disease traits were analyzed using general estimating equations model adjusted for breastfeeding and maternal smoking during 3rd trimester. RESULTS: Maternal compared to paternal elevated specific IgE increased the child's risk of elevated specific IgE from 0-6 years: adjusted odds ratio (aOR)mother = 1.49 [1.09-2.03], P = .01 and aORfather = 1.32 [0.96-1.82], P = .08. Maternal elevated total IgE also increased the child's risk of elevated total IgE: adjusted relative risk (aOR)mother = 4.32 [1.51-10.8], P < .01, while a trend was observed for paternal total IgE: aORfather = 2.01 [0.76-4.82], P = .13. Individual time point analyses showed that the maternal effect was strongest in early life, whereas the parental effects were comparable by age 6. A similar parent-specific pattern was observed for the child's risk of asthma. CONCLUSIONS AND CLINICAL RELEVANCE: The effect of mother's history of atopic traits on the child's risk of developing the same traits in early childhood was stronger than the effect from father's history, which was not evident before age 6. This suggests that maternal non-genetic factors seem to confer an added disease risk to the child, particularly in early life.

Season of Birth Impacts the Neonatal Nasopharyngeal Microbiota.

Objective: Pathogenic airway bacteria colonizing the neonatal airway increase the risk of childhood asthma, but little is known about the determinants of the establishment and dynamics of the airway microbiota in early life. We studied associations between perinatal risk factors and bacterial richness of the commensal milieu in the neonatal respiratory tract. Methods: Three hundred and twenty-eight children from the Copenhagen Prospective Studies on Asthma in the Childhood2000 (COPSAC2000) at-risk birth cohort were included in this study. The bacterial richness in each of the nasopharynxes of the 1-month old, asymptomatic neonates was analyzed by use of a culture-independent technique (T-RFLP). Information on perinatal risk factors included predisposition to asthma, allergy and eczema; social status of family; maternal exposures during pregnancy; mode of delivery; and postnatal exposures. The risk factor analysis was done by conventional statistics and partial least square discriminant analysis (PLSDA). Results: The nasopharyngeal bacterial community at 1-month displayed an average of 35 (IQR: 14-55, range 1-161) phylogenetically different bacteria groups. Season of birth was associated with nasopharyngeal bacterial richness at 1-month of age with a higher bacterial richness (p = 0.003) and more abundant specific bacterial profiles representing Gram-negative alpha-proteobacteria and Gram-positive Bacilli in the nasopharynx of summer-born children. Conclusion: Early postnatal bacterial colonization of the upper airways is significantly affected by birth season, emphasizing a future focus on the seasonality aspect in modelling the impact of early dynamic changes in airway bacterial communities in relation to later disease development.

Connectivity patterns between multiple allergen specific IgE antibodies and their association with severe asthma.

BACKGROUND: Allergic sensitization is associated with severe asthma, but assessment of sensitization is not recommended by most guidelines. OBJECTIVE: We hypothesized that patterns of IgE responses to multiple allergenic proteins differ between sensitized participants with mild/moderate and severe asthma. METHODS: IgE to 112 allergenic molecules (components, c-sIgE) was measured using multiplex array among 509 adults and 140 school-age and 131 preschool children with asthma/wheeze from the Unbiased BIOmarkers for the PREDiction of respiratory diseases outcomes cohort, of whom 595 had severe disease. We applied clustering methods to identify co-occurrence patterns of components (component clusters) and patterns of sensitization among participants (sensitization clusters). Network analysis techniques explored the connectivity structure of c-sIgE, and differential network analysis looked for differences in c-sIgE interactions between severe and mild/moderate asthma. RESULTS: Four sensitization clusters were identified, but with no difference between disease severity groups. Similarly, component clusters were not associated with asthma severity. None of the c-sIgE were identified as associates of severe asthma. The key difference between school children and adults with mild/moderate compared with those with severe asthma was in the network of connections between c-sIgE. Participants with severe asthma had higher connectivity among components, but these connections were weaker. The mild/moderate network had fewer connections, but the connections were stronger. Connectivity between components with no structural homology tended to co-occur among participants with severe asthma. Results were independent from the different sample sizes of mild/moderate and severe groups. CONCLUSIONS: The patterns of interactions between IgE to multiple allergenic proteins are predictors of asthma severity among school children and adults with allergic asthma.

Children Monosensitized to Can f 5 Show Different Reactions to Male and Female Dog Allergen Extract Provocation: A Randomized Controlled Trial.

BACKGROUND: Dog dander consists of several allergenic molecules including Can f 5, which is a protein expressed in the prostate of male dogs. OBJECTIVE: To investigate whether children monosensitized to Can f 5 show different reactions to provocation tests with male versus female dog dander in a double-blind randomized clinical trial. METHODS: Twenty-two children (15-18 years) with a history of dog sensitization were enrolled from the COpenhagen Prospective Studies on Asthma in Childhood2000 mother-child cohort. Skin prick test, specific IgE levels to dog dander (e5), and dog components Can f 1, 2, 3, and 5 were first assessed. We subsequently performed skin prick test and conjunctival allergen provocation test using dog dander collected separately from male and female dogs. RESULTS: Seven of the 22 children were monosensitized to Can f 5. Eight were sensitized to a mix of the dog components, and 7 were no longer sensitized to dog. Of the children monosensitized to Can f 5, all had a positive skin prick test result to male dog extract and 1 of 7 was also positive to female dog extract (P = .01). Furthermore, 5 of 7 had a positive conjunctival allergen provocation test result to male dog extract and 1 of 7 also reacted to the female dog extract (P = .03). There was no difference between reactions to male and female dog extract provocation in children sensitized to a mix of the dog components. CONCLUSIONS: Children monosensitized to Can f 5 show different reactions to male and female dog extract provocation using both skin prick test and conjunctival allergen provocation test, suggesting tolerance to female dogs.