- [Show abstract] [Hide abstract] ABSTRACT: Background: Atopic diseases are among the most common chronic diseases in adolescents and it is uncertain whether the prevalence of atopic diseases has reached a plateau or is still increasing. The use of the ISAAC (International Study of Asthma and Allergy in Childhood) questionnaire has provided comparable prevalence rates from many countries; whereas studies including clinical examinations and strict diagnostic criteria are scarce. We aimed to investigate the prevalence of atopic diseases, the pattern of sensitization and comorbidities at 14 years in a prospective birth cohort. Methods: The children were examined eight times from birth to 14 years. Visits included questionnaire-based interviews, clinical examination, skin prick test and specific IgE. Results: Follow-up rate at 14-years was 66.2%. The 12-month prevalence of any atopic disease was high (40.3%) mostly due to a high prevalence of rhinoconjunctivitis (32.8%) whereas the prevalence of asthma was 12.9% and of atopic dermatitis 8.1%. In children with at least one atopic disease 60% were sensitized while only 16% of those without atopic diseases were sensitized. The frequency of sensitization depended on the phenotype. Among children with rhinoconjunctivitis only, rhinoconjunctivitis with concomitant astma or atopic dermatitis or both 62.5%, 81.5%, 70% and 100% respectively were sensitized, whereas it was 7.7% and 33.3% of children with only asthma or atopic dermatitis. Conclusion: The prevalence of rhinoconjunctivitis was high in adolescence. Children with rhinoconjunctivitis with and without comorbidities were frequently sensitized. Children with asthma without concomitant allergic rhinoconjunctivitis were rarely sensitized. This article is protected by copyright. All rights reserved.
- [Show abstract] [Hide abstract] ABSTRACT: The majority of egg allergic children develops tolerance over time. However, it may take numerous of consecutive egg challenges to get there as no good indices to predict tolerance exists. To investigate if serial measurements of specific IgE to egg white, ovomucoid, ovalbumin, conalbumin, lysozyme, and egg yolk could improve the specificity of the diagnostic work up and aid in the decision when to re-challenge egg allergic children. The outcome of oral food challenges with hen's egg and corresponding specific IgE levels were evaluated in children referred to The Allergy Center within an 8-year period. The egg allergic children were re-challenged and had specific IgE levels measured once a year. During a median follow-up of 26 months, 287 challenges and corresponding 287 serum analyses were performed in 130 children. Of the 130 children, 99 were egg allergic and 82 of these were re-challenged. Based on the initial diagnostic challenges only, AUC estimates of the ability of specific IgE titers to distinguish between egg sensitization and egg allergy were only modest (maximum 0.83) and provided no clinical meaningful decision points. Specific IgE levels at baseline did not differ between tolerant and persistent allergic children. However longitudinally, acquisition of tolerance was associated with a decrease of IgE to egg white and to ovomucoid. In all cases of an increase in IgE to ovomucoid, the re-challenge was positive. The decision when to re-challenge egg allergic children should encounter the course of specific IgE. This article is protected by copyright. All rights reserved.
- [Show abstract] [Hide abstract] ABSTRACT: Background: It is questionable how repeated patch tests with nickel sulphate in infancy affect nickel patch test reactivity at a later age. Methods: The DARC cohort encompasses 562 infants invited to a clinical examination including patch tests with nickel sulphate 6 times during the first 36 months of life. At the follow-up investigation at 14 years of age (2013-14) participants were offered re-patch tests with nickel sulphate. The TOACS cohort encompasses 1501 schoolchildren evaluated for the first time at 14 years of age (1995-96) including clinical examination and nickel sulphate patch tests. The prevalence of nickel sensitization in the DARC cohort was compared to the prevalence in the TOACS cohort at 14 years of age. Results: Nickel sulphate sensitization was found in 1.2% of the participants from the DARC cohort tested repeatedly with nickel sulphate in early childhood and retested at 14 years of age compared to 8.6% of the participants from the TOACS cohort patch tested for the first time at 14 years of age using the same patch test system and test concentration CONCLUSION: The significant difference in nickel patch test reactivity comparing the two cohorts may reflect an immunologic effect or the effect of nickel regulation. This article is protected by copyright. All rights reserved.
- [Show abstract] [Hide abstract] ABSTRACT: Maternal smoking during pregnancy increases childhood asthma risk, but health effects in children of nonsmoking mothers passively exposed to tobacco smoke during pregnancy are unclear. We examined the association of maternal passive smoking during pregnancy and wheeze in children aged ≤2 years. Individual data of 27 993 mother–child pairs from 15 European birth cohorts were combined in pooled analyses taking into consideration potential confounders. Children with maternal exposure to passive smoking during pregnancy and no other smoking exposure were more likely to develop wheeze up to the age of 2 years (OR 1.11, 95% CI 1.03–1.20) compared with unexposed children. Risk of wheeze was further increased by children's postnatal passive smoke exposure in addition to their mothers' passive exposure during pregnancy (OR 1.29, 95% CI 1.19–1.40) and highest in children with both sources of passive exposure and mothers who smoked actively during pregnancy (OR 1.73, 95% CI 1.59–1.88). Risk of wheeze associated with tobacco smoke exposure was higher in children with an allergic versus nonallergic family history. Maternal passive smoking exposure during pregnancy is an independent risk factor for wheeze in children up to the age of 2 years. Pregnant females should avoid active and passive exposure to tobacco smoke for the benefit of their children's health.
- [Show abstract] [Hide abstract] ABSTRACT: MeDALL Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 20 (10) -2015 proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy(.) MeDALL linked epidemiological, clinical and basic research using a stepwise, large-scale and integrative approach: precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology omics, IgE measurement using micro-arrays and environmental data(.) Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitisation(.) IgE sensitisation should be considered differently in mono and polysensitized individuals(.) Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases(.) Environmental exposures are relevant for the development of allergy-related diseases(.) To complement the population-based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans(.) The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases(.) Ethics and gender were considered(.) MeDALL had translational activities deployed within the EU agenda(.) This article is protected by copyright. All rights reserved.
- [Show abstract] [Hide abstract] ABSTRACT: Background: Hazelnut is the most frequent cause of tree-nut allergy, but up to half of all children with hazelnut allergy additionally suffers from peanut allergy. Our aim was to identify diagnostic values of the most promising serological markers (Cor a 9 and Cor a 14) and to address the influence of concomitant peanut allergy and PR10 sensitization. Method: We included 155 children suspected off hazelnut allergy and challenged according to guidelines. Concomitant allergy to peanuts was verified or ruled out by challenge. Skin Prick Test, s-IgE and CRD to hazelnut, peanut, PR10 and LPT protein families were measured using ImmunoCap. Results: Sixty-five children had a positive hazelnut challenge, and 60% of these also had concomitant peanut allergy. Children allergic to hazelnut were sensitized to Cor a 9 and Cor a 14; peanut allergic children to Ara h 2. Sensitization to PR10 protein components were seen in 45% of all included children, irrelevant of allergy to peanut or hazelnut. A cutoff > 0.72 kU/L of IgE towards Cor a 14 diagnosed 87% correctly, making Cor a 14 the superior serology markers. However, 9 hazelnut allergic children were primarily sensitized to Cor a 9. Conclusion: Concomitant peanut allergy is common in hazelnut allergic children, but decision points as well as diagnostic values for Cor a 14 are not affected. We found 3 independent and well-characterized serotypes; hazelnut allergic children sensitized to Cor a 14, peanut allergic children sensitized to Ara h 2 and children sensitized to birch pollen protein Bet v 1. This article is protected by copyright. All rights reserved.
- [Show abstract] [Hide abstract] ABSTRACT: Asthma, rhinitis, and eczema often co-occur in children but their interrelationships at the population level have been poorly addressed. We assessed co-occurrence of childhood asthma, rhinitis, and eczema using unsupervised statistical techniques. We included 17,209 children at 4 years and 14,585 at 8 years from seven European-population-based birth cohorts (MeDALL project). At each age period, children were grouped, using partitioning cluster analysis, according to the distribution of 23 variables covering symptoms "ever" and "in the last 12 months", doctor diagnosis, age of onset, and treatments of asthma, rhinitis, and eczema, IgE sensitisation, weight, and height. We tested the sensitivity of our estimates to subject and variable selections, and to different statistical approaches, including latent class analysis and self-organising maps. Two groups were identified as the optimal way to cluster the data at both age periods and in all sensitivity analyses. The first (reference) group at 4 and 8 years (including 70 and 79% of children, respectively) was characterised by a low prevalence of symptoms and sensitisation, whereas the second (symptomatic) group exhibited more frequent symptoms and sensitisation. 99% children with comorbidities (co-occurrence of asthma, rhinitis, and/or eczema) were included in the symptomatic group at both ages. The children's characteristics in both groups were consistent in all sensitivity analyses. At 4 and 8 years, at the population level, asthma, rhinitis, and eczema can be classified together as an allergic comorbidity cluster. Future research including time-repeated assessments and biological data will help understanding the interrelationships between these diseases. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
- [Show abstract] [Hide abstract] ABSTRACT: Allergic diseases (asthma, rhinitis and atopic dermatitis) are complex. They are associated with allergen-specific IgE and non-allergic mechanisms that may coexist in the same patient. In addition, these diseases tend to cluster and patients present concomitant or consecutive diseases (multimorbidity). IgE sensitization should be considered as a quantitative trait. Important clinical and immunological differences exist between mono or polysensitized subjects. Multimorbidities of allergic diseases share common causal mechanisms that are only partly IgE-mediated. Persistence of allergic diseases over time is associated with multimorbidity and/or IgE polysensitization. The importance of the family history of allergy may decrease with age. This review puts forward the hypothesis that allergic multimorbidities and IgE polysensitization are associated and related to the persistence or re-occurrence of foetal Type 2 signalling. Asthma, rhinitis and atopic dermatitis are manifestations of a common systemic immune imbalance (mesodermal origin) with specific patterns of remodelling (ectodermal or endodermal origin). This paper proposes a new classification of IgE-mediated allergic diseases that allows the definition of novel phenotypes in order to (i) better understand genetic and epigenetic mechanisms, (ii) better stratify allergic preschool children for prognosis, and (iii) propose novel strategies of treatment and prevention. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
- [Show abstract] [Hide abstract] ABSTRACT: Allergy to wheat can present clinically in different forms: Sensitization to ingested wheat via the gastrointestinal tract can cause traditional food allergy or in combination with exercise, Wheat-Dependent Exercise-Induced Anaphylaxis (WDEIA). Sensitization to inhaled wheat flour may lead to occupational rhinitis and/or asthma. We retrospectively reviewed the case notes of 156 patients (age 0.7 - 73.3 years) with a case history of wheat allergy. The population was divided into three groups, 1: Wheat allergy elicited by ingestion, 2: By inhalation and 3: WDEIA. All patients were examined with detailed case history, specific IgE (sIgE), Skin Prick Test (SPT) and wheat challenge (nasal or oral ± exercise). Details of the case history were extracted from the patients´ case records. Group 1: Twenty one of 95 patients were challenge positive (15 children, 6 adults). All children had atopic dermatitis, and most (13/15) outgrew their wheat allergy. Most children (13/15) had other food allergies. Challenge positive patients showed significantly higher levels of sIgE to wheat and significantly more were SPT positive than challenge negative. Group 2: Eleven out of 13 adults with occupational asthma or rhinitis were challenge positive. None outgrew their allergy. Seven had positive sIgE and 10 had positive SPT to wheat. Group 3: Ten of 48 (adolescent/adults) were positive when challenged during exercise. Challenge positive patients showed significantly higher levels of sIgE to ω-5-gliadin. The natural course is presently unknown. Wheat allergy can manifest in different disease entities, rendering a detailed case history and challenge mandatory. Patient age, occupation, concomitant allergies (food or inhalant) and atopic dermatitis are important factors for evaluation.
- [Show abstract] [Hide abstract] ABSTRACT: Background: Numerous birth cohorts have been initiated in the world over the past 30 years using heterogeneous methods to assess the incidence, course and risk factors of asthma and allergies. The aim of the present work is to provide the stepwise proceedings of the development and current version of the harmonized MeDALL-Core Questionnaire (MeDALL-CQ) used prospectively in 11 European birth cohorts. Methods: The harmonization of questions was accomplished in 4 steps: (i) collection of variables from 14 birth cohorts, (ii) consensus on questionnaire items, (iii) translation and back-translation of the harmonized English MeDALL-CQ into 8 other languages and (iv) implementation of the harmonized follow-up. Results: Three harmonized MeDALL-CQs (2 for parents of children aged 4-9 and 14-18, 1 for adolescents aged 14-18) were developed and used for a harmonized follow-up assessment of 11 European birth cohorts on asthma and allergies with over 13,000 children. Conclusions: The harmonized MeDALL follow-up produced more comparable data across different cohorts and countries in Europe and will offer the possibility to verify results of former cohort analyses. Thus, MeDALL can become the starting point to stringently plan, conduct and support future common asthma and allergy research initiatives in Europe.
- [Show abstract] [Hide abstract] ABSTRACT: Eczema, rhinitis, and asthma often coexist (comorbidity) in children, but the proportion of comorbidity not attributable to either chance or the role of IgE sensitisation is unknown. We assessed these factors in children aged 4-8 years. In this prospective cohort study, we assessed children from 12 ongoing European birth cohort studies participating in MeDALL (Mechanisms of the Development of ALLergy). We recorded current eczema, rhinitis, and asthma from questionnaires and serum-specific IgE to six allergens. Comorbidity of eczema, rhinitis, and asthma was defined as coexistence of two or three diseases in the same child. We estimated relative and absolute excess comorbidity by comparing observed and expected occurrence of diseases at 4 years and 8 years. We did a longitudinal analysis using log-linear models of the relation between disease at age 4 years and comorbidity at age 8 years. We assessed 16 147 children aged 4 years and 11 080 aged 8 years in cross-sectional analyses. The absolute excess of any comorbidity was 1·6% for children aged 4 years and 2·2% for children aged 8 years; 44% of the observed comorbidity at age 4 years and 50·0% at age 8 years was not a result of chance. Children with comorbidities at 4 years had an increased risk of having comorbidity at 8 years. The relative risk of any cormorbidity at age 8 years ranged from 36·2 (95% CI 26·8-48·8) for children with rhinitis and eczema at age 4 years to 63·5 (95% CI 51·7-78·1) for children with asthma, rhinitis, and eczema at age 4 years. We did longitudinal assessment of 10 107 children with data at both ages. Children with comorbidities at 4 years without IgE sensitisation had higher relative risks of comorbidity at 8 years than did children who were sensitised to IgE. For children without comorbidity at age 4 years, 38% of the comorbidity at age 8 years was attributable to the presence of IgE sensitisation at age 4 years. Coexistence of eczema, rhinitis, and asthma in the same child is more common than expected by chance alone-both in the presence and absence of IgE sensitisation-suggesting that these diseases share causal mechanisms. Although IgE sensitisation is independently associated with excess comorbidity of eczema, rhinitis, and asthma, its presence accounted only for 38% of comorbidity, suggesting that IgE sensitisation can no longer be considered the dominant causal mechanism of comorbidity for these diseases. EU Seventh Framework Programme.
- [Show abstract] [Hide abstract] ABSTRACT: BACKGROUND: The causal link between body mass index (BMI) or obesity and asthma in children is still being debated. Analyses of large longitudinal studies with a sufficient number of incident cases and in which the time-dependent processes of both excess weight and asthma development can be validly analyzed are lacking. OBJECTIVE: We sought to investigate whether the course of BMI predicts incident asthma in childhood. METHODS: Data from 12,050 subjects of 8 European birth cohorts on asthma and allergies were combined. BMI and doctor-diagnosed asthma were modeled during the first 6 years of life with latent growth mixture modeling and discrete time hazard models. Subpopulations of children were identified with similar standardized BMI trajectories according to age- and sex-specific "World Health Organization (WHO) child growth standards" and "WHO growth standards for school aged children and adolescents" for children up to age 5 years and older than 5 years, respectively (BMI-SDS). These types of growth profiles were analyzed as predictors for incident asthma. RESULTS: Children with a rapid BMI-SDS gain in the first 2 years of life had a higher risk for incident asthma up to age 6 years than children with a less pronounced weight gain slope in early childhood. The hazard ratio was 1.3 (95% CI, 1.1-1.5) after adjustment for birth weight, weight-for-length at birth, gestational age, sex, maternal smoking in pregnancy, breast-feeding, and family history of asthma or allergies. A rapid BMI gain at 2 to 6 years of age in addition to rapid gain in the first 2 years of life did not significantly enhance the risk of asthma. CONCLUSION: Rapid growth in BMI during the first 2 years of life increases the risk of asthma up to age 6 years.
- [Show abstract] [Hide abstract] ABSTRACT: We have previously reported patch test reactivity to nickel sulphate in a cohort of unselected infants tested repeatedly at 3–18 months of age. A reproducible positive reaction at 12 and 18 months was selected as a sign of nickel sensitivity provided a patch test with an empty Finn chamber was negative. A reproducible positive reaction was seen in 8.6% of the infants. The objective of this study is to follow-up on infants with alleged nickel sensitivity. A total of 562 infants were included in the cohort and patch tested with nickel sulphate (ICDRG guidelines). The 26 children with a positive patch test reaction to nickel sulphate at 12 and 18 months were offered repeated patch tests at 3 and 6 yr. Among the 21 children tested at both 12 months, 18 months and at 3 and 6 yr only 2 of 21 had reproducible nickel reactions (one clinically relevant), 13 of 21 were negative and 6 of 21 were negative at 3 or 6 yr. Only 9.5% of the children had reproducible nickel sulphate reactivity, while 62% became negative. The results are noteworthy and can be interpreted in different ways: Repeated nickel patch tests did not cause patch test sensitization. The test reactions in infancy are probably of irritant or non-specific nature. Hence, nickel patch tests should only be performed in small children if there is a clinical suspicion of nickel-induced allergic contact dermatitis.
- [Show abstract] [Hide abstract] ABSTRACT: Introduction: As replacement for the oral food challenge, decision-points for sensitization test have been established, but suboptimal sensitivity and/or specificity, as well as regional differences, have reduced the clinical usability. IgE toward specific peanut protein components has been reported to be of value, but data on correlation with clinical data are sparse. Our aim was to correlate IgE values with the outcome of peanut challenges. Method: Data from 175 positive and 30 negative peanut challenges in patients aged 1-26 years were retrospectively correlated with the levels of specific IgE to peanut and peanut components (Ara h 1-3, h 8, and h 9). Result: The best correlation between IgE and clinical thresholds was found for Ara h 2 (ρ(s) = -0.30, P < 0.01). A cutoff of Ara h 2 > 1.63 kU/l yielded a specificity = 1.00, with a corresponding sensitivity of 0.70. Symptom severity elicited during challenge correlated significantly with the levels of Ara h 2 (ρ(s) = 0.60, P < 0.0001), but large individual variation was found. Conclusion: The level of IgE toward Ara h 2 can improve diagnostic accuracy by introducing a more clear-cut decision-point with an optimal specificity maintaining a high sensitivity. In our study, this would have reduced the necessary number of challenges to be performed from 205 to 92. Extrapolation between centers is difficult and decision-points need to be addressed in relation to settings and population. Further component-resolved diagnostic cannot replace oral challenge neither in determining thresholds nor in the assessment of severity of symptoms elicited during challenge.
Maastricht UniversityMaestricht, Limburg, Netherlands
Odense University HospitalOdense, South Denmark, Denmark