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Background: Although systemic corticosteroid (SCS) treatment, irrespective of duration or dosage, is associated with adverse outcomes for patients with asthma, the longitudinal effects of this treatment on adverse outcomes, healthcare resource utilization (HCRU), and healthcare costs are unknown., Methods: We identified patients initiating intermittent or long-term SCS who were diagnosed with active asthma from UK general practice with linked secondary care data. Control (non-SCS) patients were matched by sex and index date with those initiating SCS. Minimum baseline period was 1 year prior to index date; minimum follow-up duration was 2 years post-index date. Cumulative incidence of SCS-associated adverse outcomes and associated HCRU and costs were compared between SCS and non-SCS patient groups and among average SCS daily exposure categories. Associations between exposure and annualized HCRU and costs were assessed, adjusted for confounders., Results: Analyses included 9413 matched pairs. Median (interquartile range) follow up was as follows: SCS group: 7.1 (4.1-11.8) years; control group: 6.4 (3.8-10.0) years. Greater SCS dosages were correlated with greater cumulative incidence. For example, patients with type 2 diabetes receiving an average daily dosage of ≥7.5 mg had a 15-year cumulative incidence (37.5%) that was 1.5-5 times greater than those receiving lower dosages. HCRU and costs increased annually for SCS patients but not for non-SCS patients. Increases in all-cause adverse outcome (excluding asthma)-associated HCRU and costs were dose-dependent., Conclusions: Over the long term, adverse outcomes associated with SCS initiation were relatively frequent and costly, with a positive dosage-response relationship with SCS exposure., (© 2018 The Authors. Allergy Published by John Wiley and Sons Ltd.)

Background: Genomewide association studies (GWASs) of asthma have identified single-nucleotide polymorphisms (SNPs) that modestly increase the risk for asthma. This could be due to phenotypic heterogeneity of asthma. Bronchial hyperresponsiveness (BHR) is a phenotypic hallmark of asthma. We aim to identify susceptibility genes for asthma combined with BHR and analyse the presence of cis-eQTLs among replicated SNPs. Secondly, we compare the genetic association of SNPs previously associated with (doctor's diagnosed) asthma to our GWAS of asthma with BHR., Methods: A GWAS was performed in 920 asthmatics with BHR and 980 controls. Top SNPs of our GWAS were analysed in four replication cohorts, and lung cis-eQTL analysis was performed on replicated SNPs. We investigated association of SNPs previously associated with asthma in our data., Results: A total of 368 SNPs were followed up for replication. Six SNPs in genes encoding ABI3BP, NAF1, MICA and the 17q21 locus replicated in one or more cohorts, with one locus (17q21) achieving genomewide significance after meta-analysis. Five of 6 replicated SNPs regulated 35 gene transcripts in whole lung. Eight of 20 asthma-associated SNPs from previous GWAS were significantly associated with asthma and BHR. Three SNPs, in IL-33 and GSDMB, showed larger effect sizes in our data compared to published literature., Conclusions: Combining GWAS with subsequent lung eQTL analysis revealed disease-associated SNPs regulating lung mRNA expression levels of potential new asthma genes. Adding BHR to the asthma definition does not lead to an overall larger genetic effect size than analysing (doctor's diagnosed) asthma., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

MeDALL (Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large-scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) 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 sensitization. IgE sensitization should be considered differently in monosensitized 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 has deployed translational activities within the EU agenda., (© 2016 The Authors. Allergy Published by John Wiley & Sons Ltd.)

Allergic diseases [asthma, rhinitis and atopic dermatitis (AD)] are complex. They are associated with allergen-specific IgE and nonallergic 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- and 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 AD are manifestations of a common systemic immune imbalance (mesodermal origin) with specific patterns of remodelling (ectodermal or endodermal origin). This study proposes a new classification of IgE-mediated allergic diseases that allows the definition of novel phenotypes 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., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: 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., Methods: 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; immunoglobulin E sensitization; 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-organizing maps., Results: 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 characterized by a low prevalence of symptoms and sensitization, whereas the second (symptomatic) group exhibited more frequent symptoms and sensitization. Ninety-nine percentage of 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., Conclusion: 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., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: There are conflicting study results regarding the association of exposure to visible mould and fungal components in house dust with respiratory and allergic diseases in children. It has been suggested that functional polymorphisms of the GSTP1 gene may influence the risk for allergic disorders through an impaired defence against oxidant injury., Methods: We examined in six birth cohorts of over 14 000 children whether the association between early exposure to reported mould at home in relation to respiratory and allergic diseases is modified by a single nucleotide polymorphism of the GSTP1 gene., Results: We observed a positive association of mould exposure with nasal symptoms (2-10 year) aOR: 1.19 (1.02-11.38). Further, there was a borderline significant increased risk of rhinoconjunctivitis (6-8 year) in children homozygous for the minor allele Val/Val, aOR: 1.25 (0.98-1.60). In stratified analyses, subjects homozygous for the minor allele and exposed to mould at home were at increased risk for early wheezing aOR: 1.34 (1.03-1.75), whereas the major allele may confer susceptibility for later nasal outcomes, (6-8 year) aOR: 1.20 (1.00-1.45) and (2-10 year) aOR: 1.30 (1.04-1.61), respectively. For none of the health outcomes studied, we found gene by environment interactions., Conclusion: A genetic influence of the GSTP1 gene cannot be ruled out, but the magnitude of the effect is a matter of further research. In conclusion, the interplay between gene and environments is complex and remains subject of further study., (© 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.)

Background: Gene variants on chromosome 17q12-21 are associated with an increased risk of childhood-onset asthma, a risk known to be modified by environmental tobacco smoke (ETS)., Objectives: To assess whether the association of rs2305480 on chromosome 17q12 in the GSDML gene with asthma-like symptoms in the first 4 years of life is modified by smoke exposure during fetal and early postnatal life., Methods: We used data from two independent prospective cohort studies from fetal life onwards in the Netherlands. We genotyped rs2305480 and assessed maternal smoking during pregnancy and ETS exposure at the age of 2. Asthma-like symptoms, defined as any reported wheezing, shortness of breath or dry nocturnal cough, were reported by parents when the children were 1, 2, 3, and 4 years. Analyses were based on a total group of 4461 Caucasian children., Results: The G risk-allele of rs2305480 was associated with asthma-like symptoms [overall odds ratio 1.17 (1.11, 1.24), 2.66E-9]. The effect of rs2305480 on asthma-like symptoms was stronger among children who were exposed to smoke during fetal life (P-interaction = 0.04). Smoke exposure in early postnatal life was also associated with an increased effect of the 17q12 single nucleotide polymorphism (SNP) on asthma-like symptoms (P-interaction = 5.06E-4). These associations were consistent in both cohorts., Conclusion: A 17q12 variant, rs2305480, was associated with asthma-like symptoms in preschool children, and this association was modified by smoke exposure already during fetal life, and in infancy. Further investigation regarding SNPs in linkage disequilibrium with rs2305480 in relation to pathophysiological pathways is needed., (© 2012 John Wiley & Sons A/S.)

Background: Exposure to high levels of house dust mite (HDM) allergens is associated with the development of allergic sensitization to HDM, a risk factor for the development of asthma, rhinitis, and allergic dermatitis. We studied the effect of an early intervention with mite-impermeable mattress covers on HDM allergen levels and the development of asthma and mite allergy throughout the first 8 years of life., Methods: High-risk children (allergic mother) were prenatally recruited and randomly allocated to two groups receiving mite allergen-impermeable (n = 416) and placebo mattress covers (n = 394) or no intervention (n = 472). Asthma and allergies were assessed yearly by questionnaire. Specific immunoglobulin E and bronchial hyper-responsiveness were measured at the age of 8 years. Mattress dust samples collected at different time points were analyzed for HDM allergens., Results: At the age of 8 years, levels of HDM allergen Der f1 but not Der p1 were lower in the active than the placebo mattress cover group. In repeated measures analyses, we found a temporary decreased risk of asthma symptoms at the age of 2 years in the intervention group compared to the placebo group and a temporary association between higher HDM allergen exposure at the age of 3 months and more asthma symptoms., Conclusion: Early intervention with mite-impermeable mattress covers is successful in reducing exposure to Der f1; it only temporarily reduces the risk of asthma symptoms and does not reduce the risk of hay fever, eczema, and allergic sensitization., (© 2011 John Wiley & Sons A/S.)

The origin of the epidemic of IgE-associated (allergic) diseases is unclear. MeDALL (Mechanisms of the Development of ALLergy), an FP7 European Union project (No. 264357), aims to generate novel knowledge on the mechanisms of initiation of allergy and to propose early diagnosis, prevention, and targets for therapy. A novel phenotype definition and an integrative translational approach are needed to understand how a network of molecular and environmental factors can lead to complex allergic diseases. A novel, stepwise, large-scale, and integrative approach will be led by a network of complementary experts in allergy, epidemiology, allergen biochemistry, immunology, molecular biology, epigenetics, functional genomics, bioinformatics, computational and systems biology. The following steps are proposed: (i) Identification of 'classical' and 'novel' phenotypes in existing birth cohorts; (ii) Building discovery of the relevant mechanisms in IgE-associated allergic diseases in existing longitudinal birth cohorts and Karelian children; (iii) Validation and redefinition of classical and novel phenotypes of IgE-associated allergic diseases; and (iv) Translational integration of systems biology outcomes into health care, including societal aspects. MeDALL will lead to: (i) A better understanding of allergic phenotypes, thus expanding current knowledge of the genomic and environmental determinants of allergic diseases in an integrative way; (ii) Novel diagnostic tools for the early diagnosis of allergy, targets for the development of novel treatment modalities, and prevention of allergic diseases; (iii) Improving the health of European citizens as well as increasing the competitiveness and boosting the innovative capacity of Europe, while addressing global health issues and ethical issues., (© 2011 John Wiley & Sons A/S.)

Background: As oral allergy syndrome (OAS) symptoms to apple are frequent, we aimed to identify low allergenic apple cultivars and to validate the prick-to-prick skin prick test (SPT) as a suitable screening method., Methods: Sixty-eight apple cultivars were tested by SPTs in 33 Dutch adults with OAS, before and during the birch pollen season in 2006 and 2007, respectively. Three cultivars yielding the largest number of negative SPTs (Elise, Santana and Pink Lady®) and one reference cultivar (Golden Delicious) were subsequently tested by single-blind oral food challenges (SBFC) just after picking in fall 2007 (fresh) and in spring 2008 (stored), outside the birch pollen season and preceded by SPTs. In spring, Santana was replaced by Modi®., Results: In fresh apples, OAS symptoms of Elise, as measured by cumulative scores on a Visual Analogue Scale VASt, were significantly lower than those of Santana, Pink Lady and Golden Delicious (P = 0.021; 0.040 and 0.005, respectively). VASt scores of Santana were significantly lower than those of Golden Delicious (P = 0.049). In stored apples, VASt scores of Elise were significantly lower than that of Golden Delicious (P = 0.038). VASt scores of fresh apples did not differ significantly from stored apples, except in Golden Delicious (spring < fall: P = 0.021). The SPTs did not predict the severity of OAS., Conclusion: SPTs are not useful to assess the allergenicity of apple cultivars. By using SBFC, Elise and Santana were identified as low allergenic apple cultivars in patient with OAS. Our data on the effect of storage are inconclusive., (© 2010 John Wiley & Sons A/S.)

Background: The Forkhead Box P3 (FOXP3) gene, located on the X-chromosome, encodes a transcription factor that directs T cells toward a regulatory phenotype. Regulatory T cells may suppress development of atopy. We evaluated whether single-nucleotide polymorphisms (SNPs) of FOXP3 are associated with atopy development in childhood., Methods: Seven SNPs in FOXP3 were genotyped in 3062 children (51% boys) participating in the Allergenic study, which consists of three Dutch birth cohorts (PIAMA, PREVASC and KOALA). Association of FOXP3 SNPs with total serum IgE and sensitisation (presence of specific serum IgE to egg, milk, and indoor, i.e. house-dust mite, cat, and/or dog allergens) was investigated at ages 1, 2, 4, and 8. Analysis of variance and logistic regression were performed, stratified for gender., Results: Our most consistent finding was observed for sensitisation to egg and indoor allergens. In girls, five FOXP3 SNPs (rs5906761, rs2294021, rs2294019, rs6609857 and rs3761548) were significantly associated with sensitisation to egg at ages 1 and 2 and with sensitisation to indoor allergens at age 2 (P < 0.05), but not at 4 and 8, a finding that was observed across the three cohorts. Rs5906761 and rs2294021 were associated with remission of sensitisation to food allergens in boys, as tested in the PIAMA cohort., Conclusion: This is the first study showing across three cohorts that X-chromosomal FOXP3 genotypes may contribute to development of sensitisation against egg and indoor allergens in girls in early childhood. In addition, an association with remission of sensitisation to food allergens existed in boys only.

Background: The toll-like receptor (TLR)-related pathway is important in host defence and may be crucial in the development of asthma and atopy. Numerous studies have shown associations of TLR-related pathway genes with asthma and atopy phenotypes. So far it has not been investigated whether gene-gene interactions in this pathway contribute to atopy and asthma development., Methods: One hundred and sixty-nine haplotype tagging single nucleotide polymorphisms (SNPs) of 29 genes (i.e. membrane and intracellular receptors, TLR4 or lipopolysaccharide-binding/facilitating proteins, adaptors, interleukin-1 receptor associated kinases, kinases, chaperone molecules, transcription factors and inhibitors) were analysed for single- and multilocus associations with atopy [total and specific immunglobulin E (IgE) at 1-2 and 6-8 years] and asthma (6-8 years). A total of 3062 Dutch children from the birth cohorts PIAMA, PREVASC and KOALA (Allergenic study) were investigated. Chi-squared test, logistic regression and the data mining approach multifactor dimensionality reduction method (MDR) were used in analysis., Results: Several genes in the TLR-related pathway were associated with atopy and/or asthma [e.g. IL1RL1, BPI, NOD1, NOD2 and MAP3K7IP1]. Multiple, single associations were found with the phenotypes under study. MDR analysis showed novel, significant gene-gene interactions in association with atopy and asthma phenotypes (e.g. IL1RL1 and TLR4 with sIgE to indoor allergens and IRAK1, NOD1 and MAP3K7IP1 with asthma). Interestingly, gene-gene interactions were identified with SNPs that did not have an effect on their own., Conclusion: Our unbiased approach provided suggestive evidence for interaction between several TLR-related pathway genes important in atopy and/or asthma development and pointed to novel genes.

Background: Filaggrin gene (FLG) mutations contribute to the development of eczema and asthma, but their contribution to sensitization and hay fever remains unclear., Methods: FLG mutations R501X, 2282del4 and R2447X were genotyped in the Prevention and Incidence of Asthma and Mite Allergy birth cohort (n = 934) to evaluate longitudinally, for up to 8 years, their association with eczema, sensitization, asthma, hay fever and their interaction with cat exposure., Results: The combined FLG mutations were significantly associated with eczema at all ages when occurring in the first year of life (OR = 2.0; 95% CI: 1.4-2.8). Combined FLG mutations were associated with both atopic and nonatopic eczema, as well as asthma (OR = 3.7; 95% CI: 1.8-7.5). When the FLG 2282del4 mutation was analysed separately, it was significantly associated with the development of eczema during the first year, having eczema up to 8 years and sensitization at the age of 8 years, which was enhanced by early-life cat exposure (ORs being 8.2; 95% CI: 2.6-25.9, 6.0; 95% CI: 3.2-11.3 and 5.4; 95% CI: 1.2-23.6 respectively). FLG 2282del4 was significantly associated with hay fever from the age 5 years onwards (OR = 3.9; 95% CI: 1.5-10.5)., Conclusions: FLG mutations are associated both with atopic and nonatopic eczema starting in the first year of life. FLG mutations combined with eczema in the first year of life are associated with a later development of asthma and hay fever, a clear example of the atopic march. We confirm that cat exposure enhances the effect of a FLG mutation on the development of eczema and sensitization.

Background: Recall bias may provide discrepant relationships of pet exposure with sensitization and asthma development. We studied prospectively effects of pets at home on development of sensitization, asthma and respiratory symptoms from birth up to age 8 years., Methods: Event history analysis was performed on annually registered data of 2951 children, participating in the PIAMA birth cohort study., Results: Children with a cat or dog at home at 3 months of age had a significantly lower prevalence of sensitization to inhalant allergens at age 8, but not of asthma. A cat decreased the risk of house dust mite sensitization at age 8 [odds ratio (OR) = 0.68, 95% confidence interval (CI) 0.49-0.95], a dog of pollen sensitization (OR = 0.49, 95% CI: 0.29-0.83). A cat or dog at home did not significantly affect asthma incidence in each subsequent year. From 2 years of age onwards, the incidence of wheeze (OR = 1.52, 95% CI: 1.12-2.05) and a dry cough at night (OR = 1.28, 95% CI: 1.05-1.57) was higher in children with a dog, whereas removal of a dog increased the risk of developing asthma symptoms. Comparing analyses using prospectively and retrospectively collected data on diagnosed asthma showed important recall bias., Conclusions: Our prospective study shows a protective effect of early presence of pets at home on sensitization to inhalant allergens, but no prevention of asthma development. Furthermore, children with pets had more frequent transient or intermittent asthma symptoms. Parental report of asthma by recall may provide spurious results of these associations.

Introduction: ADAM33 is the first identified asthma gene by positional cloning, especially asthma combined with bronchial hyperresponsiveness (BHR). Moreover, ADAM33 is associated with early-life lung function and decline of forced expiratory volume in 1 s (FEV(1)) in the general population. In utero and postnatal cigarette smoke exposure (CSE) are associated with reduced lung function, and development of BHR and asthma. We hypothesized that this may occur via interaction with ADAM33., Aim: To replicate the role of ADAM33 in childhood lung function and development of BHR and asthma. Furthermore, we investigated gene-environment interaction of ADAM33 with in utero and postnatal CSE in the Dutch PIAMA cohort., Methods: Six ADAM33 single-nucleotide polymorphisms (SNPs) were genotyped. Rint was measured at age 4 and 8 years, FEV(1) and BHR at age 8 years; asthma was based on questionnaire data at age 8., Results: In the total cohort, the rs511898 A, rs528557 C, and rs2280090 A alleles increased the risk to develop asthma (+BHR). There existed interaction between in utero but not postnatal CSE and the rs528557 and rs3918396 SNPs with respect to development of BHR, the rs3918396 SNP with Rint at age 8 and the rs528557 SNP with FEV(1)% predicted., Conclusions: We confirm associations between ADAM33 and the development of asthma (+BHR). This is the first study suggesting that interaction of in utero CSE with ADAM33 results in reduced lung function and the development of BHR, which needs further confirmation.

Background: Intestinal metaplasia (Barrett's oesophagus), but not cardiac-type mucosa in columnar-lined oesophagus, is regarded as premalignant. As intestinal metaplasia and cardiac-type mucosa are endoscopically indiscernible, it is difficult to take targeted samples from columnar-lined oesophagus with consequently a risk of having undetected intestinal metaplasia., Aim: To investigate whether the intestinal markers CDX2, MUC2 and villin can predict the presence of undetected intestinal metaplasia in columnar-lined oesophagus. Methods Presence of intestinal metaplasia or cardiac-type mucosa was identified in 122 biopsy sets of columnar-lined oesophagus from 61 patients, collected at two subsequent follow-up upper endoscopies. CDX2, MUC2 and villin expression were determined by immunohistochemistry., Results: All intestinal metaplasia samples (55) were positive for CDX2 and MUC2 and 32 of 55 for villin. CDX2 expression was detected in 23 of 67 (34%) samples with only cardiac-type mucosa. Detection of CDX2 in cardiac-type mucosa increased the likelihood of finding intestinal metaplasia in another biopsy set of columnar-lined oesophagus (odds ratio 3.5, 95% CI = 1.2-10, P = 0.02). MUC2 was positive in 13 of 23 (57%) of CDX2-positive cardiac-type mucosa samples, whereas villin was detected in seven of 23 (30%)., Conclusions: CDX2 expression in cardiac-type mucosa might be able to predict the presence of undetected intestinal metaplasia in columnar-lined oesophagus, and thus may be a putative marker for the presence of intestinal metaplasia in the absence of goblet cells.

Background: Several studies reported inconsistent associations between using gas for cooking and respiratory symptoms or lung function in children. Kitchen ventilation characteristics may modify the relationship between gas cooking and respiratory health. The aim of this study was to investigate the effect of kitchen ventilation (while cooking) on the relationship between gas cooking, combustion product dispersal, and respiratory and allergic outcomes in children., Methods: Data on respiratory and allergic symptoms and diagnoses were collected by yearly questionnaires in a population of over 3000 children participating in a birth cohort study on development of allergy and asthma. At 4 years of age, a sub-sample of 647 children provided blood samples for antibody testing. Data on gas cooking and kitchen ventilation were collected when the children were 5 years old. Based on these data a model was constructed to determine the chance of accumulation of combustion products (CACP) in the kitchen., Results: No relationship was found between gas cooking and any of the respiratory or allergy outcomes except nasal symptoms. The overall results did not change when the 'CACP' was used as exposure variable instead, while the association for nasal symptoms decreased to borderline significance., Conclusion: Our results suggest that gas cooking per se is associated with nasal symptoms in young children and not with the other respiratory symptoms that were investigated. Taking kitchen ventilation characteristics into account did not lead to different conclusions in this population where, according to the classification system, the majority of households using gas for cooking have insufficient kitchen ventilation.

The PIAMA study evaluates whether application of mite impermeable mattress covers reduces exposure to mite allergen sufficiently to reduce the incidence of asthma and mite allergy. The study started in 1996. Baseline measurements of mite allergen levels were conducted on mattresses of newborn children and their parents, mostly in 1997. Mite allergen levels were surprisingly low in this study compared with previous studies among school children and infants. Mite allergen levels were measured again on mattresses in the PIAMA study in the years 2000/2001 when the children were 4 years old, and in a new study among 6-12 year old school children conducted in the fall of 2001. Data on winter climate were collected as well. In the winters of 1995/1996 and 1996/1997, which preceded and coincided with the PIAMA baseline measurements, temperatures had been extremely low, and precipitation had been extremely low as well. It is likely that these unusual winter weather conditions affected the baseline allergen levels in the PIAMA study so that the effect of the planned intervention (mite impermeable mattress covers) was considerably smaller than it could have been.

Background: Most previous epidemiological studies on the relationship between allergy and bronchial hyperresponsiveness (BHR) have made no distinction between sensitization to indoor and outdoor allergens. We studied the relationship between specific sensitization to allergen and BHR and further assessed whether this was different in young adults and older subjects., Methods: Specific IgE to indoor allergens (house dust mite and cat) and outdoor allergens (timothy grass and birch) were measured using the CAP System. BHR was defined as PD20 /= 3). Young adults with multiple sensitization had the highest risk of BHR. Subjects who were exclusively sensitized to pollen did not show increased BHR in both age groups. Total IgE had, independently of sensitization, only a significant dose-response relationship with BHR in the oldest age group., Conclusions: The association between sensitization and BHR is dependent on the nature of the allergen and the level of specific IgE. Furthermore, this study shows for the first time that total IgE is associated with BHR at older ages, independently of sensitization.

Background: While total IgE measurements are often used in clinical practice, it is unclear how they should be interpreted for the diagnosis of allergic disorders. We studied whether total IgE may be used to rule out or predict sensitization and whether there are age or gender differences., Methods: ROC curves were assessed in subjects with asthma or allergy symptoms from a general population sample. We studied predictive values and likelihood ratios. At least one positive skin test (Phazet) or specific IgE measurement (CAP) served as reference., Results: High negative predictive values, suitable to rule out sensitization, were not found. In younger subjects, high total IgE levels strongly increase the probability of sensitization. The relationship between monosensitization and total IgE was less strong, but meaningful positive likelihood ratios were found at higher levels of total IgE. The discriminating ability of total IgE was better in the age group 20-44 than 45-70 years and comparable in males and females., Conclusion: Total IgE is not useful to rule out sensitization to common inhalant allergens. High total IgE may indicate a high probability of sensitization and may be useful to decide whether further investigation is warranted in patients with negative specific allergy tests to a panel of common inhalant allergens.

To describe the distribution of serum total IgE and specific IgE to common aeroallergens by sex and age and to study their relationship to each other, we measured serum total IgE and specific IgE (CAP) to house-dust mite, timothy grass, cat, birch, and Cladosporium in a random sample of 2496 subjects, aged 20-70 years from the Dutch general population. We found that total IgE was higher in men, independently of smoking, and that total IgE had no relationship with age after adjustment for specific IgE and smoking in linear regression analysis. At least one positive specific IgE test was found in 32% in both sexes. Men had higher prevalences of specific IgE to house-dust mite and lower prevalences of specific IgE to birch than women. The proportion with positive specific IgE decreased with age. The mean total IgE increased with the number of positive specific IgE tests. Thus, total IgE is higher in men and has no relationship with age if specific IgE is taken into account. The prevalences of specific IgE to aeroallergens are high and decrease with increasing age. We suggest that sex differences in total IgE should be considered when using total IgE.