Background Problematic severe childhood asthma includes a subgroup of patients who are resistant to therapy. The specific mechanisms involved are unknown, and novel biomarkers are required to ...facilitate treatment and diagnosis of therapy-resistant asthma. The chitinase-like protein YKL-40 has been related to asthma and airway remodeling. Objectives To compare serum YKL-40 levels in children with severe, therapy-resistant asthma (n = 34), children with controlled persistent asthma (n = 39), and healthy controls (n = 27), and to investigate correlations with biomarkers of inflammation and airway remodeling. Methods The study protocol included questionnaires, measurement of exhaled nitric oxide in exhaled air, blood sampling for inflammatory biomarkers, and high-resolution computed tomography of the lungs to identify bronchial wall thickening (therapy-resistant only). Serum YKL-40 levels were measured by ELISA, and all asthmatic children were genotyped for a CHI3L1 promoter single nucleotide polymorphism (rs4950928). Results Serum YKL-40 levels were significantly higher in children with therapy-resistant asthma than in healthy children (19.2 ng/mL vs 13.8 ng/mL, P = .03). Among children with severe, therapy-resistant asthma, YKL-40 levels correlated with fraction of exhaled nitric oxide in exhaled air ( r = 0.48, P = .004), blood neutrophils ( r = 0.63, P < .001), and bronchial wall thickening on high-resolution computed tomography ( r = 0.45, P = .01). Following adjustment for CHI3L1 genotype, significantly greater levels of YKL-40 were found in children with therapy-resistant asthma than in children with controlled asthma. Conclusions YKL-40 levels are increased in children with severe, therapy-resistant asthma compared to healthy children, and also compared to children with controlled asthma following correction for genotype.
Background The nature of allergens and route and dose of exposure may affect the natural development of IgE and IgG responses. Objective We sought to investigate the natural IgE and IgG responses ...toward a large panel of respiratory and food allergens in subjects exposed to different respiratory allergen loads. Methods A cross-sectional analysis was conducted in 340 adults of the EGEA (Epidemiological study of the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy) (170 with and 170 without asthma) cohort. IgE and IgG responses to 47 inhalant and food allergen components were analyzed in sera using allergen microarray and compared between 5 French regions according to the route of allergen exposure (inhaled vs food allergens). Results Overall 48.8% of the population had allergen-specific IgE levels of 0.3 ISAC standardized units (ISU) or more to at least 1 of the 47 allergens with no significant differences across the regions. For ubiquitous respiratory allergens (ie, grass, olive/ash pollen, house dust mites), specific IgE did not show marked differences between regions and specific IgG (≥0.5 ISU) was present in most subjects everywhere. For regionally occurring pollen allergens (ragweed, birch, cypress), IgE sensitization was significantly associated with regional pollen exposure. For airborne allergens cross-reacting with food allergens, frequent IgG recognition was observed even in regions with low allergen prevalence (Bet v 1) or for allergens less frequently recognized by IgE (profilins). Conclusions The variability in allergen-specific IgE and IgG frequencies depends on exposure, route of exposure, and overall immunogenicity of the allergen. Allergen contact by the oral route might preferentially induce IgG responses.
Background The role of exposure to air pollution in the development of allergic sensitization remains unclear. Objective We sought to assess the development of sensitization until school age related ...to longitudinal exposure to air pollution from road traffic. Methods More than 2500 children in the birth cohort BAMSE (Children, Allergy, Milieu, Stockholm, Epidemiological Survey) from Stockholm, Sweden, were followed with repeated questionnaires and blood sampling until 8 years of age. Outdoor concentrations of nitrogen oxides, as a marker of exhaust particles, and particles with an aerodynamic diameter of less than 10 μm (PM10 ), mainly representing road dust, were assigned to residential, day care, and school addresses by using dispersion models. Time-weighted average exposures were linked to levels of IgE against common inhalant and food allergens at 4 and 8 years of age. Results Air pollution exposure during the first year of life was associated with an increased risk of pollen sensitization at 4 years of age (odds ratio, 1.83; 95% confidence interval, 1.02-3.28) for a 5th to 95th difference in exposure to nitrogen oxides. At 8 years, there was no general increase in the risk of sensitization; however, the risk of food sensitization was increased, particularly among children free of sensitization at 4 years of age (odds ratio, 2.30; 95% confidence interval, 1.10-4.82). Results were similar by using PM10 . No associations between air pollution exposure after the first year of life and sensitization were seen. Conclusion Traffic-related air pollution exposure does not seem to increase the overall risk of sensitization to common inhalant and food allergens up to school age, but sensitization to certain allergens might be related to exposure during infancy.
IgE signatures to peanut allergen measured in early childhood allow predicting the likelihood of peanut allergy in adolescence. Peanut symptoms and Ara h 2 IgE >2.0 ISU-E at 4 years predict peanut ...allergy in adolescence.
Background Children with problematic severe asthma have poor disease control despite high doses of inhaled corticosteroids and additional therapy, leading to personal suffering, early deterioration ...of lung function, and significant consumption of health care resources. If no exacerbating factors, such as smoking or allergies, are found after extensive investigation, these children are given a diagnosis of therapy-resistant (or therapy-refractory) asthma (SA). Objective We sought to deepen our understanding of childhood SA by analyzing gene expression and modeling the underlying regulatory transcription factor networks in peripheral blood leukocytes. Methods Gene expression was analyzed by using Cap Analysis of Gene Expression in children with SA (n = 13), children with controlled persistent asthma (n = 15), and age-matched healthy control subjects (n = 9). Cap Analysis of Gene Expression sequencing detects the transcription start sites of known and novel mRNAs and noncoding RNAs. Results Sample groups could be separated by hierarchical clustering on 1305 differentially expressed transcription start sites, including 816 known genes and several novel transcripts. Ten of 13 tested novel transcripts were validated by means of RT-PCR and Sanger sequencing. Expression of RAR-related orphan receptor A (RORA) , which has been linked to asthma in genome-wide association studies, was significantly upregulated in patients with SA. Gene network modeling revealed decreased glucocorticoid receptor signaling and increased activity of the mitogen-activated protein kinase and Jun kinase cascades in patients with SA. Conclusion Circulating leukocytes from children with controlled asthma and those with SA have distinct gene expression profiles, demonstrating the possible development of specific molecular biomarkers and supporting the need for novel therapeutic approaches.
To the Editor: It has been shown that IgE antibodies to common allergens start with the development of such antibodies to foods followed by IgE antibodies to airborne allergens.1,2 Cross-reactive IgE ...is common to pollens and some pathogenesis-related proteins in fruits, vegetables, legumes, and grains.3,4 Because information on the development and co-occurrence of allergen-specific IgE antibodies from early childhood up to adolescence is limited in large population samples, we sought to evaluate the development, progression, and transition of IgE antibodies to common airborne and food allergens. Definitions of exposures (parental allergy, breast-feeding, and second-hand tobacco smoke) and outcomes such as asthma, rhinitis, and eczema at 4 to 16 years are provided in this article's Online Repository and Table E1 at www.jacionline.org.6 At each follow-up, sera were first analyzed with Phadiatop and fx5, mixes with 14 airborne and food allergens, respectively.
Background The fraction of exhaled nitric oxide (F eno ) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants ...associated with childhood F eno values might help to define biological mechanisms related to specific asthma phenotypes. Objective We sought to identify the genetic variants associated with childhood F eno values and their relation with asthma. Methods F eno values were measured in children age 5 to 15 years. In 14 genome-wide association studies (N = 8,858), we examined the associations of approximately 2.5 million single nucleotide polymorphisms (SNPs) with F eno values. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci in genome-wide expression data sets of lymphoblastoid cell lines (n = 1,830) and were related to asthma in a previously published genome-wide association data set (cases, n = 10,365; control subjects: n = 16,110). Results We identified 3 SNPs associated with F eno values: rs3751972 in LYR motif containing 9 ( LYRM9 ; P = 1.97 × 10−10 ) and rs944722 in inducible nitric oxide synthase 2 ( NOS2 ; P = 1.28 × 10−9 ), both of which are located at 17q11.2-q12, and rs8069176 near gasdermin B ( GSDMB ; P = 1.88 × 10−8 ) at 17q12-q21. We found a cis expression quantitative trait locus for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. rs8069176 at 17q12-q21, but not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma. Conclusion This study identified 3 variants associated with F eno values, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight into the regulation of F eno values. This study highlights that both shared and distinct genetic factors affect F eno values and childhood asthma.
Allergic rhinitis and 6 of the 7 studied SNPs were significantly associated in the pooled data (Table I). Because the SNPs are in high linkage disequilibrium, the associations are not independent. ...Furthermore, the 17q21 locus appears to be a stronger risk factor for asthma than for allergic rhinitis.2 Nevertheless, because weaker borderline significant longitudinal associations for allergic rhinitis without concomitant asthma were also observed, we are unable to exclude the possibility that any effect of 17q21 variation on allergic rhinitis may also be mediated through an asthma-independent pathway, as has been suggested by others.3 However, the null associations with allergic rhinitis for those without any history of asthma observed in this study do not support this hypothesis (Fig 1).
Background Childhood asthma is a complex disease with known heritability and phenotypic diversity. Although an earlier onset has been associated with more severe disease, there has been no ...genome-wide association study of the age of onset of asthma in children. Objective We sought to identify genetic variants associated with earlier onset of childhood asthma. Methods We conducted the first genome-wide association study of the age of onset of childhood asthma among participants in the Childhood Asthma Management Program (CAMP) and used 3 independent cohorts from North America, Costa Rica, and Sweden for replication. Results Two single nucleotide polymorphisms (SNPs) were associated with earlier onset of asthma in the combined analysis of CAMP and the replication cohorts: rs9815663 (Fisher P = 2.31 × 10−8 ) and rs7927044 ( P = 6.54 × 10−9 ). Of these 2 SNPs, rs9815663 was also significantly associated with earlier asthma onset in an analysis including only the replication cohorts. Ten SNPs in linkage disequilibrium with rs9815663 were also associated with earlier asthma onset (2.24 × 10−7 < P < 8.22 × 10−6 ). Having 1 or more risk alleles of the 2 SNPs of interest (rs9815663 and rs7927044) was associated with lower lung function and higher asthma medication use during 4 years of follow-up in CAMP. Conclusions We have identified 2 SNPs associated with earlier onset of childhood asthma in 4 independent cohorts.
Celiac disease (CeD) is associated with several immune-mediated disorders, but it is unclear whether it is associated with eosinophilic esophagitis (EoE).
We sought to examine the risk of EoE in ...patients with biopsy-verified CeD compared with matched controls and siblings.
Using nationwide population-based histopathology data, we identified 27,338 patients with CeD diagnosed in the period 2002 to 2017 in Sweden. Patients with CeD were age- and sex-matched with up to 5 reference individuals (n = 134,987) from the general population. The Cox regression was used to estimate hazard ratios (HRs) for developing biopsy-verified EoE. In a secondary analysis, we used siblings with CeD as comparators to adjust for intrafamilial confounding.
The median age at CeD diagnosis was 27 years, and 63.3% were female patients. During a median follow-up of 8.1 years, 17 patients with CeD and 13 matched reference individuals were diagnosed with EoE. This corresponded to incidence rates of 0.08 versus 0.01 per 1000 person-years, respectively, and an adjusted HR for EoE of 6.65 (95% CI, 3.26-13.81). Compared with their siblings without CeD, patients with CeD were however at a no increased risk of EoE (HR, 1.39; 95% CI, 0.55-3.51).
In this study, individuals with CeD were at a 6.6-fold increased risk of later EoE compared with the general population. This association might be explained by an altered health-seeking behavior or through shared genetic or early environmental factors because the excess risk disappeared in sibling analyses.
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