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Jon R Konradsen,
Anna James, Björn Nordlund,
Lovisa E Reinius,
Cilla Söderhäll,
Erik Melén,
Asa Wheelock,
Karin C Lödrup Carlsen,
Marika Lidegran,
Marri Verhoek,
Rolf G Boot,
Barbro Dahlén,
Sven Erik Dahlén,
Gunilla Hedlin
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ABSTRACT: 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.
The Journal of allergy and clinical immunology 04/2013; · 9.17 Impact Factor
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Christina Orsmark Pietras,
Anna James,
Jon R Konradsen, Björn Nordlund,
Cilla Söderhäll,
Ville Pulkkinen,
Christophe Pedroletti,
Kameran Daham,
Maciek Kupczyk,
Barbro Dahlén,
Juha Kere,
Sven-Erik Dahlén,
Gunilla Hedlin,
Erik Melén
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ABSTRACT: The causes of severe childhood asthma are poorly understood. Our aim was in this study to define global patterns of gene expression in children with severe therapy-resistant and controlled asthma.White blood cells were isolated and the global transcriptome profile was characterised using the Affymetrix Human Gene ST 1.0 chip in children with severe, therapy-resistant asthma (SA, n=20), controlled asthma (CA, n=20) and healthy controls (Ctrl, n=19). Receptor expression was studied in separated fractions of leukocytes in adults asthmatics (n=12).1378 genes were differentially expressed in one or several of the SA vs. Ctrl, SA vs. CA or CA vs. Ctrl contrasts. Three significantly enriched KEGG pathways were represented; natural killer cell mediated cytotoxicity (upregulated in CA), N-Glycan biosynthesis (downregulated in SA) and bitter taste transduction, TAS2Rs (upregulated mostly in SA). qPCR experiments confirmed upregulation of TAS2Rs in the SA group compared to the Ctrl group. Further analysis of sorted leukocyte fractions from adult asthmatics indicated that TAS2R expression was highest in blood lymphocytes. Significant correlations between expression of the TAS2Rs and clinical markers of asthma severity were found in both adults and children.In conclusion, specific gene expression patterns were observed in children with severe, therapy-resistant asthma. The increased expression of bronchodilatory bitter taste receptors suggests a new target for treatment of asthma.
European Respiratory Journal 12/2012; · 5.89 Impact Factor
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ABSTRACT: Children with problematic severe asthma (PA) have persistent symptoms and/or severe exacerbations despite treatment with several drugs. Classification of asthma severity is currently based on level of treatment and assessment of asthma control, but objective biomarkers of asthma severity are needed. To investigate the clinical relevance of basophil allergen threshold sensitivity (CD-sens) as a measure of allergen sensitivity in a well-characterized cohort of children with different manifestations of persistent allergic asthma. Cat-allergic children (6-18 yr) with problematic severe asthma (n = 11) according to GINA were compared with eleven age-matched children with controlled, but persistent asthma (CA). The protocol included standardized questionnaires, asthma control test (ACT), spirometry, methacholine challenges, measurement of FE(NO,) IgE, cat IgE and IgG antibodies, and analysis of CD-sens (CD63-expression) by flow cytometry. The 11 cat-allergic children with PA had a significantly lower ACT score (p < 0.001), reduced FEV(1) (p = 0.04), and increased numbers of blood eosinophils (p = 0.03) compared with the 11 children with CA. The former exhibited a higher CD-sens to cat (p = 0.02). No significant differences were detected with respect to FE(NO) (p = 0.17), IgE (p = 0.84), cat IgE (p = 0.12), and the major cat-allergen rFel d 1 (p = 0.30). CD-sens significantly correlated with ACT (p = 0.002, r = -0.63) and FE(NO) (p = 0.01, r = 0.55). No significant differences between PA and CA were found regarding IgG antibodies to rFel d 1. Cat-allergic children with problematic severe asthma have higher sensitivity to cat allergen, as measured by CD-sens, compared with children with controlled asthma. This suggests that CD-sens could be used as an additional marker for identifying children with the most severe allergic asthma.
Pediatric Allergy and Immunology 03/2012; 23(4):376-84. · 2.46 Impact Factor
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ABSTRACT: Children with problematic severe asthma (PA) are either difficult to treat because of the presence of aggravating factors or else severely resistant to therapy. We investigated a cohort of school-aged children with PA and compared these children to age-matched peers with controlled persistent asthma (CA). The aims were to characterize features of children suffering from PA and identify children who were severely resistant to therapy. In this cross-sectional, multicenter comparison of children with different manifestations of persistent asthma, PA was defined as insufficient asthma control despite level 4 treatment, according to GINA. The protocol included questionnaires, spirometry, methacholine provocation, measurement of fraction of nitric oxide in exhaled (FE(NO) ) and nasal air, blood sampling for inflammatory biomarkers and atopy, and computerized tomography of sinuses and lungs (in the PA group only). Of the 54 children with PA, 61% had therapy-resistant asthma, with the remaining being difficult to treat because of identified aggravating factors. Children with PA more often had parents with asthma (p=0.003), came from families with a lower socioeconomic status (p=0.01), were less physically active (p=0.04), and had more comorbidity with rhinoconjunctivitis (p=0.01) than did the 39 children with CA. The former also exhibited lower FEV(1) values (p=0.02) and increased bronchial hyper-responsiveness (p=0.01), but there were no differences in atopy (p=0.81) or FE(NO) (p=0.16). A non-invasive protocol, involving a standardized and detailed clinical characterization, revealed distinguishing features of children with PA and enabled the identification of children with therapy-resistant asthma.
Pediatric Allergy and Immunology 09/2010; 22(1 Pt 1):9-18. · 2.46 Impact Factor
