Jon R. Konradsen

The chitinase-like protein YKL-40: a possible biomarker of inflammation and airway remodeling in severe pediatric asthma

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.

Transcriptome analysis reveals upregulation of bitter taste receptors in severe asthmatics

The causes of severe childhood asthma are poorly understood. Our aim was 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 (n=17), controlled asthma (n=19) and healthy controls (n=18). Receptor expression was studied in separated leukocyte fractions from asthmatic adults (n=12). Overall, 1378 genes were differentially expressed between children with severe/controlled asthma and controls. Three significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways were represented: natural killer cell-mediated cytotoxicity (upregulated in controlled asthma); N-glycan biosynthesis (downregulated in severe asthma); and bitter taste transduction receptors (TAS2Rs) (upregulated in severe asthma). Quantitative PCR experiments confirmed upregulation of TAS2Rs in severe asthmatics. TAS2R expression was replicated in leukocytes from adult asthmatics, in which TAS2R agonists also inhibited LPS-induced cytokine release. Significant correlations between expression of 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 TAS2Rs suggests a new target for the treatment of asthma.

IgE antibodies to animal‐derived lipocalin, kallikrein and secretoglobin are markers of bronchial inflammation in severe childhood asthma

Component‐resolved allergy diagnostics enables the detection of crossreactive or species‐specific allergen components. This study analysed Immunoglobulin E (IgE) profiles to single allergen components in relation to bronchial inflammation in severe childhood asthma.

Crystal structure of the dog lipocalin allergen Can f 2: implications for cross-reactivity to the cat allergen Fel d 4.

The dog lipocalin allergen Can f 2 is an important cause of allergic sensitization in humans worldwide. Here, the first crystal structure of recombinant rCan f 2 at 1.45 A resolution displays a classical lipocalin fold with a conserved Gly-Xaa-Trp motif, in which Trp19 stabilizes the overall topology of the monomeric rCan f 2. Phe38 and Tyr84 localized on the L1 and L5 loops, respectively, control access to the highly hydrophobic calyx. Although the rCan f 2 calyx is nearly identical with the aero-allergens MUP1, Equ c 1 and A2U from mouse, horse and rat, respectively, no IgE cross-reactivity was found using sera from five mono-sensitized subjects. However, clear IgE cross-reactivity was demonstrated between Can f 2 and the cat allergen Fel d 4, although they share less than 22% sequence identity. This suggests a role for these allergens in co-sensitization between cat- and dog-allergic patients.

Problematic severe asthma: A proposed approach to identifying children who are severely resistant to therapy

To cite this article: Konradsen JR, Nordlund B, Lidegran M, Pedroletti C, Gro¨nlund H, van Hage M, Dahlen B, Hedlin G and In Cooperation with the Swedish network of Pediatric Allergists, Severe Asthma Network. Problematic severe asthma: A proposed approach to identifying children who are severely resistant to therapy. Pediatric Allergy Immunology 2011: 22: 9–18.

Severe childhood asthma and allergy to furry animals : Refined assessment using molecular-based allergy diagnostics

Allergy to cats and dogs and polysensitization towards these animals are associated with severe childhood asthma. Molecular‐based allergy diagnostics offers new opportunities for improved characterization and has been suggested to be particularly useful in patients with polysensitization and/or severe asthma. The aim was to use extract‐ and molecular‐based allergy diagnostics to compare patterns of IgE sensitization towards aeroallergens in children with problematic severe and controlled asthma.

Identifying problematic severe asthma in the individual child – does lung function matter?*

Aim:  Measures of lung function (usually FEV1 <80% predicted) are used to classify asthma severity in both adults and children, despite evidence that lung function impairment is less pronounced in the paediatric asthma population. The present study assesses the relevance of lung function measurements as discriminators of severe childhood asthma.

An update on paediatric asthma

In this Update we will discuss aspects of the definitions, epidemiology, diagnostics, asthma-associated comorbidities, assessment and treatment of asthma including a specific focus on severe asthma in school children. The Update will mainly cover data published during the last 3 yrs. In 2009, an expert panel was tasked to propose a World Health Organization definition of asthma severity and control. The result of this Task Force was a uniform definition of asthma severity, control and exacerbation [1]. As we will discuss later in an overview of asthma outcomes [2], symptom evaluation is the key to the diagnosis and outcome measures in clinical studies. Airway inflammation is one of the pathophysiological characteristics of asthma, which is mediated through infiltration of inflammatory cells, including mast cells, and eosinophilic and neutrophilic granulocytes in the airway wall. This cell infiltration subsequently leads to bronchial hyperresponsiveness (BHR) and, in the case of chronic inflammation, persistent changes of the airways, i.e. airway remodelling [3, 4]. Immunoglobulin (Ig)E-mediated allergy leading to allergic inflammation is common among children with persistent asthma. There are ongoing studies worldwide (the MeDALL initiative) aiming to identify allergic phenotypes [5] and understand the complexity of the IgE related phenotypes in children and adults [6]. The purpose of paediatric asthma treatment is for the child to control symptoms, to be able to lead a normal active life, to have normal lung function and to prevent asthma exacerbations [7, 8]. The care of asthmatic children does not only include the prescription of asthma medication. The families need to be convinced and educated to actually make the parents give the medication as prescribed and in a proper manner [9]. Furthermore, healthcare providers must teach the families how to avoid or …

Predicting asthma morbidity in children using proposed markers of Th2-type inflammation.

Assessment of inflammation is becoming a common practice in the clinical work‐up of children with persistent asthma. Biomarkers of Th2‐mediated inflammation include blood eosinophils (B‐Eos), exhaled nitric oxide (FeNO), total serum IgE (S‐IgE), and serum periostin. The aim of this study was to investigate the associations between asthma morbidity and increased levels of these biomarkers in pediatric asthma.

Subnormal levels of vitamin D are associated with acute wheeze in young children

This study evaluated risk factors for acute wheeze in preschool children and investigated whether subnormal levels of vitamin D were associated with increased risk for acute wheeze, atopy or viral/bacterial respiratory infections.