Björn Nordlund

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.

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.

The clinical benefit of evaluating health-related quality-of-life in children with problematic severe asthma

Aim:  To evaluate health‐related quality‐of‐life (HR‐QoL) and the asthma control test (ACT) in children with problematic severe asthma and those with controlled asthma and to identify whether clinical characteristics show correlations with these measurements.

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.

Prevalence of severe childhood asthma according to the WHO

BACKGROUND The World Health Organization (WHO) recently proposed a new definition of severe asthma to facilitate standardized characterization of patients, and enable more accurate estimations of the prevalence of severe asthma. The aim of this study was to estimate the prevalence of severe asthma according to the WHO definition in children aged 12 years, in Stockholm, Sweden. METHODS The birth cohort BAMSE enrolled 4089 children during 1994-96. Parental questionnaires provided information on asthma-related symptoms, diagnosis and medication from 3015 enrolled children at the age of 12 years. Severe asthma was defined as the presence of asthma, as well as continuous treatment with inhaled corticosteroids and long-acting beta-2 agonists, based on information from the Swedish prescribed drug register demonstrating prescriptions of at least 800 μg budesonide daily (or equivalent). RESULTS The prevalence of asthma was 11% among 12-year-olds (n = 329). Based on information from the Swedish prescribed drug register, seven children with asthma fulfilled the definition of severe asthma. The estimated prevalence corresponds to 0.23% (95% CI, 0.06-0.4) of the population, or 2.1% (95% CI, 0.5-3.7) of children with asthma. Based on assessed markers of asthma control, 3/7 with severe asthma were considered to have controlled asthma and 4/7 had partly or uncontrolled asthma. CONCLUSION Severe asthma appears rare both among 12-year-old schoolchildren with asthma and in the general population. Combining self-reported information from a population-based birth cohort with data from a drug register seems trustworthy in estimating severe asthma as defined by the WHO.

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.

High basophil allergen sensitivity (CD-sens) is associated with severe allergic asthma in children

To cite this article: Konradsen JR, Nordlund B, Nilsson OB, van Hage M, Nopp A, Hedlin G, Grönlund H. High basophil allergen sensitivity (CD‐sens) is associated with severe allergic asthma in children. Pediatr Allergy Immunol 2012: 23: 376–384.

Allergy testing in children with persistent asthma: comparison of four diagnostic methods

Multiple allergic sensitizations are common in persistent childhood asthma, and thorough assessment of allergy is crucial for optimal care of these children. Microarray testing offers opportunities for improved sIgE characterization, which has been projected to be useful in the management of multisensitized patients.