Clustering based on clinicophysiologic parameters yielded 4 stable and reproducible clusters that associate with different pathobiological pathways.

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 (n517), controlled asthma (n519) and healthy controls (n518). Receptor expression was studied in separated leukocyte fractions from asthmatic adults (n512).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. @ERSpublications Bitter taste receptors are up-regulated in children with severe asthma, suggesting a new therapeutic target

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Rationale: Serum chitinases may be novel biomarkers of airway inflammation and remodeling, but less is known about factors regulating their levels.Objectives: To examine serum chitotriosidase activity and YKL-40 levels in patients with asthma and chronic obstructive pulmonary disease (COPD) and evaluate clinically relevant factors that may affect chitinase levels, including genetic variability, corticosteroid treatment, disease exacerbations, and allergen exposure.Methods: Serum chitotriosidase (CHIT1) activity and YKL-40 (CHI3L1) levels, as well as the CHIT1 rs3831317 and CHI3L1 rs4950928 genotypes, were examined in subsets of patients with mild to moderate asthma (n = 76), severe asthma (n = 93), and COPD (n = 64) taking part in the European multicenter BIOAIR (Longitudinal Assessment of Clinical Course and Biomarkers in Severe Chronic Airway Disease) study. Blood was obtained at baseline, before and after a 2-week oral steroid intervention, up to six times during a 1-year period, and during exacerbations. Baseline chitinase levels were also measured in 72 healthy control subjects. The effect of allergen inhalation on blood and sputum YKL-40 levels was measured in two separate groups of patients with mild atopic asthma; one group underwent repeated low-dose allergen challenge (n = 15), and the other underwent high-dose allergen challenge (n = 16).Measurements and Main Results: Serum chitotriosidase and YKL-40 were significantly elevated in patients with asthma and those with COPD compared with healthy control subjects. Genotype and age strongly affected both YKL-40 and chitotriosidase activity, but associations with disease remained following adjustment for these factors. Correlations were observed with lung function but not with other biomarkers, including exhaled nitric oxide, blood eosinophils, periostin, and IgE. Generally, acute exacerbations, allergen-induced airway obstruction, and corticosteroid treatment did not affect circulating chitinase levels.Conclusions: YKL-40 and chitotriosidase are increased in asthma and more so in COPD. The data in the present study support these substances as being relatively steroid-insensitive, non-T-helper cell type 2-type biomarkers distinctly related to chronic inflammatory disease processes.

The aim of this study was to compare exhaled nitric oxide concentrations obtained during controlled slow exhalation, presently considered as the method of choice, with two sampling methods that are easily performed by children: blowing air into a balloon and tidal breathing through a mouthpiece.One hundred and one well controlled, stable allergic asthmatic children (median age 11.7 yrs) performed the following tasks in duplicate: 1) exhalation from total lung capacity through a mouthpiece against a resistor with a standardized flow rate of 20% of the subject's vital capacity per second, using a biofeedback system; 2) a single deep exhalation into an NO-impermeable mylar balloon; and 3) tidal breathing through a low resistance mouthpiece over 2 min. NO was measured using a chemiluminescence analyser.Twenty-nine children (29%) were not able to perform a constant-flow exhalation of at least 3 s. All children performed the balloon and tidal breathing methods without difficulty. NO concentrations (meansSEM) were 5.30.2 parts per billion (ppb) at the end-expiratory plateau, 5.20.3 ppb in balloons (intraclass correlation coefficient (r i )=0.73) and 8.00.4 ppb during tidal breathing (p<0.001, r i =0.53 compared to plateau values). Mean values of NO during tidal breathing increased significantly with time, suggesting increasing contamination with nasal air.It was concluded that, in asthmatic children, the end-expiratory plateau concentration of nitric oxide during exhalation at 20% of the vital capacity per second is similar to the values obtained with the balloon method, with satisfactory agreement, but differs from values obtained during tidal breathing. The balloon method is cheap, simple and offers the interesting possibility to study exhaled nitric oxide in young children independently of the presence of a nitric oxide analyser. Eur Respir J 1999; 13: 1406±1410.