Christophe Pedroletti

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.

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.

Nitric Oxide Airway Diffusing Capacity and Mucosal Concentration in Asthmatic Schoolchildren

Asthmatic patients show increased concentrations of nitric oxide (NO) in exhaled air (Feno). The diffusing capacity of NO in the airways (Dawno), the NO concentrations in the alveoli and the airway wall, and the maximal airway NO diffusion rate have previously been estimated noninvasively by measuring Feno at different exhalation flow rates in adults. We investigated these variables in 15 asthmatic schoolchildren (8–18 y) and 15 age-matched control subjects, with focus on their relation to exhaled NO at the recommended exhalation flow rate of 0.05 L/s (Feno0.05), age, and volume of the respiratory anatomic dead space. NO was measured on-line by chemiluminescence according to the European Respiratory Societys guidelines, and the NO plateau values at three different exhalation flow rates (11, 99, and 382 mL/s) were incorporated in a two-compartment model for NO diffusion. The NO concentration in the airway wall (p < 0.001), Dawno (p < 0.01), and the maximal airway NO diffusion rate (p < 0.001) were all higher in the asthmatic children than in control children. In contrast, there was no difference in the NO concentration in the alveoli (p = 0.13) between the groups. A positive correlation was seen between the volume of the respiratory anatomic dead space and Feno0.05 (r = 0.68, p < 0.01), the maximal airway NO diffusion rate (r = 0.71, p < 0.01), and Dawno (r = 0.56, p < 0.01) in control children, but not in asthmatic children. Feno0.05 correlated better with Dawno in asthmatic children (r = 0.65, p < 0.01) and with the NO concentration in the airway wall in control subjects (r < 0.77, p < 0.001) than vice versa. We conclude that Feno0.05 increases with increasing volume of the respiratory anatomic dead space in healthy children, suggesting that normal values for Feno0.05 should be related to age or body weight in this age group. Furthermore, the elevated Feno0.05 seen in asthmatic children is related to an increase in both Dawno and NO concentration in the airway wall. Because Dawno correlates with the volume of the respiratory anatomic dead space in control subjects and Feno0.05 correlates with Dawno in asthmatic children, we suggest that Dawno partly reflects the total NO-producing surface area and that a larger part of the bronchial tree produces NO in asthmatic children than in control children.

Evaluation of Exhaled Nitric Oxide in Schoolchildren at Different Exhalation Flow Rates

Nitric oxide (NO) in exhaled air is believed to reflect allergic inflammation in the airways. Measured levels of exhaled NO vary with the exhaled flow rate, which therefore must be standardized. The aim of this study was to estimate the optimal exhalation flow rate when measuring NO in exhaled air. We studied 15 asthmatic children (8-18 y) with elevated NO levels and 15 age-matched controls and focused on how the quality of the NO curve profile, the discriminatory power, and the reproducibility were influenced by the exhalation flow rate. We used an on-line system for NO measurements at six different exhalation flow rates in the interval of 11-382 mL/s. The fraction of exhaled nitric oxide (FENO) was highly flow-dependent as was expected. Intermediate flow rates yielded a flat and stable NO plateau and were considerably easier to interpret than those obtained at the highest and lowest flow rates. The ratio of FENO between asthmatics and controls was lower at higher flow rates and a considerable overlap in NO values was demonstrated at all flow rates except 50 mL/s. The reproducibility was much lower at more extreme flow rates and was best at 50 mL/s. We conclude that a target exhalation flow rate of approximately 50 mL/s is to be preferred using the single-breath method for on-line NO measurements in schoolchildren.

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.

Effect of nasal steroid treatment on airway inflammation determined by exhaled nitric oxide in allergic schoolchildren with perennial rhinitis and asthma

Rhinitis is common in asthmatic schoolchildren who are allergic to animal dander and constantly and indirectly exposed to these allergens in their everyday environment. As a patho‐physiological linkage between nasal and bronchial inflammation has been proposed to exist, the primary objective of this study was to determine whether nasal administration of mometasone furoate (MSNF) can reduce bronchial inflammation, as reflected in the level of exhaled nitric oxide (FENO) in asthmatic schoolchildren with dander allergy and mild‐to‐moderate rhinitis. Forty such children were assigned randomly to be treated for 4 wk with MSNF or placebo, employing a double‐blind procedure. FENO was the primary end‐point measured and secondary end‐points were nasal levels of NO, the concentration of eosinophilic cationic protein (ECP) in nasal lavage, the relative numbers of eosinophils in blood, forced expiratory volume in 1 s (FEV1), peak expiratory flow (PEF) and scoring of symptoms. There was no significant difference in the FENO values of the treated and control groups at any time‐point, whereas the nasal level of ECP was lower in the treated group compared with placebo (p = 0.05) on both days 7 and 28, and compared with baseline for the treated group (p = 0.06 on day 7, p = 0.02 on day 28). Furthermore, the mean blood eosinophil count decreased in the treated group, which also demonstrated lower scores for nasal symptoms compared with placebo, but neither of these differences were statistically significant. FEV1, PEF and nasal levels of NO remained unchanged in both groups. Four weeks of nasal treatment with MSNF had no effect on bronchial inflammation, as reflected by exhaled NO, whereas signs of nasal and systemic eosinophil activation were reduced. Thus, nasal administration of a steroid as a strategy to reduce asthmatic inflammation remains questionable in mild‐to‐moderately severe cases of perennial rhinitis and 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.

Exhaled nitric oxide in asthmatic children and adolescents after nasal allergen challenge.

Epidemiological data suggest a comorbidity link between nasal and bronchial allergic disease. Exhaled nitric oxide (FENO) is a sensitive marker of bronchial inflammation and increases after bronchial allergen provocation. We studied FENO in 19 children and adolescents with allergic asthma and 10 controls before and 2, 6 and 24 h after a single nasal allergen challenge. The correlation between FENO and other markers of allergic inflammation, such as eosinophils in blood and eosinophil cationic protein (ECP) in serum and nasal lavage was also assessed. FENO remained unchanged 24 h post‐challenge in both steroid and steroid‐naïve patients. At 6 h post‐challenge, FENO decreased in both asthmatics and controls. The asthmatic subjects showed a positive correlation between FENO and blood eosinophils before (r = 0.71, p = 0.001) and after the challenge, and between FENO and ECP in nasal lavage (r = 0.62, p = 0.02) 2 h after the challenge. Mean ECP in nasal lavage increased post‐challenge but not significantly. We conclude that a single nasal allergen challenge does not augment bronchial inflammation although FENO, is related to blood eosinophil count and to the nasal inflammatory response. Our data do not support the theory of a direct transmission of the nasal inflammation to the lower airways.