Glucocorticoid receptor ß and histone deacetylase 1 and 2 expression in the airways of severe asthma.

RATIONALE: Upregulation of glucocorticoid receptor ß (GRß) has been implicated in steroid resistance in severe asthma, although previous studies are conflicting. GRß has been proposed as a dominant negative isoform of glucocorticoid receptor α (GRα) but it has also been suggested that GRß can cause steroid resistance via reduced expression of histone deacetylase 2 (HDAC2), a key regulator of steroid responsiveness in the airway. OBJECTIVES: To examine GRß, GRα, HDAC1 and HDAC2 expression at transcript and protein levels in bronchial biopsies from a large series of patients with severe asthma, and to compare the findings with those of patients with mild to moderate asthma and healthy volunteers. METHODS: Bronchoscopic study in two UK centres with real-time PCR and immunohistochemistry performed on biopsies, western blotting of bronchial epithelial cells and immunoprecipitation with anti-GRß antibody. MEASUREMENTS AND MAIN RESULTS: Protein and mRNA expression for GRα and HDAC2 did not differ between groups. GRß mRNA was detected in only 13 of 73 samples (seven patients with severe asthma), however immunohistochemistry showed widespread epithelial staining in all groups. Western blotting of bronchial epithelial cells with GRß antibody detected an additional 'cross-reacting' protein, identified as clathrin. HDAC1 expression was increased in patients with severe asthma compared with healthy volunteers. CONCLUSIONS: GRß mRNA is expressed at low levels in a minority of patients with severe asthma. HDAC1 and HDAC2 expression was not downregulated in severe asthma. These data do not support upregulated GRß and resultant reduced HDAC expression as the principal mechanism of steroid resistance in severe asthma. Conflicting GRß literature may be explained in part by clathrin cross-reactivity with commercial antibodies.

Exhaled nitric oxide in relation to the clinical features of childhood asthma.

BACKGROUND: Exhaled nitric oxide (ENO) has been shown to be a noninvasive marker of eosinophilic inflammation in asthmatic children. Few studies have evaluated the relationship between ENO levels and the clinical features of children with asthma. The aim of this study was to examine children attending a routine asthma clinic and evaluate the relationship between ENO levels and clinical parameters including decision making. METHODS: Asthmatic children (n= 133, aged 5 to 14 years) attending a hospital asthma clinic were studied. ENO levels were measured and compared between subgroups of subjects according to recent symptoms, asthma control and treatment, and the clinician's decision (blinded to ENO levels) regarding further management. RESULTS: ENO levels (median [IQR] ppb) were significantly elevated in children who had recent symptoms compared to those without recent symptoms (14.6 [6.5 to 45.3] vs. 6.0 [3.2 to 17.4], difference between medians 8.6, 95% confidence interval [CI] (1.8 to 13.9, p=0.004). ENO levels differed significantly between the controlled and uncontrolled subgroups (8.5 [4.2 to 26.4] vs. 26.4 [5.0 to 62.0], difference between medians 17.9, 95% CI 0.1 to 22.8, p=0.03) and between the three treatment decision subgroups (up, down, or unchanged; p < 0.001). CONCLUSIONS: ENO levels are strongly related to the clinical features of childhood asthma and the clinical decision making process. To fully evaluate the role of ENO in the clinical management of asthma, this "proof of concept" study paves the way for prospective randomized trials of the inclusion of ENO levels in the decision making process in childhood asthma.

Psychogenic cough in a schoolboy: evaluation using an ambulatory cough recorder.

Psychogenic cough occurs most commonly in patients under 18 years of age. Making the diagnosis on clinical features alone is problematic, and it is usually a diagnosis of exclusion after several negative clinical investigations. We report on the case of a 13-year-old schoolboy with a 3-month history of persistent dry cough with no other associated symptoms. Clinical examination and investigations revealed no abnormality, and empirical trials of antiasthma and antacid medications proved unsuccessful. An objective assessment of his cough frequency was made using an ambulatory cough monitor. A large number of cough episodes were recorded during the day, but during the time he was in bed there were very few episodes recorded. This suggested a diagnosis of psychogenic cough, and he underwent behavior modification therapy under the guidance of a clinical psychologist, with good result. Objective cough monitoring may therefore improve the evaluation and management of chronic cough.

Possible association between passive smoking and lower exhaled nitric oxide in asthmatic children.

In adults, both active and passive smoking reduce levels of exhaled nitric oxide (eNO); however, to date, passive exposure to environmental tobacco smoke (ETS) has not been shown to affect eNO in children. The authors recruited 174 asthmatic children (96 male, 78 female) and 79 nonasthmatic controls (46 male, 33 female) from a group of children aged 5 to 14 yr who attended a children's hospital for an outpatient visit or elective surgery. Each subject's exposure to ETS was ascertained by questionnaire, and their eNO levels were measured. Asthmatic children had higher eNO levels (ppb) than nonasthmatic children (p = 0.04), and asthmatic children exposed to ETS had significantly lower eNO levels than unexposed children (p = 0.005). Exposure to ETS did not alter eNO levels in nonasthmatic children (p = 0.4). Results of the study suggest that ETS exposure is associated with lower eNO levels among childhood asthmatics. Consequently, ETS exposure may need to be considered when physicians interpret eNO levels in asthmatic children. Further study of the effects of ETS on eNO levels is recommended.