Bronchial epithelial cell transcriptional responses to inhaled corticosteroids dictate severe asthmatic outcomes.

BACKGROUND: Inhaled corticosteroids (CSs) are the backbone of asthma treatment, improving quality of life, exacerbation rates, and mortality. Although effective for most, a subset of patients with asthma experience CS-resistant disease despite receiving high-dose medication. OBJECTIVE: We sought to investigate the transcriptomic response of bronchial epithelial cells (BECs) to inhaled CSs. METHODS: Independent component analysis was performed on datasets, detailing the transcriptional response of BECs to CS treatment. The expression of these CS-response components was examined in 2 patient cohorts and investigated in relation to clinical parameters. Supervised learning was used to predict BEC CS responses using peripheral blood gene expression. RESULTS: We identified a signature of CS response that was closely correlated with CS use in patients with asthma. Participants could be separated on the basis of CS-response genes into groups with high and low signature expression. Patients with low expression of CS-response genes, particularly those with a severe asthma diagnosis, showed worse lung function and quality of life. These individuals demonstrated enrichment for T-lymphocyte infiltration in endobronchial brushings. Supervised machine learning identified a 7-gene signature from peripheral blood that reliably identified patients with poor CS-response expression in BECs. CONCLUSIONS: Loss of CS transcriptional responses within bronchial epithelium was related to impaired lung function and poor quality of life, particularly in patients with severe asthma. These individuals were identified using minimally invasive blood sampling, suggesting these findings may enable earlier triage to alternative treatments.

Characteristics of perimenstrual asthma and its relation to asthma severity and control: data from the Severe Asthma Research Program.

BACKGROUND: Although perimenstrual asthma (PMA) has been associated with severe and difficult-to-control asthma, it remains poorly characterized and understood. The objectives of this study were to identify clinical, demographic, and inflammatory factors associated with PMA and to assess the association of PMA with asthma severity and control. METHODS: Women with asthma recruited to the National Heart, Lung, and Blood Institute Severe Asthma Research Program who reported PMA symptoms on a screening questionnaire were analyzed in relation to basic demographics, clinical questionnaire data, immunoinflammatory markers, and physiologic parameters. Univariate comparisons between PMA and non-PMA groups were performed. A severity-adjusted model predicting PMA was created. Additional models addressed the role of PMA in asthma control. RESULTS: Self-identified PMA was reported in 17% of the subjects (n = 92) and associated with higher BMI, lower FVC % predicted, and higher gastroesophageal reflux disease rates. Fifty-two percent of the PMA group met criteria for severe asthma compared with 30% of the non-PMA group. In multivariable analyses controlling for severity, aspirin sensitivity and lower FVC % predicted were associated with the presence of PMA. Furthermore, after controlling for severity and confounders, PMA remained associated with more asthma symptoms and urgent health-care utilization. CONCLUSIONS: PMA is common in women with severe asthma and associated with poorly controlled disease. Aspirin sensitivity and lower FVC % predicted are associated with PMA after adjusting for multiple factors, suggesting that alterations in prostaglandins may contribute to this phenotype.

Urinary bromotyrosine measures asthma control and predicts asthma exacerbations in children.

OBJECTIVES: To determine the usefulness of urinary bromotyrosine, a noninvasive marker of eosinophil-catalyzed protein oxidation, in tracking with indexes of asthma control and in predicting future asthma exacerbations in children. STUDY DESIGN: Children with asthma were recruited consecutively at the time of clinic visit. Urine was obtained, along with spirometry, exhaled nitric oxide, and Asthma Control Questionnaire data. Follow-up phone calls were made 6 weeks after enrollment. RESULTS: Fifty-seven participants were enrolled. Urinary bromotyrosine levels tracked significantly with indexes of asthma control as assessed by Asthma Control Questionnaire scores at baseline (R = 0.38, P = .004) and follow-up (R = 0.39, P = .008). Participants with high baseline levels of bromotyrosine were 18.1-fold (95% CI 2.1-153.1, P = .0004) more likely to have inadequately controlled asthma and 4.0-fold more likely (95% CI 1.1-14.7, P = .03) to have an asthma exacerbation (unexpected emergency department visit; doctor's appointment or phone call; oral or parenteral corticosteroid burst; acute asthma-related respiratory symptoms) over the ensuing 6 weeks. Exhaled nitric oxide levels did not track with Asthma Control Questionnaire data; and immunoglobulin E, eosinophil count, spirometry, and exhaled nitric oxide levels failed to predict asthma exacerbations. CONCLUSIONS: Urinary bromotyrosine tracks with asthma control and predicts the risk of future asthma exacerbations in children.