Inflammation and Corticosteroid Responsiveness in Severe Asthma

Study Design Patients referred to the Royal Brompton Hospital with severe asthma will be entered into a protocol that will determine whether they have asthma, and if so, the severity and clinical features of their asthma. Patients will also undergo investigations relating to asthma as detailed below. We will use an agreed Severe Asthma Research protocol (SARP) screening system to diagnose asthma (history, bronchodilator response and presence of bronchial hyperresponsiveness) (Screening questionnaire in SARP Handbook). Usually, the protocol will be carried out while the patient is admitted over 3-night admission.

Patients will undergo fiberoptic bronchoscopy. We will obtain cells by bronchoalveolar lavage and bronchial biopsies of the airway mucosa. These cells and biopsies will be studied in vitro as to the expression of corticosteroid receptor nuclear translocation, expression of cytokines, and the degree of histone acetylation/deacetylation status. These findings will be compared to those cells and biopsies obtained from mild and moderately severe asthma.

In a subgroup of patients with severe asthma, patients will be treated with oral prednisolone 40 mg/day or increase in maintenance dose of prednisolone by 40 mg/day. Fiberoptic bronchoscopy will then be repeated.

Details of the interventions proposed Some of the interventions listed below are in routine clinical use for investigation of severe asthma. For example, the computed tomogram is only ordered on clinical grounds. A fiberoptic bronchoscopy will be performed.

1. Demographic history and history of their symptoms of asthma and treatments using a comprehensive questionnaire
2. Quality of life questionnaire (AQLQ)
3. Skin prick tests to 16 common allergens
4. Measuring lung function tests
5. Bronchial responsiveness to methacholine
6. Bronchial reversibility test to inhaled salbutamol
7. Keeping a diary card of symptoms, treatments and peak flows for 2 weeks
8. Observance of compliance to treatments
9. Provision of sample of sputum, spontaneous or induced
10. Measuring exhaled nitric oxide; collecting of exhaled breath condensates
11. Fiberoptic bronchoscopy to obtain bronchoalveolar lavage cells, bronchial brushings and bronchial biopsies
12. Obtaining sample of blood for DNA extraction for genetic analysis
13. Obtaining blood for blood mononuclear cells for in vitro analysis of the effects of corticosteroids In patients with mild-to-moderate asthma, test 8 will not be performed. The details of these interventions are enclosed in the SARP Handbook.