Inflammation and Corticosteroid Responsiveness in Severe Asthma

Asthma

Severe asthma, corticosteroid responsiveness

Some patients with mild asthma may develop severe asthma. It is not known what makes patients with mild asthma become severe, and we plan to find out why this happens. Patients with severe asthma may have a different type of inflammation in the airway tubes. Patients with severe asthma do not get as much benefit from taking steroid inhalers or tablets compared to asthma patients with mild disease. The study hypothesis is that the inflammation in severe asthma is such that it makes steroids less effective in treating asthma. We will find out what possible abnormalities there are in the blood cells and the bronchoalveolar macrophage cells in the lungs of patients with severe asthma compared to those with mild or moderate 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. Sources and Recruitment of Subjects: Patients will be recruited from all patients referred to the Royal Brompton Hospital with a referral diagnosis of severe or difficult asthma for further management. The Royal Brompton Hospital is recognized nationally as a center for referral of such patients. 7Inclusion criteria The final diagnosis of severe asthma will be made according to the screening steps we have set up. The definition will require the presence of one or both major criteria (treatment with continuous or near continuous oral corticosteroids and/or requirement for treatment with high dose inhaled steroids) and two minor criteria. Patients who do not fit the criteria of severe asthma will not be entered into the study. Age 18-60; both sexes. For the investigation of fiberoptic bronchoscopy, other additional inclusion criteria will be imposed: 1. Post-bronchodilator FEV1 greater than 40% on the day of the bronchoscopy 2. No evidence of an exacerbation of asthma within the past 4 weeks. 3. Ability to cooperate with procedures 4. Ability to give consent 5. The bronchoscopist has determined the subject is clinically appropriate for bronchoscopy Patients will be excluded for fiberoptic bronchoscopy if: 1. FEV1 is less than 35% predicted before or less than 40% predicted after bronchodilator administration 2. Asthma is clinically unstable 3. Communication channels is not established for follow-up contacts 4. Clinically significant, unstable co-morbidities are present Exclusion criteria Current smokers, and ex-smokers with greater than 10 pack years history of smoking. Pregnancy or unreliable contraceptive measures in child-bearing woman. Volunteer subjects We will need comparative asthmatic subjects with mild to moderately severe asthma. The groups will be defined as follows, according to their need for treatments (as established in the Asthma Management GINA or BTS guidelines): (i) Mild: intermittent symptoms and need for reliever bronchodilator less than once a day; (ii) moderate asthma: well-controlled asthma with minimal symptoms while on inhaled corticosteroid therapy not exceeding 2,000 microgram beclomethasone equivalent . These patients will be recruited from the Asthma clinics attending the Royal Brompton Hospital, and also the milder patients will be recruited by advertisement within the Hospital, or from local general practices. Current involvement in research The patients entered into this study will not be involved in any other research project, and must have Completed any other project within a month of entry into the current study. From previous experience, we aim to recruit 12 patients with severe asthma per year; in total, 50 patients with severe asthma over a 4 year period. Concomitantly, we will recruit 40 mild-to-moderately severe asthma patients. Pharmacology and Dispensing (i) substance: Prednisolone tablets (ii) route of administration: Oral (iii) frequency : once a day (iv) dosage: 30 mg/day (or addition of 30 mg on top of maintainence dose) (v) stage of CSM evaluation: n/a.

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