Inflammation and Corticosteroid Responsiveness in Severe Asthma
Inflammation and Corticosteroid Responsiveness in Severe Asthma
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.
Inclusion 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. Current smokers, and ex-smokers with greater than 10 pack years history of smoking.

 Exclusion criteria

 Pregnancy or unreliable contraceptive measures in child-bearing woman. he bronchoscopist
 has determined the subject is clinically appropriate for bronchoscopy

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 Exclusion Criteria:

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