The Investigators hypothesise that asthma is not a single disease, but a syndrome resulting from several distinct underlying disease processes known as endotypes. There are approximately 30,000 genes in humans, and each gene is responsible for the production of a particular protein. Using a technique called "whole genome expression profiling" The Investigators have undertaken a small study looking at the activity of all 30,000 genes in the airway tissue of people with asthma. This work has identified 3 mutually exclusive distinct molecular patterns (endotypes) of severe asthma and has identified other potentially important molecular targets (manuscripts in preparation). In particular,the Investigators have found that 25-50% of patients have asthma associated with the activity of proteins called Th2 cytokines (Th2-high asthma). New treatments are in development that target this pathway. However, the Investigators do not know what is driving severe asthma in patients who do not express these Th2 cytokines. The aim of this study is to investigate in more detail the molecular mechanisms driving severe asthma in patients who do not express Th2 cytokines (Th2-low asthma), so that the Investigators can identify new targets for treatment in this group. To do this the Investigators will collect airway tissue via a telescope (bronchoscope), and analyse gene and protein expression in the tissue. The Investigators will then compare the molecular activity between patients with Th2-high and Th2-low asthma, and healthy control subjects (data obtained from a parallel study).

Asthma is a very common disorder which causes a great deal of distress for patients, and occasionally results in premature death. Approximately 10% of people with asthma have severe disease which is not helped by current treatments; The Investigators need to find new treatments for these patients urgently. Patients with asthma are not all the same, but have distinct features which characterise their asthma.The Investigators therefore hypothesise that asthma is not a single disease, but a syndrome resulting from several distinct underlying disease processes known as endotypes. There are approximately 30,000 genes in humans, and each gene is responsible for the production of a particular protein. Using a technique called "whole genome expression profiling" The Investigators have undertaken a small study looking at the activity of all 30,000 genes in the airway tissue of people with asthma. This work has identified 3 mutually exclusive distinct molecular patterns (endotypes) of severe asthma and has identified other potentially important molecular targets (manuscripts in preparation).

In particular, the Investigators have found that 25-50% of patients have asthma associated with the activity of proteins called Th2 cytokines (Th2-high asthma). New treatments are in development that target this pathway. However, the Investigators do not know what is driving severe asthma in patients who do not express these Th2 cytokines. The aim of this study is to investigate in more detail the molecular mechanisms driving severe asthma in patients who do not express Th2 cytokines (Th2-low asthma), so that the Investigators can identify new targets for treatment in this group. To do this the Investigators will collect airway tissue via a telescope (bronchoscope), and analyse gene and protein expression in the tissue. The Investigators will then compare the molecular activity between patients with Th2-high and Th2-low asthma, and healthy control subjects (data obtained from a parallel study).

Inclusion Criteria:

1. Ability and willingness to provide written informed consent and to comply with the study protocol

2. Age 18-65 years at the time of informed consent

3. Severe asthma (BTS treatment step 4/5) despite intensive follow-up by an asthma specialist for at least 3 months

4. Diagnosis of asthma at least 12 months prior to informed consent

5. Baseline post bronchodilator FEV1 ≥ 40% of predicted

6. History of asthma treatment with high doses of inhaled glucocorticosteroids ( ≥1000 μg fluticasone propionate daily or equivalent (Clenil [BDP] 2000 μg, Fostair [BDP] 800 μg, fluticasone furoate 192 μg, budesonide dry powder 1600 μg, ciclesonide 640 μg), and LABA, with or without an additional controller, for at least 3 months prior to screening or previous corticosteroid optimisation (RASP workstrand 1).

7. For patients using oral corticosteroids, adherence with oral prednisolone regimen, as demonstrated by detectable serum prednisolone and evidence of suppressed cortisol within 6 hours of reported daily dose on at least one occasion during the screening period

8. Assessment according to the standards of the BTS UK Difficult Asthma Network or equivalent

9. Chest X-ray or computed tomography (CT) scan obtained within 12 months prior to consent (Visit 1) or chest X-ray during the screening period (prior to Visit 2) confirming the absence of other clinically significant lung disease

10. Documented history of bronchodilator reversibility response of ≥12% and ≥ 200 mL within the past 18 months, as demonstrated by any of the following:

    i) Documented airflow obstruction (FEV1/forced vital capacity [FVC] <70%), where FEV1 has varied by ≥ 12% either spontaneously or in response to oral corticosteroid therapy, or ii) PC20 (provocative concentration of methacholine producing a 20% fall in FEV1) to methacholine <8 mg/mL indicating the presence of airway hyperresponsiveness, or iii) change in FEV1 by ≥ 12% and ≥200 mL after acute reversibility testing with 400 μg albuterol or 2.5-5 mg nebulized salbutamol

    Exclusion Criteria:

    • Treatment with intravenous [IV], intramuscular [IM]) or intraarticular corticosteroids within 4 weeks prior to Visit 1 or during the screening period for any reason, including an acute exacerbation event

    • A severe asthma exacerbation requiring oral corticosteroids within 4 weeks. The patient has had an exacerbation of asthma requiring the new administration of oral steroids or an increase of at least 10 mg in their usual oral prednisolone dose within the last 4 weeks - defined from the last day of adjusted prednisolone therapy (such patients can re-screened >4 weeks from the last exacerbation)..

    • Infection that meets any of the following criteria:

      • Any infection that resulted in hospital admission for ≥24 hours within 4 weeks prior to Visit 1 or during screening
      • Any infection that required treatment with IV or IM antibiotics within 4 weeks prior to Visit 1 or during screening
      • Any active infection that required treatment with oral antibiotics within 2 weeks prior to Visit 1 or during screening
      • Upper or lower respiratory tract infection within 4 weeks prior to Visit 1 or during screening
      • Antibiotics include any antimicrobial therapy used to treat bacterial, fungal, parasitic, viral, or other infections. Antibiotics prescribed for lung infection prophylaxis would also exclude the patient.

    • Active tuberculosis requiring treatment within 12 months prior to Visit 1 Patients who have completed treatment for tuberculosis at least 12 months prior to Visit 1 and have no evidence of recurrent disease are permitted.

    • Known immunodeficiency, including, but not limited to, HIV infection

    • Evidence of acute or chronic hepatitis or known liver cirrhosis

    • AST, ALT, or total bilirubin elevation ≥ 2.0x the upper limit of normal (ULN) during screening

    • Clinically significant abnormality on screening electrocardiogram (ECG) or laboratory tests (haematology, serum chemistry, and urinalysis) that, in the opinion of the investigator, may pose an additional risk of bronchoscopy

    • History of clinically significant lung disease other than asthma

    • Known current malignancy or current evaluation for a potential malignancy

    • Unable to safely undergo elective flexible fiberoptic bronchoscopy because of any one of the following:

      • History of allergic reactions to local anesthetics to be used in the procedure
      • History of a clinically significant clotting abnormality, including on Screening Coagulation Panel
      • History of acute myocardial infarction, unstable angina, or other medical conditions that, in the opinion of the investigator, may make the patient unsuitable for elective bronchoscopy

    • Other clinically significant medical disease that is uncontrolled despite treatment, that is likely, in the opinion of the investigator, to impact the patient's ability to participate in the study

    • Current smoker, former smoker with smoking history of >15 pack-years A current smoker is defined as someone who has smoked at least one cigarette per day (or pipe, cigar, or marijuana) for ≥ 30 days within the 12 months prior to Visit 1. A pack-year is defined as the average number of packs of cigarettes per day times the number of years of smoking.

    • Use of a licensed or investigational monoclonal antibody including anti-IL 13, anti-IL-4/IL-13, omalizumab, anti-IL-5, or anti-IL 17, within 6 months or 5 drug half-lives prior to Visit 1 (whichever is longer) or during screening

    • Use of a systemic immunomodulatory or immunosuppressive therapy (other than a monoclonal antibody or corticosteroids [see separate exclusion]) within 3 months or 5 drug half-lives prior to Visit 1 (whichever is longer) or during screening

    • Use of other investigational therapy not described above within 4 weeks or 5 drug half-lives prior to Visit 1 (whichever is longer) or during screening

      - Patients participating in a clinical trial that has not been unblinded should be assumed to have received the active drug

    • Initiation of or change in allergen immunotherapy within 3 months prior to Visit 1 or during screening

    • Receipt of a live attenuated vaccine within 4 weeks prior to Visit 1 or during screening

    • Pregnant or lactating

    • History of bronchial thermoplasty

Refractory asthma patients attending secondary care refractory asthma clinics within the national health services.