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Difficult to treat asthma affects up to 20% of patients with asthma despite currently available therapies and is associated with significant healthcare cost. Treatment guidelines advise the ?step wise? increase of corticosteroids but the response is often poor as this ?one size fits all? approach does not benefit all patients. Characterising a patient?s response to treatment will help our understanding of non-response and will aid development of new drugs and is the key to delivering personalised medicine in severe asthma.

The successful candidate will be embedded within the MRC funded Refractory Asthma Stratification Programme (RASP-UK) Consortium (http://www.rasp.org.uk/) which brings together a partnership of clinical and academic excellence from UK and Irish Universities and Severe Asthma Centres, together with the Pharmaceutical Industry. The primary focus is to target corticosteroid treatments more effectively and to understand why some patients do not respond to corticosteroids. Our industry partners are developing new treatments for severe asthma that will be tested in these patients and asthma ?biomarkers? will be identified to predict response to these new therapies.

Biomarker based stratification of severe asthma within the programme will identify two populations of severe asthma patients, with different patterns of lung inflammation, one with corticosteroid responsive disease which we call "T2-High"severe asthma and the other with corticosteroid unresponsive disease or "T2-Low" severe asthma. The T2-High group will be available for clinical trials of new treatments which have already been developed by the Pharmaceutical Industry. We currently understand much less about the T2-Low group, so these patients will be studied intensively to help us understand mechanisms of disease in this group.

International asthma treatment guidelines recommend a 'step-wise' increase of inhaled corticosteroid dose to achieve asthma control (1.2). For many patients, this is the correct strategy; however, there is strong evidence that as many as 50% of patients have minimal response to corticosteroids (3,4,5). When asthma symptoms do not respond to treatment, the corticosteroid dose is further increased to try and produce a treatment response, often including progression to oral corticosteroids, with potential to cause multiple side-effects without any therapeutic benefit.

The MRC funded RASP-UK programme ((6) will clinically stratify patients with severe asthma using a "composite" biomarker-based algorithm (using easy to measure biomarkers - FeNO, blood eosinophil count and serum periostin concentration) to optimise corticosteroid treatment. This will define the key groups of interest in severe asthma for further investigation of disease mechanisms in workstrand 2. We are particularly interested in identifying patients with severe asthma in whom a role for Type 2 cytokines is not evident (T2-Low asthma) and who remain uncontrolled despite corticosteroid optimisation. Our current understanding of disease mechanism in T2-Low asthma is poor

The aims of this PhD project are as follows:
- co-ordinate a multi-centre cohort of T2-Low asthma in the RASP-UK programme
- development of a standardised protocol for cross-sectional phenotyping of T2-Low asthma
- longitudinal follow-up of this cohort to examine clinical outcomes on optimised corticosteroid dose to determine phenotype stability and exacerbation frequency
- detailed mechanistic assessment in patients with T2?Low asthma ? in partnership with University of Leicester and Genentech and other Consortium partners which will involve bronchoscopic sampling to define the airway transcriptome, inflammatory profile and microbiome in this population (with relevant control groups).

References
1. http://www.ginasthma.org/guidelines-gina-report-global-strategy-for-asthma.html
2. http://www.brit thoracic.org.uk/Portals/0/Guidelines/AsthmaGuidelines/sign101%20Jan%202012.pdf
3. Woodruff PG et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med 2009;180(5):388-95
4. McGrath KW et al. A large subgroup of mild-to-moderate asthma is persistently noneosinophilic. Am J Resp Crit Care Med 2012:15;185(6):612-9
5. Pavord ID et al. Non-eosinophilic corticosteroid unresponsive asthma. Lancet 1999;353 (9171);2213-2214
6. Heaney LG et al. Research in progress: Medical Research Council United Kingdom Refractory Asthma Stratification Programme (RASP-UK). Thorax 2015 Jul 23. [Epub ahead of print]