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Title: Novel biomarkers of steroid responsiveness and adherence in difficult asthma
Author: Lindsay, John Thomas
ISNI:       0000 0004 6061 715X
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2016
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Difficult asthma is characterised by frequent exacerbations and persistent symptoms despite being prescribed high dose inhaled corticosteroid (ICS) therapy. Non-adherence to ICS is an important cause of difficult asthma. In this thesis, novel biomarkers of steroid responsiveness were investigated to try to identify a simple test for non-adherence. FKBP5 and F3 are genes which have been shown to be up-regulated in a number of tissues following exposure to steroids. We hypothesised that levels of expression of these genes in throat swabs and in sputum would be higher in difficult asthmatics who were adherent to ICS treatment, than in those who were not. The Fractional Exhaled Nitric Oxide (FeNO) suppression test was employed to robustly characterise 20 difficult asthmatics into adherent and non-adherent groups. This test is effective but difficult to deliver clinically as it requires at least 5 days of direct observation of ICS (DOICS) use. 10 steroid-naive mild asthmatics were also recruited. FKBP5 was found to be expressed more highly in throat swabs and in sputum from both groups of difficult asthmatics than in mild asthmatics. No difference in expression was observed between the adherent and non-adherent groups. There was no difference in F3 expression between any of the asthmatic groups. Therefore, it can be concluded that neither gene can identify non-adherence in difficult asthma at baseline. After a week of high-dose DOICS, an up-regulation of FKBP5 occurred in sputum in the mild group but no changes in expression were observed in the difficult groups. After DOICS, F3 was unexpectedly down-regulated in sputum from the adherent group. Periostin (a serum marker of airway interleukin(IL)13) signalling) and % sputum eosinophils were non-discriminatory. Because none of these markers can replace FeNO suppression as the gold standard test for adherence in difficult asthma, a method of delivering the test using remote monitoring was developed, in which the onus of DOICS is replaced with a device which records date and time of inhaler use, as well as a sound file which can be analysed to ensure correct use. This significantly increases the ease with which this key test can be delivered.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available