• Jethin Rafique

Student thesis: Doctor of Medicine


INTRODUCTION: Asthma is a very heterogeneous disease characterised by chronic airway inflammation and bronchial hyper-responsiveness. As the knowledge of the characteristics and inflammatory pathways of different subpopulations within asthma increase, biomarkers which are reliable, stable and reproducible are needed to identify target populations for “personalised treatments”, track drug effect in clinical drug trials and monitor disease activity over a period of time. With new emerging targeted therapeutic agents being developed, they are initially tested in early small clinical trial in patients with mild disease (usually in the corticosteroid naïve asthma subpopulation). Biomarkers for asthma related to neutrophil inflammation (so-called neutrophilic phenotype) and for subgroup of patients who respond to anticholinergic agents need to be studied. AIMS: (1) To study the reproducibility of physiological measurements, sputum/blood eosinophil and neutrophil cell counts and characterise the corticosteroid naïve asthma population. (2) To study the characteristics and long term reproducibility of sputum neutrophils in patients with asthma who have raised/high sputum neutrophils count. (3) To assess whether a short acting β2 agonist (salbutamol) is more effective than a short acting anticholinergic (ipratropium) and identify similar characteristics/biomarkers of those who are “responders” to an anticholinergic agent (ipratropium). METHODS: 30 patients who were corticosteroid naïve were screened. Their symptom scores, airway physiology, FeNO, lung clearance index (LCI), bronchial hyper-responsiveness and sputum/blood differential counts were all measured. A reproducibility visit took place within one month. 19 patients with a historic sputum neutrophil% count of ≥ 50% were recruited. Lung physiology including plethysmography and impulse oscillometry, FeNO, LCI and sputum differential counts were measured. Lastly 38 patients with asthma of varying severities were screened. Their physiological measurements and sputum cell counts were assessed. Reversibility testing to 400μg of salbutamol was done. Within on week, patients came back for measuring reversibility to 80μg of ipratropium. RESULTS AND CONCLUSIONS: (1) Symptom scores, most physiological measurements, FeNO and sputum eosinophils show excellent reproducibility in corticosteroid naïve asthma. Measurements could be used as potential biomarkers or endpoints in clinical trials. (2) Long term reproducibility of sputum neutrophil is poor and raises the question as to whether sputum neutrophils can be used as a stable long term marker of disease activity. (3) Salbutamol is more effective than ipratropium as a bronchodilator in asthma. Increased symptoms (more severe disease) and raised sputum eosinophils may be a marker for those who are anticholinergic “responders” and warrants further study in the future.
Date of Award31 Dec 2018
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorThomas Southworth (Supervisor) & Sukh Singh (Supervisor)

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