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Title: The pathophysiology of rhinovirus induced exacerbations in mild and moderate asthma
Author: Jackson, David
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Rhinovirus infection is the most common cause of asthma exacerbations, however mechanisms underlying this remain poorly understood. A human model of experimental rhinovirus induced asthma exacerbation has been developed, however to date the exclusion of moderately-severe and poorly-controlled asthmatics has meant that the role of asthma severity and control on the outcome of rhinovirus infection is unknown. In addition, conventional sampling techniques such as bronchoalveolar lavage dilute many cytokines below limits of detection and consequently it has not been possible to measure key mediators of type 1 and 2 inflammation in-vivo. Thirty-two mild-to-moderate asthmatics and 14 healthy subjects were inoculated nasally with rhinovirus-16. Bronchoscopies were performed 2 weeks prior to inoculation and on day 4 post-inoculation. A novel technique to sample undiluted mucosal airway lining fluid called 'bronchosorption' was developed and performed via bronchoscopy to enable more accurate measurement of cytokines. A similar technique termed 'nasosorption' was performed in the nose. Levels of a range of type 1 and 2 mediators were measured simultaneously in both the upper and lower airway throughout the infection. Twenty-eight asthmatic and 11 healthy subjects developed objective evidence of infection. Asthmatics with moderately-severe disease and poor baseline control developed significantly greater lower respiratory symptoms and falls in lung function than milder and well-controlled asthmatics. The techniques of nasosorption and bronchosorption were able to identify significantly augmented type 2 immunity during infection in-vivo in asthmatic but not healthy subjects with levels of key mediators including IL-4, -5, -13, -33, TARC/CCL17, MDC/CCL22 all relating to exacerbation severity. Induction of type 1 mediators was comparable in the asthmatic and healthy nose but was increased in the asthmatic lung in keeping with the lower airway involvement by rhinovirus in asthma. This is the first study to have demonstrated that baseline asthma severity and control influences the outcome of rhinovirus infection highlighting the importance of maintaining good asthma control. It is also the first to have shown the significant induction of a range of type 2 mediators by rhinovirus in asthma in-vivo. The novel sampling techniques that have been developed will greatly advance our understanding of a range of respiratory conditions through the ability to measure previously undetectable inflammatory mediators.
Supervisor: Johnston, Sebastian ; Hansel, Trevor ; Mallia, Patrick Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral