Airway Hyperresponsiveness To Mannitol As A Theragnostic Marker Of Response To Daily Treatment With Inhaled Corticosteroids

Abstract

Airway inflammation and airway hyperresponsiveness (AHR) are the key pathophysiological features of asthma. AHR measured using an indirect stimulus such as mannitol, reflects the presence of airway inflammation, disease severity and activity, and may be a useful marker of response to daily treatment with inhaled corticosteroids (ICS). This thesis explores the utility of the mannitol bronchial provocation test (BPT) as a theragnostic marker of ICS treatment in asthma. All studies were performed on clinical patients that attended a pulmonary function laboratory (PFL) and had AHR to mannitol. The first study was a retrospective analysis in a large cohort of military and police recruits. We investigated responsiveness to mannitol in recruits that had a positive BPT and repeated the test after using daily treatment with ICS for 4 months. AHR persisted in only a small proportion of recruits. Lung function parameters and other clinical features in these recruits were assessed to determine what characteristics predicted persistent AHR. The second study was a prospective pilot randomised parallel group trial of two forms of monitoring facilitated by the PFL. We recruited asthmatics referred to the PFL for assessment, who had AHR to mannitol and symptoms indicating their asthma was not well-controlled, and who subsequently commenced daily treatment with ICS. The mannitol group attended the PFL for serial monitoring of AHR to mannitol. The comparator group had spirometry measured, in accordance with asthma management guidelines, which recommend the inclusion of an objective marker such as spirometry to complement symptoms in monitoring asthma. Along with feedback of each marker, the goal of either resolving AHR or improving spirometry was reinforced at each visit and the importance of ongoing adherence to therapy to achieve this goal. We aimed to determine if serial monitoring and providing feedback of AHR to mannitol improved asthma control when compared to using spirometry and symptoms alone. The third study using the same dataset of the second study explored the time-course of improvement in objective and subjective markers of asthma with the introduction of ICS. Symptoms and spirometry results improve rapidly with the introduction of ICS therapy. However, there are few data regarding the time-course of improvements that occur in AHR to mannitol over the initial months of daily treatment with ICS. We assessed the change in symptoms, spirometry, fraction of exhaled nitric oxide (FeNO) and AHR to mannitol over an 18-week period, following daily ICS therapy. This thesis found; with 4-5 months of daily treatment with ICS, AHR to mannitol is attenuated and can be resolved. More severe AHR and lower spirometry before starting daily therapy increases the likelihood of persistent AHR. Feedback and goal setting using response to mannitol appear to result in greater improvement in AHR, in those with moderate to severe AHR prior to treatment compared to using symptoms and spirometry alone. AHR to mannitol takes longer to improve compared to symptoms, spirometry, and exhaled nitric oxide.