Non-invasive Assessment of Small Airway Obstruction in Asthma

Small airway inflammation and remodelling occurs in asthma and may underpin disease persistence, since conventional inhaled treatments do not penetrate to the small airway compartment. There is an important unmet need for reliable and non-invasive methods to measure small airway obstruction. This thesis describes the development and validation of such methods, with a particular focus on the multiple breath inert gas washout (MBW) technique. In vitro validation of the sulphur hexafluoride wash-in technique for performing MBW demonstrated that the method yields accurate and repeatable results. We developed novel methods for analysing inert gas washout curves, and showed that the parameters derived are repeatable, capture the full information content of the curve, and may be superior to standard parameters in distinguishing between subphenotypes of airway diseases. MBW and impulse oscillometry (IOS) parameters were found to be repeatable within-visit, but IOS parameters displayed greater stability over time. IOS parameters were independent predictors of asthma symptoms, quality of life and exacerbation frequency, suggesting that IOS may add value to spirometry in the assessment of patients with asthma. The response of small airway biomarkers to an intervention was assessed within a clinical trial of a novel anti-eosinophilic agent. Significant treatment effects were observed with respect to spirometric airflow obstruction and air trapping, as well as with a number of MBW parameters. The structural correlates of ventilation heterogeneity in asthma were examined using hyperpolarised 3helium magnetic resonance and quantitative computed tomography. There was evidence for a structural abnormality in the pulmonary acinus in patients with asthma causing subtle alterations in diffusion within this compartment. Future studies should seek to further understand the structural basis of IOS and MBW parameters through computational modelling and the coupling of physiological measurements and functional imaging. Longitudinal studies are also required to assess the long-term significance of small airway biomarkers

Modelling the effect of gravity on inert-gas washout outputs

Multiple-breath washout (MBW) is a pulmonary function test (PFT) that is used to infer lung function through measurement of ventilation heterogeneity (VH). However, the body position that a test is taken in may also influence VH, due to the "Slinky" effect of gravity on the lungs. In healthy subjects this has minimal effect, but in unhealthy groups, PFT outputs have been seen to change drastically with body position. In this study, we used a combined computational and clinical approach to better understand the response of outputs from the MBW to body position. A patient-specific model of the MBW was developed, then validated against clinically measured washout data, as well as broader results in the literature. This model was then used to compare changes in MBW outputs with respect to body position, showing that output changes sensitively predict regional airway size differences between lobes. We then highlight cases in which body position effects may bias MBW outputs, leading to elevated or masked responses to bronchoconstriction. We close by placing this result in context with broader clinical practice, and showing how it can help improve interpretation of test outputs

Effects of personal air pollution exposure on asthma symptoms, lung function and airway inflammation.

BACKGROUND: There is evidence that air pollution increases the risk of asthma hospitalisations and healthcare utilisation, but the effects on day-to-day asthma control are not fully understood. OBJECTIVE: We undertook a prospective single-centre panel study to test the hypothesis that personal air pollution exposure is associated with asthma symptoms, lung function and airway inflammation. METHODS: Thirty-two patients with a clinical diagnosis of asthma were provided with a personal air pollution monitor (Cairclip NO2/O3) which was kept on or around their person throughout the 12-week follow-up period. Ambient levels of NO2and particulate matter were modelled based upon satellite imaging data. Directly measured ozone, NO2and particulate matter levels were obtained from a monitoring station in central Leicester. Participants made daily electronic records of asthma symptoms, peak expiratory flow, and exhaled nitric oxide. Spirometry and asthma symptom questionnaires were completed at fortnightly study visits. Data were analysed using linear mixed effects models and cross-correlation. RESULTS: Cairclip exposure data were of good quality with clear evidence of diurnal variability and a missing data rate of approximately 20%. We were unable to detect consistent relationships between personal air pollution exposure and clinical outcomes in the group as a whole. In an exploratory subgroup analysis, total oxidant exposure was associated with increased daytime symptoms in women but not men. CONCLUSIONS AND CLINICAL RELEVANCE: We did not find compelling evidence that air pollution exposure impacts on day-to-day clinical control in an unselected asthma population, but further studies are required in larger populations with higher exposure levels. Women may be more susceptible than men to the effects of air pollution, an observation which requires confirmation in future studies

Domiciliary exhaled nitric oxide and eosinophilic airway inflammation in adults with asthma

Exhaled nitric oxide home monitoring is a promising surrogate marker of eosinophilic airway inflammation in asthma

Characterization of acinar airspace involvement in asthmatic patients by using inert gas washout and hyperpolarized 3helium magnetic resonance

Background The multiple breath washout (MBW) parameter Sacin is thought to be a marker of acinar airway involvement, but has not been validated using quantitative imaging techniques in asthma. Objective We aimed to utilise 3He diffusion magnetic resonance ( 3 He-MR) at multiple diffusion timescales and quantitative computed tomography (CT) densitometry to determine the nature of acinar airway involvement in asthma. Methods Thirty-seven patients with asthma and seventeen age-matched healthy controls underwent spirometry, body plethysmography, MBW (using the tracer gas sulphur hexafluoride) and He-MR. A subset of patients with asthma (n = 27) underwent quantitative CT densitometry. Results Ninety-four percent (16/17) of patients with an elevated Sacin had GINA treatment steps 4/5 asthma and 13/17 had refractory disease. The apparent diffusion coefficient (ADC) of 3 He at 1s was significantly higher in patients with Sacin-high asthma compared to healthy controls (0.024 vs 0.017, p < 0.05). Sacin correlated strongly with ADC at 1s (R = 0.65, p < 0.001), but weakly with ADC at 13ms (R = 0.38, p < 0.05). ADC at both 13ms and 1s correlated strongly with the mean lung density expiratory / inspiratory ratio, a CT marker of expiratory air trapping (R = 0.77, p < 0.0001 for ADC at 13ms; R = 0.72, p < 0.001 for ADC at 1s). Conclusion Sacin is associated with alterations in long-range diffusion within the acinar airways and gas trapping. The precise anatomical nature and mechanistic role in severe asthma requires further evaluation