Title: Hyperpolarised gas MRI and multiple breath inert gas washout to improve management and understanding of cystic fibrosis lung disease
Funder: Health Education England

Abstract: Cystic fibrosis (CF) is the most common inherited fatal disease in the Caucasian population. In the lungs of CF patients, thick sticky mucus accumulates that develops into chronic infection and inflammation, causing airway narrowing and bronchiectasis. This pattern is progressive and eventually causes respiratory failure. The priority of CF care is early detection of disease progression and appropriate intervention. Accurate assessment of CF lung disease is therefore central to effective care, however current standards are recognised as being inadequate for effective CF patient management. Hyperpolarised gas magnetic resonance imaging (HP MRI) is a highly sensitive tool that assesses global and regional ventilation heterogeneity within the lungs. Pilot studies in CF have shown; that it is feasible as a diagnostic and assessment tool, that ventilation defects are evident, that it is capable of demonstrating treatment response and that ventilation defects are present when all measures of lung function remain within normal limits. HP MRI is therefore a potentially very strong outcome tool but is currently limited by the lack of large volumes of clinical data. HP MRI measures regional lung function unlike conventional lung function tests that represent measures of global function. It therefore has the capability to inform about emerging lung function tests such as multiple breath washout (MBW) and complex exercise assessments (CPET) of exercise limitation. MBW is non-invasive and has scalability in terms of application in non-expert centres.Aims This primary aim of my PhD research project is to assess and establish the role of HP MRI in detecting and monitoring CF lung disease progression, using regional and global measures of lung disease.In addition I will perform MBW measurements to establish the relationship between regional MRI lung physiology measures with established and experimental MBW measures. I will also establish the relationship of HP MRI with conventional lung function tests, quality of life and the relationship with disease severity. Finally, I will assess the impact of exercise (a standard therapeutic intervention in CF) on both regional and global measures of lung function, in order to measure exercise performance and the effects of exercise on the lungs. Plan of Investigation This is an observational-longitudinal study in clinically stable CF patients (aged 5 years and above) with all stages of disease severity. I will recruit 35 patients, with a target retention of 26. These patients will perform conventional lung function tests, MBW and HP MRI at three visits spaced evenly over 2 years. At one visit only, patients will be invited to perform a CPET and have repeat HP MRI post exercise. I will analyse the change in HP MRI over time and whether underlying variables such as infection status, genotype or disease severity relate to disease progression. I will correlate HP MRI with MBW, conventional lung function tests, exercise test data and quality of life scores. I will assess the difference in HP MRI and MBW after a bout of maximal exercise. Benefit to Patients HP MRI is the only outcome tool that offers regional lung function assessment for disease monitoring. Once fully characterised and evaluated in larger studies, it has the potential to be a powerful clinical tool, and offers considerable advantages over current imaging standards. The data generated will help interpretation and understanding of MBW tests, which are increasingly applied in CF care. Finally, since both tools are highly sensitive to treatment effects they will help in the design of early phase studies involving fewer patients, assisting in bringing new treatments to later phase clinical trials. The ultimate aim is to provide clinical tools to detect and prevent disease progression and maintain lung health in CF.

Lay abstract: Aims This study aims to measure the lung function of patients with cystic fibrosis (CF) in greater detail than has previously been possible. I aim to use the most advanced new tests of lung function to monitor CF lung disease progression. I will also compare these tests with breathing tests that patients currently perform on a regular basis. Using these new tests I will also measure what effect exercise has upon the lungs of patients.Background CF is a condition that patients are born with. It affects their lungs throughout their life. As patients get older their lungs become clogged with thick, sticky mucus that causes damage to the lungs. Measuring patient's lungs is therefore very important. Accurate assessment is essential to effective care, however the best tests we have are poor at measuring lung function in the detail needed. This study will look at two new lung function tests. The main test is called magnetic resonance imaging (MRI) of the lungs whilst breathing in a safe gas. The MRI scanner takes pictures of gas inside the lungs, a technique that has not been possible before. In CF, this MRI technique has shown that patients with very mild disease and without symptoms have problems with their lungs. So far this technique has been measured in small numbers of patients and therefore needs to be measured in larger numbers. The second test is called multiple breath washout (MBW) and involves breathing into a small machine for a few minutes. This test is similar to MRI and is also able to measure problems in the lungs that other tests cannot pick up. It produces numbers that describe how air flows in and out of the lungs, but is not able to take a picture like the MRI. The MRI will be able to teach us more about breathing tests like the MBW from the pictures it takes. These two tests will also be used to measure what happens to CF lungs after performing heavy exercise. Patients with CF can get very out of breath when they exercise, but exercise is still important as it improves their fitness and helps to cough up sticky mucus. It is not known what happens in the lungs after exercise so by measuring MRI and MBW before and after exercise it will help to understand what is happening. Design and Methods Children and adults with CF, including those with a range of lung disease from mild through to severe, will be asked to take part in this study. They will be asked to attend on three occasions at regular intervals over two years.At each visit they will perform the MRI and MBW tests alongside the breathing tests they would normally perform. They will also complete a short questionnaire that measures their quality of life.At one of these visits patients will be invited to perform an exercise test followed by repeat MRI and MBW tests.Once I have collected these measurements I will look to see how lung disease changes over time using MRI. I will also see what extra information the MRI can teach us about MBW and other breathing tests and also about how exercise affects the lungs. PPI This proposal has been designed with the help of patients with CF and parents of patients. Through their support and advice I have identified that this topic is important to patients and that the design of the study is appropriate. These individuals will be involved in this proposal in the reviewing of documents such as patient information sheets', advising me on recruiting patients and how best to describe the study and the results to the CF population. Dissemination The results collected will be written up as part of my PhD. The highlights will also be published in scientific journals aimed at professionals with an interest in lung function and lung disease. These results will be presented at relevant national and international conferences to reach a large clinical-academic audience. I will discuss with my patient advisers the best way to highlight this work to the public and to patients with CF. Initial discussions have highlighted the CF trust, Facebook groups and local parents evenings. Justification This study is important since studies suggest that the MRI test can tell us more about problems in the lungs of a patient with CF at an earlier stage than ever before. This allows for earlier detection of lung disease and better preservation of a patient with CF's lungs.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CONGENITAL DISORDERS