Title: Developing the utility of multiple breath washout in the paediatric tertiary centre
Funder: Health Education England

Abstract: There is a need for improved outcome measures and monitoring tools in paediatric lung disease, as existing tests are not sensitive to early disease or small airway disease. The multiple breath washout (MBW) test is a safe and non-invasive measure of lung function, even in young children, which has the potential to provide this missing information, but it has not as yet been properly evaluated in children.To date, most MBW test work has focussed on one particular measure that can be calculated from an MBW test, the lung clearance index (LCI), and one particular group of patients, those with cystic fibrosis (CF). However, there are several other parameters that can be calculated from the same MBW test. This means there is the potential to get more detailed information on the lung disease of these children, but the patient does not have to perform any additional tests.Phase III analysis is a relatively novel technique where the slope of the third, alveolar phase of a single breath exhalation is studied. This is a true non-invasive small airway measure. Obtaining clinical information on the small airways of a patient without the need for invasive tests (or those that incur a radiation dose) is very rare and this is an important opportunity to monitor our patients better without needing these invasive procedures.Curv and MR are additional under-used techniques also calculated from the same MBW, which are primarily sensitive to focal abnormalities, patchy areas of lung disease where gas trapping is more likely to occur, surrounded by more normal tissue. Focal abnormalities have been shown to occur in both obstructive lung disease and asthma. In these cases Curv and MR may be more sensitive and therefore a superior assessment tool to anything else clinically available at present.This study aims to evaluate novel analysis from the MBW and their role, if any, in disease monitoring and progression in paediatric lung disease, including rare diseases and asthma and wheeze. Our hypothesis is that these additional MBW analyses will be more sensitive tools to monitor lung disease in children compared with existing techniques, and will be a practical tool to use in the NHS to optimise treatment and outcomes for these patients and their families.This study consists of retrospective analysis of existing MBW data and a small amount of prospective collection of new data to increase the database in a very rare disease.OBJECTIVES Establish a normal range and variability for this methodology. For this objective, data from healthy volunteers will be analysed to establish the baseline for these measures. This will allow comparisons with the disease groups to be made. Establish variability and extent of abnormality for these measures in in CF, primary ciliary dyskinesia (PCD), non-CF bronchiectasis, asthma and wheeze. From this, I will be able to make recommendations of the suitability of MBW indices for endpoints, monitoring tools and outcome measures.Overall, there is an urgent need for better biomarkers of respiratory disease in children, beyond those already available to us. Many lung conditions seen in the tertiary centre are lifelong and may be progressive; better monitoring and improved assessment of treatment efficacy are essential for improving clinical outcomes and reducing the burden of ill health for children, their families and the NHS. This Fellowship will establish the utility of these sophisticated indices, aiming to include them in routine lung function testing within five years.

Lay abstract: In children with lung disease, it is important to be able to measure the health of their lungs accurately. These measurements can tell us if they are getting worse, or if a treatment they've been trying is working. Any test we use in children needs to be easy to do, accurate, and representative of the whole lung. The most commonly used measure of lung health, spirometry, has several drawbacks when used in children. This test requires coordination of breathing, which may be difficult for young children, and the test doesn't pick up early stages of the disease or ones from the small airways at the edges of the lung. This test is not a good indicator of long-term progress and we can't always use it to measure how effective treatments are. This means we need new lung function tests to be developed to allow us to measure these things. There are some other ways of measuring the small airways or early disease changes, but these may be very uncomfortable or even painful, or involve a radiation dose (such as X-rays). We need a test that will be easy to do, not painful, and will not expose our patients to any radiation. The Multiple Breath Washout (MBW) is a test that I have significant experience of and believe would be a good candidate as a new, more advanced, lung function test. This test is a safe and easy way of measuring lung function even in quite young children. Over a few minutes, the child breathes in and out normally into a machine that allows us to analyse how evenly their lung ventilates. The results of this test will show up infection, inflammation and any other damage. There are several different ways of measuring ventilation, but most people up until now have concentrated on one method, called the Lung Clearance Index. Some of the other methods available might be more useful in some cases, but as the research hasn't been done we don't know for sure. Most of the research that's been performed up until now has also concentrated on one disease, cystic fibrosis, and we don't really know what MBW could be telling us about other conditions. This is true both in common conditions such as asthma and wheeze but also rarer lung diseases. Primary ciliary dyskinesia and non-CF bronchiectasis are two very rare diseases that we see in our centre which can become very serious if these children experience repeated infections, but we are still not sure what the best way of measuring their lung function is. In this research project, I want to try and work out which MBW measure is most useful in children with lung disease and what these measures might be telling us about diseases other than CF. There are already many recorded MBW tests done by children and adults at our centre over the last 7 years, both on people with lung disease and healthy volunteers. I want to analyse this previous, valuable data and calculate the other MBW measures alongside lung clearance index. This means patients won't have to do any extra tests and I can just use the tests we have recorded. From these results I will work out which test may be most useful in these different lung diseases. In some of the rare diseases, we don't have enough recorded tests to be able to say definitely what the best test may be. In these rare groups, I'd like to recruit people to help with my research and to do an extra MBW test for me. This will be done when they are feeling well, and we will pay for their families' expenses if they need to make a special hospital visit to do the test. I've discussed the project with our patient involvement group and one of the charities that supports our patients, to understand how to improve its real world application including ideas such as using a puppet to demonstrate the test and a booklet for children to show siblings and teachers. Also, I will be setting up a focus group of some of the parents of children with respiratory disease, so they can advise me what is of most interest to patients and their families as I go through the study. The development of this test has been a long term effort that we'd like to take further, as we think it could lead to better monitoring and better health for our patients and their families.

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