Title: Impulse oscillometry in idiopathic pulmonary fibrosis
Funder: Health Education England

Abstract: BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is a progressive fibrotic interstitial lung disease (ILD) of unknown origin that has a poor prognosis with median survival of 2-3 years from the time of diagnosis. Change in forced vital capacity (FVC), a traditional lung function measure, is the physiological index that is currently used in clinical practice and research trials to monitor disease progression in IPF. However, there are limitations; not all patients with IPF can perform a FVC manoeuvre, due to cough or discomfort, with 20-25% missing FVC data observed in clinical trials. Impulse oscillometry (iOS) is an effort-independent test that uses sound impulses to provide information on peripheral airways resistance and compliance. Previous work using iOS in patients with interstitial lung disease are limited to small cross-sectional studies, and iOS has not been previously investigated in an IPF-specific population. HYPOTHESIS: iOS measures of lung reactance are well-tolerated, reliable, valid and responsive in IPF. AIMS: To determine the test-retest reliability, patient acceptability, validity (concurrent and predictive) and minimal clinically important difference (MCID) of iOS measures of reactance in patients with IPF. DESIGN: STUDY 1: Cross-sectional study of 62 patients with IPF. Concurrent validity of iOS with lung function indices (especially forced vital capacity (FVC) and transfer factor of the lung for carbon monoxide (TLCO)), six-minute walk distance (6MWD), health-related quality of life (HrQoL) and extent of fibrosis assessed by high resolution computer tomography scanning will be determined. During iOS measurement and lung function tests, time taken to complete tests will be recorded. Furthermore, participants will complete visual analogue scales (VAS) to determine the ease of performing each of the tests, and the discomfort/coughing/breathlessness each test provokes. Participants will attend a second visit two weeks later to compare intra- and inter- test-retest reliability of iOS and FVC. STUDY 2: Prospective longitudinal cohort study of 132 patients with IPF. iOS, lung function (FVC, TLCO), 6MWD and HrQoL will be performed at baseline (T0), six months (T1) and 12 months (T2). Survival status and the number of non-elective hospital admissions between T0 and T2 will be recorded. The predictive value of baseline iOS and change in iOS over six months will be assessed by calculating hazard ratios (HR) using Cox proportional regression, adjusting for potential confounding variables. Receiver Operating Characteristic curves will compare discriminatory ability of the multivariable regression models and with current established prognostic indices in predicting mortality and hospitalization. Using FVC, TLCO, 6MWD, HrQoL and global rating of change scores as potential external anchors, linear regression will also be used to compare change in iOS with change in these external anchors. Distribution- and anchor-based approaches will be used to estimate the minimal clinically important difference of iOS measures. BENEFITS TO PATIENTS AND NHS: Validation of a feasible, effort independent measure of lung function such as iOS has the potential to improve the routine monitoring of patients with IPF and has implications for clinical trial design, providing further impetus to the NHS and industry to develop and test therapies for a vulnerable patient group.

Lay abstract: Idiopathic pulmonary fibrosis (IPF) is a condition where scar tissue (called fibrosis) builds up in the lungs. It usually gets worse over time. Fibrosis causes the lungs to become stiff, and reduces the amount of oxygen that the lungs can take up. People with IPF complain of worsening breathlessness, which limits their day to day activities. Lung function tests are breathing tests that measure how well your lungs are working, and are used by doctors to decide whether to start or stop medicines in people with IPF. However, people with IPF tell us that lung function tests require a lot of effort, can make them cough, and feel very short of breath. About 1 in 5 people with IPF are unable to perform lung function results accurately. This might unfairly lead to some people with IPF not receiving the right medications or for their medications to be stopped too soon. Impulse oscillometry (iOS) is a new type of breathing test. It uses sound waves to measure the stiffness of the lung. The test is very quick (30 seconds), does not require any effort from the patient, and only requires a patient to breathe in their usual way. iOS has been used successfully in children who are unable to perform normal lung function tests. The overall aim of the research is to see whether iOS tests provide useful information about IPF; for example, by judging the overall impact of the disease on the lungs, or predicting future deterioration. We will assess whether people with IPF can perform iOS tests accurately and to compare their experiences of having iOS tests with their experience of performing current lung function tests. We will also compare whether there is a relationship between iOS tests and the information gathered from the tests currently used by doctors to measure the impact of IPF (lung function tests, exercise tests, lung scans and questionnaires that measure quality of life). We will look at how iOS changes over time in patients with IPF, and to see whether these measurements can tell us about whether IPF is getting worse or predict important health events, such as hospital admission. Finally, we will compare change in iOS with changes in other tests routinely used to monitor IPF and with patient reported ratings of change in their condition. This will help decide the amount of iOS change that is noticed and considered meaningful by people with IPF. We anticipate that the new iOS tests are quicker and more comfortable to perform for patients than current lung function tests. The research will help improve the monitoring and treatment of patients with IPF, and importantly to help improve the experiences of patients with IPF. Being able to assess the severity and outcomes accurately in more people with IPF will help the development of new medicines.

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