Title: Improving clinical phenotyping of interstitial lung disease for better diagnosis and disease management
Funder: Department of Health and Social Care

Abstract: Background: Interstitial lung disease (ILD) is an important cause of morbidity and mortality that results in almost 10 000 hospital admissions and over 5000 deaths in the United Kingdom each year.Whilst approximately two thirds of individuals with fILD fulfil a specific clinical diagnosis (most commonly either idiopathic pulmonary fibrosis (IPF) or connective tissue disease(CTD)). However, a third of patients have either unclassifiable disease or disease of unknown aetiology. For these patients prognosis is difficult to predict and best therapy remains to be defined. This issue is of significant clinical importance following the emergence of specific anti-fibrotic therapies and with the knowledge that immunosuppression is harmful in some patients with ILD (i.e. IPF) Aims: This research will examine strategies for better diagnosing ILD and will deliver a proof of concept study of anti-fibrotic and anti-inflammatory therapy in unclassifiable disease to better define best treatment for this group of patients. Specifically the research will i) prospectively recruit atients in to a longitudinal observational study to enable deep phenotyping of unclassifiable fILD with results to be compared to IPF and CTD-ILD, ii) evaluate pirfenidone and predniolone, together with placebo, in a factorial randomized controlled trial, iii) use clinical bioinformatic methodologies to re-evaluate current diagnostic algorithms and iv) undertake multiscale integration of clinical, imaging and -omic data to detect disease clusters and reevaluate current diagnostic groupings in ILD Plan of Investigation: i) A prospective, longitudinal biomarker study in unclassifiable ILD will seek to recruit 120 patients over two years. Biological samples for proteiomics, genomics and transcriptomics will be collected at baseline 3, 6, 12 and 24 months. Clinical data including lung function, healthcare utilisation and quality of life questionnaires will be collected at each time point. ii) A pragmatic 2 x 2 factorial randomised controlled trial will seek to compare pirfenidone, prednisolone and placebo for 4 months in individuals with unclassifiable ILD. Subjects will be stratified according to wether their treating physicians believe their disease to be predominantly fibrotic or inflammatory. A range of study outcomes will be measured including change in FVC, QoL, safety, healthcare utilisation and a panel of inflammatory and fibrotic biomarkers. iii) Reevaluation of current diagnostic algorithms will be undertaken using the recently developed RB&HFT Clinical Research Database. Clinical information will be evaluated separately against outcomes and clinical diagnosis. iv) The final strand of the study will seek to combine all the information collected whilst undertaking the other research aims and will utilise a range of bioinformatics tools to perform multi-scale integration of clinical, imaging and -omic data.Expected Outcomes: It is anticipated that data derived from these studies will improve and simplify the diagnosis and classification of ILD and may reduce the need for invasive investigations such as surgical lung biopsy. Improved classification of disease together with data from the clinical trial will begin to inform best treatment of this group of patients with the outputs from the clinical trial informing the subsequent design and delivery of stratified medicine treatment studies in this group of patients. The integration of clinical and -omics data should identify novel disease clusters and may inform understanding of disease pathogenesis as well as guide treatment and identify potential disease strata. Overall, it is expected that this study will raise the standards of care for a group of patients with currently unclassifiable disease and for whom best treatment is yet to be defined. In turn it is hoped that this will lead to improved prognosis and reduced healthcare utilisation.

Lay abstract: The interstitial lung diseases (ILDs) are characterised by inflammation or scarring that damages the air sacs in the lung. Current methods of diagnosing ILD are limited and fail to identify the cause of disease in upwards of a third of patients with the condition. Consequently, individuals with unclassifiable disease live with an uncertain prognosis and a lack of available treatments. This study will re-evaluate traditional diagnostic approaches in ILD and, by means of a clinical trial of anti-fibrotic and anti-inflammatory therapy combined with novel molecular research techniques will seek to improve diagnostic approaches and therapeutic strategies for this patient group.

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