Title: The phenotypes of early COPD: the role of eosinophils and other biomarkers in defining categories of treatment responsiveness
Funder: Department of Health and Social Care

Abstract: There is a growing understanding of the heterogeneous nature of chronic obstructive pulmonary disease (COPD). Studies have sought to classify patients with COPD according to lung function, symptom score, exacerbation frequency and molecular and cellular biomarkers. The biomarker approach has begun to elucidate underlying inflammatory mechanisms which characterise different phenotypes of COPD and may guide future treatment decisions. Eosinophils and fractional exhaled nitric oxide (FeNO) have emerged as promising markers of steroid sensitivity in obstructive lung disease. Elevated levels of these markers are particularly apparent in patients with asthma exacerbations. There is acknowledgement that a high proportion of patients with obstructive lung disease have a mixed picture of COPD and asthma, whilst a further subgroup have an eosinophilic COPD, all of whom may be responsive to inhaled corticosteroids (ICS). Little is known about the influence of ICS on biomarkers in patients with mild and moderate COPD. Study participants often have severe or very severe disease, whilst those with mild and moderate disease are infrequently the subject of research. COPD, even when mild or moderate, has a major impact on patients and healthcare services. The majority of drug treatments for COPD patients are initiated and prescribed in primary care. My project will seek to establish the presence of a group of patients in primary care with mild or moderate COPD who have blood eosinophilia (0.3x109/L). If demonstrated this marker would guide future therapeutic approaches towards these patients. My hypothesis is that phenotypic subgroups, especially an eosinophilic subgroup, of patients with COPD can be identified during the early stages of the disease. This work would be essential to the conduct of a clinical trial which sought to establish the value of drugs in groups of patients with COPD with different inflammatory phenotypes. The work may identify different phenotypes in mild and moderate COPD which, while they might not be responsive to ICS at that stage of the disease, would link with the same inflammatory phenotypes in severe and very severe disease where ICS may be effective. In this research I will use patients recruited to the NIHR RfPB-funded (PB-PG-0214-33060) feasibility study at King's College London on the safety and acceptability of the withdrawal of ICS in mild and moderate COPD prescribed outside guidelines. My primary outcome measure will be the proportion of patients with blood eosinophilia (0.3x109/L) after withdrawal of ICS. My programme of research will include a systematic review of the evidence for molecular and cellular biomarkers of steroid responsiveness in COPD. This will be followed by a quantitative study in primary care to determine if an eosinophilic subgroup can be identified among patients with mild and moderate COPD from whom ICS have been withdrawn. In addition I will seek associations between changes in blood and exhaled cellular and molecular biomarkers (eosinophils, periostin, fibrinogen, leukocytes, CRP, FeNO) and changes in lung function (spirometry), breathlessness (neural respiratory drive (NRD)) and quality of life following the withdrawal of ICS. Patients with mild and moderate COPD using ICS will be recruited from primary care. Baseline measures of eosinophils and other biomarkers, spirometry, NRD and quality of life will be taken. Patients will be randomized either to an ICS continuation group or to an ICS withdrawal group. Both groups will be followed up at 3 and 6 months with repeated measurements taken. Those in the continuation group will then have ICS withdrawn with follow up at 9 and 12 months. Novel aspects of this project include its setting in primary care and the identification of an eosinophilic phenotype in patients with mild and moderate COPD, who are unlikely to have had involvement with secondary care.

Lay abstract: Background Chronic Obstructive Pulmonary Disease (COPD) is a major cause of hospital admissions in the UK and globally. There is an increasing understanding of the complex and variable nature of the disease. Those diagnosed with mild and moderate COPD may include patients with a variety of different underlying disease processes and with different responses to available drug treatments. Treatment is usually life-long and all medications may cause side effects. An estimated 25% of patients with mild to moderate COPD are prescribed high dose inhaled corticosteroids (ICS) outside guidelines. For many of these patients the medication is unlikely to provide any treatment value and confers the risk of harm including the potential for pneumonia, bone fractures and cataracts. It is thought that up to 50% of patients with COPD have a condition which overlaps or resembles the obstructive lung disease asthma. ICS are effective and safely prescribed to patients with asthma, but the doses in asthma are much lower than in COPD. It is of crucial importance that those patients with COPD, who may benefit from specific treatments, including ICS at three or four times the dose used in asthma, are identified to improve their treatment and that those who are unlikely to benefit are shielded from potential harm from the drugs. Research suggests that several biological markers (biomarkers) including the presence of high levels of blood cells called eosinophils are promising identifiers of corticosteroid sensitivity in patients with obstructive lung disease. Aims Most research examining the underlying disease processes in COPD has been conducted in patients with severe and very severe disease, whilst little is known about those with mild and moderate disease. The main aim of my research project is to identify the proportion of patients with mild or moderate COPD who have a high level of blood eosinophils on withdrawal of ICS. My secondary aims are to describe the distribution of other biomarkers before and after withdrawal of ICS and to examine the associations between changes in biomarkers and changes in patients' lung function, breathlessness and quality of life following withdrawal of ICS. By identifying different subgroups among these patients I hope to improve their treatment and increase knowledge of the natural history of COPD. Design and methods My study will be set in primary care. I will recruit from general practices a group of 75 patients with mild to moderate COPD who use ICS. I will take a series of baseline measures from these patients including blood and exhaled inflammatory biomarkers, spirometry to assess lung function, a quality of life questionnaire and a measure of breathlessness called neural respiratory drive. I will allocate patients at random to continue using ICS or to gradually withdraw from using ICS over a month. Both groups will be followed up at 3 and 6 months and each of the measures described above will be repeated. Following this those patients who had continued using ICS will withdraw from taking them. I will follow these patients up at 9 and 12 months and repeat the measures. Patient and public involvement A group of patients with mild and moderate COPD were consulted on the objectives and design of the study and on the acceptability to them of the outcome measures. All patients were open to the idea of the research and were willing to consider having the measurements and withdrawing from using ICS. They were unanimous in wanting information about the drugs and the risk of side effects. Patients will be recruited to join the patient advisory board. Their views will contribute to the patient information materials used by the study. Dissemination I will disseminate the findings of this research to our study participants and advisors, to participating general practices, and to local Breathe Easy groups, patient groups set up for people with chest disease by the British Lung Foundation. I will use written summaries in the form of a newsletter at the half way stage and at the end of the project. I will also inform the British Lung Foundation at the same time. I will disseminate the findings to professional groups (i.e. primary care clinicians, respiratory clinicians, respiratory physiologists, respiratory nurse specialists and physiotherapists) via papers in peer review journals and at local, national and international scientific meetings.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RESPIRATORY