Title: Novel vascular complications of chronic obstructive pulmonary disease: a prospective clinical and imaging study to evaluate the effect of acute exacerbations of chronic obstructive pulmonary disease on cerebral small vessel disease and microvasculature.
Funder: Department of Health and Social Care

Abstract: Background.Chronic obstructive pulmonary disease (COPD) is common and important. In the UK one million people have COPD, which accounts for 25,000 deaths per year (HSE, 2015). COPD is a chronic inflammatory lung condition characterized by progressive airflow obstruction and has no cure (Vestbo, 2013). COPD is not just a disease of the lungs, but rather a systemic disease commonly associated with other chronic illnesses. Cognitive impairment in COPD is common. Prevalence ranges from 10% to 61% depending on study population and method of cognitive testing (Dodd, 2015). It impacts on morbidity and mortality so is a target for prevention. During exacerbations of COPD, patients demonstrate a significant degree of cognitive impairment that does not recover over time (Dodd, 2013). In stable COPD patients, magnetic resonance imaging (MRI) studies demonstrate widespread structural abnormalities of cerebral white matter exist, consistent with cerebral small vessel disease, which could account for cognitive impairment (Dodd, 2012; Zhang, 2012). We know that in non-COPD patients, CSVD is associated with systemic inflammation (Elkind, 2014; Fornage, 2008), and that in exacerbations of COPD systemic inflammation is high (Wedzicha, 2000). However the impact of exacerbations on cerebral small vessels and microvasculature has not been investigated. We will address the hypothesis that exacerbations of COPD drive small vessel and microvascular disease through mechanisms including systemic inflammation, which in turn causes end-organ damage and co-morbidity including cognitive impairment. Research questions What effect do COPD exacerbations have on large, small and microvascular structure and function? Do COPD exacerbations drive end-organ damage i.e. changes to brain structure and cognition? Are any changes in vascular structure and function and end-organ damage associated with systemic inflammation during COPD exacerbations? Plan of investigation A prospective observational study of 70 patients with stable COPD followed up at 1 year, with additional assessment during their first exacerbation in this period. Measures of large, small and micro-vascular structure and function (serum troponin T, pulse wave velocity, retinal vascular imaging, capillaroscopy, microalbuminuria) will be acquired alongside MRI of brain and cognitive function tests as indicators of end-organ damage. Demographics, disease severity, comorbidities and inflammatory markers will be assessed. Summary of potential benefits to patients and the NHS This has the potential benefit to improve the health of COPD patients. Findings will inform decisions regarding vascular risk modification or new treatments during COPD exacerbations to prevent comorbid disease secondary to small vessel disease, which could improve quality of life, reduce hospitalisation rates and increase survival. We believe this study can have a real impact on patients within 5 years. The study itself is anticipated to take 2 years to complete and we anticipate following up findings with a pragmatic clinical trial. It is likely that targets identified from this study could be modified by re-purposing of existing drugs such as antiplatelets, statins or anti-inflammatories. As these drugs are already licensed this would facilitate rapid progress for future study approval. Patients we collect in this study would be a good sample for future trials, so again this will facilitate early trials. We see this study as the first step towards reducing the burden of comorbidities on patients, the NHS and social care.

Lay abstract: Aim. The aim of the research is to investigate the association between exacerbations of Chronic Obstructive Pulmonary Disease (COPD) and damage to small blood vessels in the body. The results will help us to decide if treatments that prevent damage to blood vessels could be used in the future to reduce the risk of health problems associated with COPD, such as memory loss, strokes and heart disease. Background. COPD, sometimes known as chronic bronchitis or emphysema, is a lung condition caused by inflammation of the airways and damage to the air sacs in the lungs. In the UK the most common cause is cigarette smoking. In COPD the airways become inflamed, narrowed and produce excess mucus. This makes breathing harder and increases production of phlegm. People with COPD can have flare-ups of these symptoms, known as exacerbations. During an exacerbation people experience worsening breathlessness, increased phlegm and/or change in colour of phlegm. COPD is a leading cause of lung disease worldwide. However it does not just affect the lungs, but also affects the brain, heart, bones and muscles. For example, people with COPD have an increased risk of memory problems, strokes and heart attacks. These can have a significant impact on day-to-day living. Some of these problems appear to be due to damage to the small blood vessels of the body. Small blood vessels supply blood and oxygen deep into the brain, heart and kidneys. Research suggests that they are more prone to damage in COPD. This may reduce delivery of blood and oxygen, causing injury to those body organs. For example, studies using brain scans have shown that parts of the brain that rely on small blood vessels are more prone to damage in people with COPD compared to people without COPD. It is not clear why small blood vessels are susceptible to damage in COPD. We think that increased inflammation in the body may be responsible for damaging the lining of the vessels. We also know that, during exacerbations, levels of inflammation in the body increase. We want to see if there is a link between exacerbations and inflammation with changes to small blood vessels and subsequent damage to body organs they supply. Design and methods. This study is an observational study. This means we will not make any changes to participants' usual treatment but we will ask them to undergo additional tests that they may not otherwise have. People with COPD who have been well for at least the previous 6 weeks and don't have other long term conditions that might affect study results will be invited to take part. Participants will be asked to undergo several tests, including eye, urine, memory tests and a brain scan, to look at the structure and function of their blood vessels and to find out if they have any damage to their organs due to injured small blood vessels. These measurements will be made when people are well at the beginning of the study, then 1 year later. Additionally we will ask people to let us know if they have an exacerbation and to repeat the tests when they are unwell. This will help us find out how exacerbations affect the small blood vessels and organs. Patient and public involvement. Patients are integral to this research. Although there is no direct medical benefit to participants it is hoped this research will lead to development of new treatments that could help them in the future. Patient and carer input into study design and conduct has been invited through attendance at meetings of patient advisory groups, surveys in outpatient clinics and online through peopleinresearch.org. Dissemination. The results of this study will be discussed through publication in scientific journals and presentation at scientific meetings. At the end of the study, participants and carers will be invited back to discuss the research findings and plan future research, such as a drug trial aimed at preventing damage to body organs due to exacerbations of COPD. We believe this study can have a real impact on patients within 5 years. The study itself is anticipated to take 2 years to complete and we expect to follow up findings with a clinical trial. It is likely that targets identified from this study could be modified by re-purposing existing drugs such as aspirin, statins or anti-inflammatories. As these drugs are already in common usage this would allow us to start a clinical trial quickly. We hope patients involved in the current study would also participate in future studies.

Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY