MRC/ABPI COPD Consortium Work Package 1: COPD Phenotyping

Lead Research Organisation: University of Leicester
Department Name: Infection Immunity and Inflammation

Abstract

COPD (which used to be called chronic bronchitis and emphysema) is a common disease which causes considerable difficulty to sufferers. The pharmaceutical industry has been relatively unsuccessful in bringing new treatments to the marketplace for COPD, with many products failing when they are first given to patients. This is largely because not all COPD sufferers are the same and it is likely that drugs will treat certain aspects of the disease and therefore are more likely to benefit some but not all patients. We propose to try to understand what makes people with COPD different from each other and to use these differences to further our understanding of which types of drugs will benefit which types of people. Using this approach we aim to identify markers in blood and sputum that will help us to predict the progression of COPD and response to therapy.

Technical Summary

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and healthcare expenditure in the UK (#1B/annum). Worldwide, over 27,000 people died from COPD in 2004 and the WHO forecasts COPD to be the 3rd leading cause of death in the world by 2030. Current therapies are ineffective in preventing the progressive airway remodelling and emphysema, or recurrent exacerbations which are COPD hallmarks. New therapeutic approaches targeting these processes would address a major unmet need. This application will provide the patient-specific data and samples that will underpin the phenotyping effort described here and all the mechanistic studies described in the other work packages of the consortium. This MRC/ABPI COPD consortium will build on existing COPD cohorts and bio-resources from early to established disease and relevant controls. These cohorts and bio-resources include MRC funded, Industry, EU-FP7, NIH, and NIHR-led cohorts. Importantly this application provides the framework for the consortium to evolve to support its changing needs and is sufficiently flexible to allow integration with future initiatives. The available data comprise extensive clinical characterisation, standard physiological measurements, CT-scans, and biological phenotyping from genome to proteome. Additional data are available from some cohorts at exacerbation events complemented with detailed molecular microbiology and virology. In others detailed measures of co-morbidities, activity monitoring, systemic inflammation and skeletal muscle biology has been assessed. We shall harmonise the data between the cohorts and will add follow-up data, and in pre-specified subgroups innovative small airway physiology, imaging and the sampling of tissue and blood to facilitate, target validation and ex vivo modelling and potentially high throughput ?omic? analyses. These data will be used to identify biologically relevant sub-phenotypes required to support the studies outlined in the other work packages, and will be interrogated using bio-statistical modelling to identify novel phenotypes to drive future hypothesis driven mechanistic studies. This connectivity with the other work packages will undergo an iterative process of ?test? and ?validation? groups each further refining the phenotyping effort; informing the mechanistic studies and the sample sizes required for adequate statistical power. Through this integrated joint academic and industry consortium we shall provide the framework necessary to achieve a step-change in our understanding of COPD which we anticipate will lead onto improvements in the treatment of this devastating disease.

Publications

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Alahmari AD (2016) Physical activity and exercise capacity in patients with moderate COPD exacerbations. in The European respiratory journal

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Beeh KM (2017) How Do Dual Long-Acting Bronchodilators Prevent Exacerbations of Chronic Obstructive Pulmonary Disease? in American journal of respiratory and critical care medicine

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Bewley MA (2018) Opsonic Phagocytosis in Chronic Obstructive Pulmonary Disease Is Enhanced by Nrf2 Agonists. in American journal of respiratory and critical care medicine

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Donaldson GC (2013) Factors associated with change in exacerbation frequency in COPD. in Respiratory research

 
Description NICE COPD guidelines
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact We have shown the importance of exacerbations in COPD and why they are an important outcome in studies for clinical and economic reasons.
 
Description Inflamamtory Therapeutic Capability Clusters (TRPs) 
Organisation Imperial College Healthcare NHS Trust
Department Respiratory Medicine
Country United Kingdom 
Sector Hospitals 
PI Contribution Developed the first protocol for drug development
Collaborator Contribution The Capability Cluster has been awarded to centres in the UK and we are one of the Centres - this includes Imperial, Nottingham, Manchester, KGT, Leicester, Southampton
Impact Collaboration recently commenced
Start Year 2010
 
Description MRC ABPI COPD Collaboration 
Organisation Imperial College Healthcare NHS Trust
Department Respiratory Medicine
Country United Kingdom 
Sector Hospitals 
PI Contribution Major part of this collaboration and the London COPD cohort is the main source of patient study and clinical samples
Collaborator Contribution Enabled the MRC ABPI consortium
Impact Contracts now signed and work packages under way
Start Year 2011
 
Description RSV infection and co-morbidity 
Organisation Imperial College Healthcare NHS Trust
Department Respiratory Medicine
Country United Kingdom 
Sector Hospitals 
PI Contribution Provide COPD patients from cohort that are wekll phenotyped. Studies of viral and bacterial infection and airway and systemic inflammatory markers
Collaborator Contribution Collaborators have provided experience on immunology of RSV
Impact In progress Abstracts to be presented at meetings. papers in preparation
Start Year 2010
 
Description Studies of macrophage phagocytosis in COPD 
Organisation Imperial College Healthcare NHS Trust
Department Respiratory Medicine
Country United Kingdom 
Sector Hospitals 
PI Contribution Provision of samples form well phenotyped patients
Collaborator Contribution Expertise in phagocytosis experiments
Impact Original Paper published
Start Year 2009
 
Description Patient cohort meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Study participants or study members
Results and Impact Regular meetings of our research cohort, where we discuss studies and also future ones. Review protocols etc.,
Year(s) Of Engagement Activity 2016