Biomarkers to target antibiotic and systemic corticosteroid therapy in COPD exacerbations

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

Abstract

Chronic obstructive pulmonary disease (COPD) is a common chronic lung disease. Its prevalence is rising and it will become the third leading cause of death by 2020 (1). In the UK 900,000 people are diagnosed with COPD and it is likely that many more remain undiagnosed. COPD is a burden for sufferers and an enormous drain on health care provision with annual costs estimated at #492 million. The times when a patient?s condition worsens is known as an exacerbation and COPD exacerbations account for 15% of all medical admissions and can lead to death. The current treatment for COPD exacerbations is supportive care together with antibiotics and oral corticosteroids. The clinical response to treatment varies considerably and to date we have no robust well-validated measurements to direct therapy for COPD exacerbations. Importantly, the widespread use of antibiotic therapy is implicated as the major contributing factor leading to the recent increase in the ?Superbugs? MRSA and Clostridium difficile infection and oral corticosteroids complicate heart disease and diabetes. Therefore our current inability to target therapy for COPD exacerbations means that some patients with COPD are inappropriately treated and this places a vulnerable population at risk. Therefore there is a pressing need to target antibiotic and oral corticosteroid therapy for COPD exacerbations. In this proposal we shall invite 110 patients with COPD to enter a 1 year study in which we shall further assess mediators that can be measured in sputum and blood that are already known to closely relate to infections and inflammation. These mediators will be measured when patients are well and when they have an exacerbation. This will provide us with precise levels of the mediators of interest that can then be used to decide whether we treat patients with antibiotics, corticosteroids, both or neither. Indeed we shall use these measurements to direct treatment in a second 1 year intervention study that will include the same patients as for the first study. At exacerbations half of the patients will be treated according to standard care and the other half will have their treatment directed by the measurements derived from the first study. We anticipate that this will provide us with an opportunity to treat patients with COPD at times of exacerbations more effectively with a reduction in the total use of treatment without any detrimental effects.

Technical Summary

Chronic obstructive pulmonary disease (COPD) is a common condition and its prevalence is increasing. COPD exacerbations are responsible for 15% of all medical admissions and result in significant morbidity, mortality and health care costs. Current guidelines advocate the use of oral corticosteroids and antibiotics for patients with COPD exacerbations, but only a minority benefit from these treatments. Critically corticosteroids are associated with significant side-effects and the widespread use of antibiotics in the community has been implicated in the increase of antibiotic resistance, particularly MRSA, and an increase in cases of Clostridium difficile infection. Therefore there is an urgent need for near-patient tests using biomarkers to direct therapy in COPD exacerbations. Approximately half of COPD exacerbations are associated with a sputum eosinophilia. Current evidence demonstrates that a sputum eosinophilia predicts response to corticosteroids. Total sputum eosinophilic cationic protein (ECP) is an excellent marker of the total sputum eosinophil count and provides an attractive biomarker to guide corticosteroid therapy. Currently, sputum purulence is the only recommended biomarker to guide antibiotic therapy in COPD exacerbations. Other potential biomarkers have been examined including CRP and cytokine profiles, but are neither sensitive nor specific enough for clinical application. Alternative sputum biomarkers are soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) and procalcitonin. sTREM-1 in bronchoalveolar-lavage fluid has a sensitivity of 98% and specificity of 90% to identify a bacterial pneumonia and serum procalcitonin has shown promise in directing antibiotic therapy particularly in pneumonia. In this proposal we shall study 110 COPD patients, GOLD stage II-IV. Subjects will participate in a two-phase study. Phase I is a 1-year observational study with visits 3-monthly and at exacerbations. Subjects will be carefully assessed including spirometry, sputum induction, health status questionnaires and symptom scores. Sputum will be processed for detailed bacteriology and virology assessment, total and differential cell counts, total ECP, sTREM-1, and procalcitonin. The aim of phase I is to validate and identify the most appropriate biomarkers to direct therapy in COPD exacerbations. Phase II is a randomised controlled trial of directed antibiotic and corticosteroid therapy for 1-year. Follow-up and assessments will be as for phase I, but in the intervention group treatment will be targeted using cut-offs for biomarkers identified in phase I. We predict that targeted therapy will lead to an overall reduction in treatment without any deleterious effects. Importantly, the findings from this study can be translated immediately to large-scale clinical trials and clinical practice.

Publications

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Bafadhel M (2009) Sputum IL-5 concentration is associated with a sputum eosinophilia and attenuated by corticosteroid therapy in COPD. in Respiration; international review of thoracic diseases

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Bafadhel M (2014) Aspergillus fumigatus during stable state and exacerbations of COPD. in The European respiratory journal

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Bafadhel M (2012) Profiling of sputum inflammatory mediators in asthma and chronic obstructive pulmonary disease. in Respiration; international review of thoracic diseases

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Bafadhel M (2011) Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. in American journal of respiratory and critical care medicine

 
Description AirPROM Airway Disease Predicting Outcomes through Patient Specific Computational Modelling (12m euros across 33 participants)
Amount £290,976 (GBP)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 03/2011 
End 02/2016
 
Description COPDMAP MRC/ABPI COPD Consortium
Amount £6,000,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 03/2011 
End 02/2015
 
Description Clinical Research Training Fellowship
Amount £296,000 (GBP)
Funding ID 107302/Z/15/Z 
Organisation Wellcome Trust 
Department Wellcome Trust Bloomsbury Centre
Sector Academic/University
Country United Kingdom
Start 01/2015 
End 09/2018
 
Title Bacterial exacerbation biomarker 
Description In development for preparation of further validation studies. Pharma support in early stage of negotiation 
Type Diagnostic Tool - Imaging
Current Stage Of Development Initial development
Year Development Stage Completed 2010
Development Status Under active development/distribution
Impact None as of yet 
 
Title Sputum eosinophil exacerbation biomarker 
Description Biomarker to detect sputum eosinophilic COPD exacerbations 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2010
Development Status Closed
Impact Straight forward blood test 
 
Description MRC feedback forum -Media 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Media (as a channel to the public)
Results and Impact 130 patient and carers attended feedback forum, which was found to be invaluable by patients and local media

Recruitment via local BBC news increased, for airways disease at the Glenfield
Year(s) Of Engagement Activity 2010
 
Description MRC patient feedback forum 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact 130 patients and carers attended afternoon feedback session to hear from the researchers about why study was performed, what was studied and the results. Patient orientated informal session

Patients & carers interested to take part in more research activities at the centre, and recruitment for other studies increased. Patient understanding into COPD, causes and treatments greatly improved
Year(s) Of Engagement Activity 2010
 
Description Newspaper/ television 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact The MRC funded project was featured in a local newspaper article (Leicester mercury) and the regional ITV news programme.

We had feedback from over 100 people interested in participating in research.
Year(s) Of Engagement Activity 2008
 
Description Research Newsletter 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact Launch of MRC COPD/Respiratory Research newsletter

Patient led important services acted upon from newsletter - including smoking cessation services, local BLF breathe easy group
Year(s) Of Engagement Activity 2010