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Biomarker testing for COPD flare-ups: Picking up the pace in the battle against antimicrobial resistance?

Nick Francis and Chris Butler write about their NIHR research revealing that a finger-prick blood test at GP surgery could safely reduce antibiotic use in patients with COPD.

Tackling antimicrobial resistance (AMR) is one of the biggest challenges in healthcare.
Reducing unnecessary antibiotic use is a key way to overcome this problem, while also ensuring resources and medicines aren’t wasted.

However, antibiotic stewardship initiatives have to be balanced against the possibility of causing harm by restricting antibiotic use in those patients who are likely to benefit from taking them.

More than a million people in the UK live with chronic obstructive pulmonary disease (COPD). Flare-ups of the condition – symptoms of which include breathlessness, coughing, and phlegm - are frequent. During these flare-ups, known as acute exacerbations (AECOPD), three out of four patients are prescribed antibiotics. However, up to two-thirds of these flare-ups are not caused by bacterial infections and antibiotics often do not benefit patients.

Reducing unnecessary antibiotic use benefits patients in the short term by minimising side effects from antibiotics and by reducing the selection of resistant bacteria in individuals’ lungs. Society also benefits from reduced risk of infections that are resistant to treatment with antibiotics.

So how can we better target antibiotics treatment for acute exacerbations of COPD while at the same time safely ensure that often elderly and vulnerable COPD patients can undergo a suitable alternative treatment?

Biomarker testing

Point of care testing is being vigorously promoted as a critical solution for better targeted antibiotic prescribing.  However, there have been virtually no trials of point of care tests that measure impact on clinician behaviour, patient behaviour and patient outcomes (what are often called ‘pragmatic trials’). 

The results of the PACE study, funded by the NIHR Health Technology Assessment (HTA) Programme as part of the 2014 Antimicrobial Resistance Themed Call, have now published in the NEJM. To our knowledge, it is the first trial of biomarker guided management of AECOPD in ambulatory care.

C-reactive protein (CRP) is a marker of inflammation that rises rapidly in the blood in response to serious infections. When people with a COPD flare-up have low levels of CRP, they are much less likely to benefit from antibiotics.

In the PACE study we found that when UK GPs used a C-Reactive Protein (CRP) rapid finger-prick test, there was an absolute 20% reduction in antibiotic prescribing by clinicians as well as antibiotic use by patients suffering with flare ups of their COPD. This reduction is about twice the magnitude of that achieved by most antimicrobial stewardship interventions. Furthermore, we found no evidence of detrimental effects on clinical outcomes, suggesting that using fewer antibiotics did not harm patients. Findings from this trial likely take us closer to a more stratified approach, where patients get treatments targeted to their individual requirements. 

Evaluating diagnostics

We believe our study also is a model for the evaluation of diagnostics: The O’Neill Review on Antimicrobial Resistance urges us never to prescribe an antibiotic without doing a test first.  While this recommendation is obviously overkill, point of care diagnostics for better targeting antibiotics  is a burgeoning area for research and development, and point of care tests are now increasingly being used in GP practices. However, most research into diagnostics stops after testing the accuracy of new devices.  The EU and many regulatory bodies around the world now rightly expect far more from diagnostics research. Determining accuracy alone will no longer be enough to get a test used in routine care: studies will need to show that tests are cost effective in benefiting patients without causing harm.  And evidence is required from the context in which tests are intended for use and the differences these tests make when put into practice. 

The next steps of our research include publishing the health economic findings from the PACE study and identifying steps to overcome implementation barriers - such as ensuring mechanisms for funding the test are in place and clinicians feel confident in using it. Our process evaluation found that money and time considerations will be absolutely critical to the implementation of this evidence. Patients attending our dissemination event were keen to have access to CRP testing, but some had concerns about timely access to general practice.

We started applying for funds to trial CRP POCT to guide antibiotic prescribing decisions in the early noughties, and encountered many challenges along our long research journey.

An editorial in the New England Journal accompanying the PACE trial report paper commented, “In our view, the findings from this study are compelling enough to support CRP testing as an adjunctive measure to guide antibiotic use in patients with acute exacerbations of COPD.”1  

We are therefore encouraged by this sense that evidence from our trial could improve clinical practice, and are grateful for the support and vision of the NIHR that has enabled us to bring potentially practice-changing findings from our trial into the public domain.

More information on the PACE trial is available on the NIHR Journals Library website.

1. Allan S. Brett, M.D., and Majdi N. Al‑Hasan, M.B., B.S. COPD Exacerbations — A Target for Antibiotic Stewardship n engl j med 381;2 July 11, 2019). 

The views and opinions expressed in this blog are those of the authors and do not necessarily reflect those of the NIHR or the Department of Health and Social Care.