UK researchers identify inflammatory protein linked to severe COVID-19

Patients with severe COVID-19 show increased levels of a key protein in their blood, which researchers believe may help identify those most at risk.

In an analysis of more than 500 COVID-19 patients across the UK, researchers identified several inflammatory markers in blood which increased within the early stages of COVID-19 in those who went on to become critically ill.

One marker in particular, a cytokine called GM-CSF, was found at higher levels in those who later progressed to severe disease, compared to healthy controls or those with influenza, and was found to be almost 10 times higher in those who died from COVID-19.

According to the team, led by Imperial College London, University of Edinburgh and University of Liverpool, increased GM-CSF could help to identifying those at risk of developing severe COVID-19 and provide a target for new treatments which could modify their course of disease.

The findings, published in Science Immunology, come from the largest study to date to look at inflammatory markers in COVID-19. The work builds on more than a decade of collaborative research incorporating a global research consortium (ISARIC), which collected samples during the 2009 H1N1 swine flu outbreak, as well as a collaborative network of UK institutions and more than 200 hospitals collecting data from hospitalised COVID-19 patients (ISARIC4C study).

Dr Ryan Thwaites, from the National Heart & Lung Institute at Imperial, said: “We identified one inflammatory marker in particular, a cytokine called GM-CSF, which appears to specifically mark out severe COVID-19 and may play a role in driving severe disease. In future studies, we need to determine whether elevated levels of this protein in the blood at an early stage allows us to identify patients at increased risk of becoming very ill and may benefit most from receiving targeted treatments aimed at GM-CSF.”

Analysing the blood samples for 33 known inflammatory markers showed increased levels of clusters of inflammatory proteins common to respiratory diseases, including a cytokine called IL-6, which was found to be elevated in both mild and severe COVID-19 as well as influenza.

Several markers were elevated in COVID-19 groups, including those known to be linked to general inflammation, inflammation of the lining of blood vessels, and increased blood clotting – suggesting they may be driving the underlying processes seen in severe disease.

Samples from patients with severe COVID-19 showed elevated levels of an additional inflammatory protein, GM-CSF, which was not elevated in people with mild disease or those with influenza.

The team found that GM-CSF levels increased in relation to severity of COVID-19 and were elevated early on in patients that would progress to severe disease – typically within four days of symptoms emerging. Levels of GM-CSF in COVID-19 patients were elevated compared to healthy controls and influenza, on average, increasing 9.6-fold in patients who died from COVID-19.

In its paper, the team highlights it is possible that historical, frozen samples from H1N1 influenza cases may have degraded over time, resulting in reduced levels of some protein markers. They also highlight a lack of a current influenza samples for direct comparison – with UK lockdown and social distancing resulting in very few cases of severe influenza.

The researchers caution further research would be needed to determine its use as a prognostic tool, but they believe identifying it as a key marker and its potential role in driving underlying disease processes in severe COVID-19 could offer opportunity to identify patients at highest risk of severe disease and mortality at an early stage of their illness. Several therapies which target GM-CSF are currently in clinical trials, though not currently approved for use in the treatment of COVID-19.

Professor Peter Openshaw, Professor of Experimental Medicine at Imperial College London and senior author on the paper, said: “These insights into the molecular drivers of disease are crucial in improving our understanding and clinical management of COVID-19. Through world-leading collaborative clinical investigations such as ISARIC4C, we hope to inform the worldwide community of clinicians and investigators about where to look and what to target.”

Dr Kenneth Baillie, Academic Consultant in Critical Care Medicine and Senior Research Fellow at University of Edinburgh, said: “This is another step forward in understanding this new disease. By studying patients with severe Covid-19 at large scale across the UK, we’re building a clearer picture of lung disease in Covid-19: the lungs are being damaged by the patient’s own immune system, rather than directly being damaged by the virus, and we can see specific signals in the immune system that might be responsible. Of course, clinical trials are needed before any change to the way patients are treated.”

Professor Calum Semple, Professor of Child Health and Outbreak Medicine at the University of Liverpool, said: “ISARIC’s planning for an outbreak just like this has enabled timely discoveries that are informing case management and driving therapeutic developments. Also deserving recognition are the NIHR clinical research staff at all our NHS hospitals and the university staff that support the outbreak laboratories in Glasgow and Liverpool, who together collated the data and samples that enabled these discoveries.”

The research was supported by funding from the NIHR and UKRI MRC.

Image credit: Volodymyr Hryshche

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