Inflammatory Protein Linked to Severe COVID-19 Identified

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 today 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: “People may be familiar with the term ‘cytokine storm’, in which patients hospitalised with COVID-19 have increased levels of inflammatory proteins in their body linked with severe outcomes and death. Our new study shows that there are many inflammatory markers raised in COVID-19, but that these are more in the range of a ‘response’ than a ‘storm’.

“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.”Protein clues in the bloodIn the study, the team analysed blood samples taken from 471 patients hospitalised with COVID-19 across England, recruited through the ISARIC4C study. They also analysed blood from 39 outpatients with mild COVID-19 as well as stored samples taken from 20 patients with fatal H1N1 influenza, isolated during the 2009/10 swine flu outbreak. The researchers also analysed samples from 36 healthy volunteers without respiratory disease as a control.

Analysing the 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.

However, samples from those 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 their 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 that GM-CSF is not the only important driver of severe disease, that its presence alone in blood does not increase risk for patients, and that further research would be needed to determine its use as a prognostic tool.

However, 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 those 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.

“This work is the culmination of more than a decade of research from UK collaborators, starting during the outbreak of H1N1 influenza in 2009 and carrying through to the current COVID-19 pandemic. It proves beyond all else the power and effect of collaborative working”

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.”

Reference: Thwaites RS, Uruchurtu ASS, Siggins MK, et al. Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19. Sci. Immunol. 2021;6(57). doi: 10.1126/sciimmunol.abg9873

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