Researchers Identify New Inflammatory Biomarkers that Indicate COVID-19 Severity as Well as Distinguish It from Severe Influenza

A study has identified new biomarkers of inflammation that both indicate the severity of COVID-19 and distinguish it from severe influenza.

The study involving researchers at the University of Liverpool (Liverpool, UK) is the largest of its kind to date and identifies clusters of inflammatory disease markers (including two called GM-CSF and IL-6) that scale with COVID-19 severity. IL-6 is already proven to be a target for therapies that reduce disease severity in severe COVID-19, but GM-CSF has potential as a new marker of severity that distinguishes COVID-19 from influenza, giving insights into the causes of severe disease and potentially offering a new focus for therapy.


A ‘cytokine storm’, where uncontrolled levels of cytokines (proteins released by immune cells) cause excessive inflammation, has been identified as a driver of COVID-19 severity. Teams of researchers from across the UK, including Imperial College London, demonstrated that only select features of the cytokine response to COVID-19 distinguish the most severe forms of disease. Using the ISARIC4C platform, the researchers recruited 471 hospitalized COVID-19 patients (who were stratified by disease severity) along with 39 outpatients with mild disease. They analyzed 33 disease markers in the blood plasma of these patients.

They found that many inflammatory cytokines were elevated in severe COVID-19 and that levels are generally indicative of disease severity. The investigators identified patterns within the data that are characteristic of the most severe cases of COVID-19; two cytokines in particular, IL-6 (interleukin 6) and GM-CSF (granulocyte-macrophage colony stimulating factor) playing central roles. When compared with archived samples from severe influenza patients, GM-CSF stood out as a specific marker for severe COVID-19. This cytokine can also be detected in early COVID infection, indicating it may play a pathologic role in early disease development in some patients.

While older patients showed a greater all-round inflammatory response, age was not a specific determinant of GM-CSF levels in this study. This suggests that a disease-specific mechanism that exacerbates age-dependent inflammatory responses is likely to operate in COVID-19. There was also no difference found between responses of men and women as has previously been reported in other smaller studies.

The findings from this study could impact patient care and treatment in two ways. First, the study has rationally identified GM-CSF as a key component of the inflammatory response and as a potential therapeutic target. Further research is also needed to see if GM-CSF could be used as a marker in early disease to identify those at risk of going on to develop more severe symptoms.

“Understanding the underlying mechanism of the immune response in patients who are very ill with COVID-19 is crucial to allowing us to identify potential therapeutic targets,” said Dr. Ryan Thwaites, author and Research Associate at Imperial College London. “The immune response is incredibly complex but by assessing levels of multiple markers and how they relate to each other, we’ve been able to increase our knowledge of the immune profile of severely ill COVID-19 patients.”

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