In the largest study of its kind to date, the UK’s International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) Coronavirus Clinical Characterisation Consortium (ISARIC-4C), supported by the UK Coronavirus Immunology Consortium (UK-CIC), has identified new biological markers (biomarkers) of inflammation that both reveal the severity of COVID-19 and set it apart from severe influenza.
In a study published in the academic journal Science Immunology, groups of proteins linked to the immune inflammatory response (including two called GM-CSF and IL-6) scale with COVID-19 severity.
IL-6 is already known as a target for therapies that reduce the severity of symptoms in COVID-19, but GM-CSF has potential as a new marker of severity that differentiates COVID-19 from influenza, giving insights into the causes of severe disease and potentially offering a new focus for therapy.
It is important to understand why some patients with COVID-19 experience severe disease, while others recover with less medical support. Uncontrolled levels of cytokines (proteins released by immune cells) can cause a ‘cytokine storm’ with excessive inflammation. This has been proposed as a driver of COVID-19 severity. Anti-inflammatory drugs such as corticosteroids (e.g., dexamethasone) or those that interrupt cytokine function (e.g. tocilizumab, which targets IL-6) substantially reduce mortality in patients with COVID-19. However, studying the underlying inflammatory response in more detail can help researchers to identify new therapies and target healthcare resources to those most at risk.
Teams of researchers from across the UK, including Imperial College London, University of Edinburgh and University of Liverpool, combined their efforts to show 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 patients who had been in hospital with COVID-19 (grouped by disease severity) along with 39 outpatients with mild disease. They analysed 33 disease markers in the blood plasma of these patients.
They found that many inflammatory cytokines were found at greater levels in the blood of patients with severe COVID-19. The investigators identified patterns within the data that were the most clearly linked to severe cases of COVID-19; two cytokines in particular, IL-6 (interleukin 6) and GM-CSF (granulocyte-macrophage colony stimulating factor) play central roles. When compared with samples from patients with severe influenza that researchers had stored from the 2009-2011 swine flu pandemic, GM-CSF stood out as a specific marker for severe COVID-19. This cytokine can also be detected in early COVID infection, indicating that it may play a role in early disease development in some patients.
While older patients showed a greater all-round inflammatory response, age did not determine the differences in GM-CSF levels between COVID-19 and influenza. This suggests that a disease-specific mechanism that worsens age-dependent inflammatory responses is likely to occur in COVID-19. No difference was found between the responses of men and women after disease severity had been accounted for.
The findings from this study could impact patient care and treatment. The study has identified GM-CSF as a key part of the inflammatory immune response to SARS-CoV-2 and as a potential target for treatments. Further research is 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.