Identification of GM-SCF as possible distinctive blood marker predicting severe COVID-19


The results from a prospective multicenter UK’s study, published in Science Immunology indicate that increased levels of interleukin (IL)-6, C-X-C motif chemokine ligand 10 (CXCL10), and granulocyte-macrophage colony-stimulating factor (GM-CSF) are associated with COVID-19 severity but reveals, perhaps for the first time that GM-SCF is a distinctive blood marker predicting severe COVID-19.

Patients with severe COVID-19 infection display an excessive and uncontrolled inflammatory response, causing organ damage and leading to an acute respiratory distress syndrome (ARDS). COVID-19 severity has been associated with depletion of CD3+ T lymphocytes, particularly the CD4+ and CD8+ fractions, and with increased levels of IL-6 and IL-8.

Recent studies show beneficial effects of anti-inflammatory therapies with corticosteroids and encouraging results with the use of anti-IL-6 or IL-6 Inhibitors (e.g., tocilizumab), particularly in the treatment of severe cases. However, it appears that the mechanisms that drive severity and distinguish COVID-19 from other viral diseases are still poorly understood.

In the Science Immunology study researchers from the Imperial College London, University of Edinburgh, University of Liverpool, and from the Coronavirus Clinical Characterisation Consortium (ISARIC4C) in the UK, analyzed plasma samples from 471 hospitalized patients and 39 outpatients with mild disease, and measured 33 known blood inflammatory markers in these patients. In addition, they analyzed 20 plasma samples from fatal cases of H1N1 influenza from 2009-2011 pandemic.

The authors report that patients with severe COVID-19 displayed high levels of blood CXCL10, GM-CSF, and IL-6, consistent with pro-coagulability, endothelial activation and a broad inflammatory response in severe cases.

Elevated GM-CSF and IL-1α stood out as being characteristic of COVID-19, and, in fact, GM-CSF and IL-1α levels distinguished fatal COVID-19 from fatal influenza infection.

Of note, a hierarchical correlation matrix analysis revealed a strongly correlated group of inflammatory markers, such as GM-CSF, CXCL10, D-dimer, vWF-A2, and IL-6, were associated with the most severe COVID-19 outcome groups. According to the authors this may indicate a coordinated myeloid and vascular inflammatory response in severe cases.

Importantly, the data analysis also revealed differences in plasma cytokine levels between patients with severe and moderate COVID-19. Thus, within the first 4 days of symptoms IL-2, IL-6, and GM-CSF significantly increase in the severe group, but not in the moderate disease group, indicating a pronounced inflammatory response early in severe cases. Of note, the authors report 9.7-fold elevation of the blood levels of GM-CSF in fatal COVID-19 cases relative to the healthy control group.

Although older patients are more likely to develop severe COVID-19, and they overall had higher blood levels of pro-inflammatory cytokines relative to younger counterparts within severity groups, older age was not a determinant factor for GM-CSF production specifically in this study.

GM-CSF stimulates stem cells to produce granulocytes (neutrophils, eosinophils, and basophils) and monocytes. Monocytes exit the circulation and migrate into tissue, whereupon they mature into macrophages and dendritic cells.

In fact, an influx of monocytes/macrophages into the pulmonary parenchyma and a myeloid pulmonary artery vasculitis have been reported in autopsy studies of COVID-19. Thus, in their discussion, Ryan Thwaites et al. emphasise that the elevations of CCL2, CXCL10, and GM-CSF in severe disease reported in their study may be causally linked to the monocyte recruitment and activation leading to this vasculitis, combined with the role of GM-CSF in the recruitment of neutrophils to the pulmonary vasculature.

Of note, and as per a recent study in Italy, GM-CSF blockade with mavrilimumab was associated with improved clinical outcomes compared with standard care in non-mechanically ventilated patients with severe COVID-19 pneumonia and systemic hyperinflammation.

Moreover, anti-GM-CSF therapy with neutralizing antibodies or antagonists is currently under clinical trials as treatment for different inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, asthma, and ankylosing spondylitis. Among the anti-GM-CSF compounds tested, Otilimab (GlaxoSmithKline), Lenzilumab (Humanigen), TJM2 (I-Mab), and (Roivant), are now in clinical trials and recruiting patients with severe coronavirus disease.

Ryan Thwaites et al., the authors the Science Immunology study also discuss that baseline IL-6 and GM-CSF measurements might allow patients’ stratification and identification of subgroups that might be expected to develop severe disease and benefit from anti-cytokine therapies.

Importantly, the authors conclude that their results and the presence of mediators and cytokines that may distinguish severe from moderate development of COVID-19 may also indicate that “early therapeutic intervention may be crucial to effective disease modification”.

Source: Sci Immunol, 2021. 6(57): eabg9873. doi: 10.1126/sciimmunol.abg9873
Read more: Science Immunology
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