Public health

A unique storm: Cytokine response in severe COVID-19 differs from other inflammatory conditions


The inflammatory response associated with severe COVID-19 infections differs at the molecular level from other conditions that can cause a cytokine storm, according to new serum biomarker analysis.

“Studies addressing the relevance of cytokine storm conditions in COVID-19 are frequently limited to discussions on IL-6 and draw conclusions based on comparisons with many different critical clinical conditions or even healthy controls,” wrote study authors led by Prof Christoph Kessel, of University Children’s Hospital Muenster in Germany.

Though IL-6 inhibitors have shown to be effective in some trials, they have failed in others, highlighting the confounding nature of COVID-19’s hyperinflammatory state.

In the new study, published in Arthritis & Rheumatology, the researchers measured levels of 22 biomarkers in serum samples of 30 patients with COVID-19. They compared this to samples from 50 patients with either macrophage activation syndrome (MAS) or secondary hemophagocytic lymphohistiocystosis (sHLH), both strongly associated with cytokine storm, as well as to nine healthy controls.

Importantly, no COVID-19 patients had received immunosuppressive or biologic therapies, or anti-viral treatments, which could have confounded the results.

In the sHLH/MAS samples, they found a “dramatic” activation of the IL-18-IFN-γ axis. In the COVID-19 samples, meanwhile, there was an increased level of IL-1 receptor antagonist, as well as of intracellular adhesion molecule 1 (ICAM-1), and IL-8. There were also strongly reduced levels of soluble Fas ligand (sFasL).

“Our present research delivers broad insights on the nature and significance of systemic hyperinflammation following SARS-COV-2 infection,” said co–lead author Prof Richard Vollenberg, of University Hospital Muenster. “We consider this relevant as we still lack proper angles of attack to treat critically ill patients.”

The authors wrote that while blockade of IFN-γ is promising in treatment for HLH and potentially for MAS, it is likely to be less effective for COVID-19, given the reduced activation of the IL-18-IFN-γ axis.

“Our data may further support the use of combined medications directed against different targets, medications with broader immunoregulatory effects, such as glucocorticoids/dexamethasone, or suggest strategies to bypass low sFasL expression or block IL-8 signaling in treating COVID-19,” they wrote.

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