Infectious Disease

Serum biomarkers clearly separate COVID-19 from classic cytokine storm syndromes

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The researchers do not report any relevant financial information.

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According to Arthritis & Rheumatology, elevated interleukin-1Ra and IL-8 serum levels as well as other biomarker profiles clearly separate COVID-19 from macrophage activation syndrome and secondary hemophagocytic lymphohistiocytosis.

“Based on our knowledge, we wanted to investigate to what extent the inflammatory response in severe COVID-19 can actually be compared with other cytokine storm syndromes and whether approaches for treatment options for COVID-19 can actually be derived from this.” Christoph Kessel, PhD, of the University Children’s Hospital Münster in Germany reported Healio Rheumatology.

According to the data, serum biomarker profiles clearly “separate” COVID-19 from macrophage activation syndrome and secondary hemophagocytic lymphohistiocytosis, both classic cytokine storm syndromes.

“Up until the point in time when we completed our study, the scientific discussion about it was very often limited to the role of interleukin (IL) -6, which is certainly a powerful mediator of inflammation, but, to our current knowledge, its role in the classic area Das Cytokine Storm Syndrome is limited, ”he added. “This calls into question the potential success of therapeutic targeting of IL-6 in COVID.”

To investigate whether the immune activation in COVID-19 mimics the conditions of secondary hemophagocytic lymphohistiocytosis (sHLH) or macrophage activation syndrome (MAS), Kessel and colleagues analyzed 83 serum samples from 30 patients with COVID-19 at the University of Münster Hospital.

All samples were collected during the first wave of the pandemic in Germany, with the patients in the course of the disease from the time they entered hospital. None of the patients had received immunosuppressive, biological therapies, or experimental antiviral treatments. However, they received anti-infectives for bacterial or fungal superinfection.

The researchers also included 20 sHLH serum samples as well as 17 MAS samples associated with Still’s disease, which occurs in adults. These serum samples were collected from adults in previous studies. In the meantime, four samples from juvenile sHLH and nine from juvenile MAS as well as nine samples from health checks were collected from the University Hospital of Münster.

Kessel and colleagues used a bead array assay and a single marker ELISA to quantify the concentrations of 22 biomarkers in the included serum samples. These included IL-1, IL-1 receptor antagonist (Ra), IL-4, IL-6, IL-8, IL-10, IL-18, TNF, interferon (IFN), IFN, IFN-, MCP2 (CCL8 )), MCP3 (CCL7), CXCL9, CXCL10, MCSF, LRG1, soluble Fas ligand (sFasL), intracellular adhesion molecule 1 (ICAM-1), VCAM-1 and galectin-3.

According to the researchers, sHLH and MAS samples showed “dramatic activation” of the IL-18-IFN axis. Meanwhile, increased serum levels of IL-1Ra, ICAM-1 and IL-8 as well as greatly reduced sFasL levels during COVID-19 separated the immune dysregulation in critical SARS-CoV-2 cases from the cytokine storm conditions.

“Our analyzes could cast further doubts about the effectiveness of clinical trials targeting key molecules and pathways associated with sHLH and / or MAS in the treatment of COVID-19,” wrote Kessel and colleagues. “The therapeutic blockade of IFN-, which appears to be a promising therapeutic option in the treatment of HLH and possibly MAS, may be less effective in COVID-19 because the overall activation of the IL-18-IFN axis is associated with far less SARSCoV2 infection appears to be pronounced. In contrast to IL-18 and IFN-, the IL-1Ra levels in COVID-19 are significantly increased. ”

“This observation could indicate limited therapeutic use of IL-1 blockade in patients with COVID-19, as it has been reported that high endogenous levels of IL-1Ra indicate a rather poor response to drugs containing IL-1 or Neutralize IL-1 signals. They added. “However, elevated circulating levels of IL-1Ra usually reflect an IL-1 signature, for example the correct timing of IL-1 blockade in COVID-19 can be critical and likely complicate the interpretation of the available data. Early intervention in acute hyperinflammatory respiratory failure can therefore have a therapeutic effect. “

The researchers added that the IL-18-IFN axis is “safely” active in critical COVID-19, albeit at a different level than sHLH or MAS. As such, the simultaneous alignment of this axis and IL-1 could prove a rescue treatment for extremely ill patients, they wrote.

“A corresponding RCT is running,” wrote Kessel and colleagues. Indeed, our data could further support the use of combined drugs against multiple targets, drugs with broader immunoregulatory effects such as glucocorticoids / dexamethasone, or suggest strategies to circumvent low sFasL expression or IL-8 signaling in the treatment of Block COVID-19. ”

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