Serum biomarkers 'clearly separate' COVID-19 from classic cytokine storm syndromes
Increased interleukin‐1Ra and IL‐8 serum levels, and other biomarker profiles, “clearly separate” COVID-19 from macrophage activation syndrome and secondary hemophagocytic lymphohistiocytosis, according to data published in Arthritis & Rheumatology.
“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 of COVID-19 can be indeed be derived from those,” Christoph Kessel, PhD, of the University Children’s Hospital Muenster, in Germany, told Healio Rheumatology.
“Up to the point when we completed our study, the scientific discussion around this was very frequently limited to the role of interleukin (IL)-6, which is certainly a potent inflammatory mediator but, according to our present knowledge, its role in classic cytokine storm syndromes is limited,” he added. “This questions the potential success of therapeutic targeting of IL-6 in COVID.”
To examine whether immune activation in COVID-19 mimics conditions seen in secondary hemophagocytic lymphohistiocytosis (sHLH) or macrophage activation syndrome (MAS), both classic cytokine storm syndromes, Kessel and colleagues analyzed 83 serum samples from 30 patients with COVID-19 from the University Hospital Muenster.
All samples were collected during the first wave of the pandemic in Germany, with patients ranging in disease course from hospital admission. None of the patients had received immunosuppressive, biologic therapies or experimental antiviral treatment. However, they did receive anti-infective drugs in cases of bacterial or fungal superinfection.
The researchers also included 20 sHLH serum samples, as well as 17 samples of MAS linked to adult-onset Still’s disease. These serum samples were collected from adults in previous studies. Meanwhile, four samples of juvenile sHLH and nine of juvenile MAS, as well as nine from health controls, were collected from the University Hospital Muenster.
Kessel and colleagues used bead array assay, as well as single‐marker ELISA, to quantify levels 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 demonstrated “dramatic activation” of the IL‐18‐IFN‐ axis. Meanwhile, increased serum levels of IL‐1Ra, ICAM‐1 and IL‐8, as well as strongly reduced levels of sFasL, during COVID-19 separated immune dysregulation in critical SARS‐CoV‐2 cases from the cytokine storm conditions.
“Our analyses may further raise doubt regarding the efficacy of clinical trials targeting key molecules and pathways associated with sHLH and/or MAS in the treatment of COVID-19,” Kessel and colleagues wrote. “Therapeutic blockade of IFN-, which appears as promising therapeutic option in treating HLH and potentially also MAS, may be less effective in COVID-19, as the overall activation of the IL-18-IFN- axis seems far less pronounced in context of SARS-CoV-2 infection. In contrast to IL-18 and IFN-, IL-1Ra levels in COVID-19 are substantially elevated.”
“This observation may point to a limited utility of therapeutic IL-1 blockade in patients with COVID-19 since high endogenous levels of IL-1Ra have been reported to indicate rather poor response to drugs neutralizing IL-1 or IL-1-signaling,” they added. “However, elevated circulating concentrations of IL-1Ra usually reflect an IL-1 signature, such as the correct timing of IL-1 blockade in COVID-19 may be critical and likely complicates the interpretation of present data. Thus, early intervention upon acute hyperinflammatory respiratory failure can have a therapeutic effect.”
The researchers added that the IL-18-IFN- axis is “certainly” active in critical COVID-19, although at a different level than sHLH or MAS. As such, targeting this axis and IL-1 simultaneously may prove to be rescue treatment for extremely ill patients, they wrote.
“A corresponding RCT is ongoing,” Kessel and colleagues wrote. “Indeed, 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.”