Discrimination of COVID‐19 From Inflammation‐Induced Cytokine Storm Syndromes Using Disease‐Related Blood Biomarkers

Abstract

Objective Infection with the novel coronavirus SARS–CoV‐2 triggers severe illness with high mortality in a subgroup of patients. Such a critical course of COVID‐19 is thought to be associated with the development of cytokine storm, a condition seen in macrophage activation syndrome (MAS) and secondary hemophagocytic lymphohistiocytosis (HLH). However, specific data demonstrating a clear association of cytokine storm with severe COVID‐19 are still lacking. The aim of this study was to directly address whether immune activation in COVID‐19 does indeed mimic the conditions found in these classic cytokine storm syndromes. Methods Levels of 22 biomarkers were quantified in serum samples from patients with COVID‐19 (n = 30 patients, n = 83 longitudinal samples in total), patients with secondary HLH/MAS (n = 50), and healthy controls (n = 9). Measurements were performed using bead array assays and single‐marker enzyme‐linked immunosorbent assay. Serum biomarker levels were assessed for correlations with disease outcome. Results In patients with secondary HLH/MAS, we observed pronounced activation of the interleukin‐18 (IL‐18)–interferon‐γ axis, increased serum levels of IL‐1 receptor antagonist, intercellular adhesion molecule 1, and IL‐8, and strongly reduced levels of soluble Fas ligand in the course of SARS–CoV‐2 infection. These observations appeared to discriminate immune dysregulation in critical COVID‐19 from the well‐recognized characteristics of other cytokine storm syndromes. Conclusion Serum biomarker profiles clearly separate COVID‐19 from MAS or secondary HLH in terms of distinguishing the severe systemic hyperinflammation that occurs following SARS–CoV‐2 infection. These findings could be useful in determining the efficacy of drugs targeting key molecules and pathways specifically associated with systemic cytokine storm conditions in the treatment of COVID‐19.

Calming the cytokine storm in COVID-19

“…One thing that is clearly emerging from this pandemic is that the CSS associated with COVID-19 is relatively unique, with only modestly elevated levels of IL-6, CRP and ferritin, for example. Studies exploring serum biomarkers clearly distinguish COVID-19induced CSS from more classic CSS such as macrophage-activation syndrome or hemophagocytic lymphohistiocytosis 10 . Conceivably, some of the relatively lower cytokine levels in patients with COVID-19 CSS may be related to the profound lymphopenia seen in these patients.…”

“…Beyond glucocorticoids, it remains to be seen precisely which targeted approaches are likely to be effective in treating the unique CSS induced by COVID-19. The finding of elevated levels of endogenous antagonist to the IL-1 receptor in patients with severe COVID-19 suggests that there is an IL-1 gene signature 10 . Perhaps IL-1 blockade with anakinra in select patients with COVID-19 pneumonia will gain traction as further data emerge.…”

Rapid and Effective Vitamin D Supplementation May Present Better Clinical Outcomes in COVID-19 (SARS-CoV-2) Patients by Altering Serum INOS1, IL1B, IFNg, Cathelicidin-LL37, and ICAM1

“…IFNg serum levels were found to be decreased in COVID-19 compared with both macrophage activation syndrome (MAS) and secondary hemophagocytic lymphohistiocytosis (sHLH), in which cytokine storm is seen [50]. In a study that investigated the expression levels of several cytokine genes in leukocytes of ICU and non-ICU COVID-19 patients, it was shown that IFNg had higher expression levels in non-ICU than in ICU patients [51].…”

“…Li et al showed that serum VCAM-1 and ICAM-1 levels were elevated in mild and severe COVID-19 cases compared with healthy subjects [61]. Kessel et al were found that serum levels of ICAM-1 were increased in COVID-19 patients compared with both (MAS) and (sHLH) patients [50]. In COVID-19-related acute respiratory distress syndrome, plasma ICAM-1 levels were found to be higher in non-survivors than in survivors [62].…”

Aging whole blood transcriptome reveals candidate genes for SARS-CoV-2-related vascular and immune alterations

“…These immune responses are thought to drive antiviral immunity against SARS-CoV-2. By contrast, recent studies using blood cells of patients with severe COVID-19 found decreased levels of sFASLG and increased blood sVCAM1 levels following disease progression [ 58 , 59 ]. These contradictory results on FASLG levels might be due to the kind of secreted FASLG or the particular biological response of patients unrelated to blood aging.…”