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

Arthritis Rheumatol. 2021 Oct;73(10):1791-1799. doi: 10.1002/art.41763. Epub 2021 Sep 3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers / blood
  • COVID-19 / blood
  • COVID-19 / complications
  • COVID-19 / diagnosis*
  • Cytokine Release Syndrome / blood
  • Cytokine Release Syndrome / etiology*
  • Diagnosis, Differential
  • Female
  • Humans
  • Interleukin-18 / blood*
  • Interleukin-8 / blood*
  • Lymphohistiocytosis, Hemophagocytic / blood
  • Lymphohistiocytosis, Hemophagocytic / complications
  • Lymphohistiocytosis, Hemophagocytic / diagnosis*
  • Macrophage Activation Syndrome / blood
  • Macrophage Activation Syndrome / complications
  • Macrophage Activation Syndrome / diagnosis*
  • Male
  • Middle Aged
  • Young Adult


  • Biomarkers
  • Interleukin-18
  • Interleukin-8