Deciphering the COVID-19 cytokine storm: Systematic review and meta-analysis

Eur J Clin Invest. 2021 Jan;51(1):e13429. doi: 10.1111/eci.13429. Epub 2020 Nov 2.


Introduction: The coronavirus pandemic has affected more than 20 million people so far. Elevated cytokines and suppressed immune responses have been hypothesized to set off a cytokine storm, contributing to ARDS, multiple-organ failure and, in the most severe cases, death. We aimed to quantify the differences in the circulating levels of major inflammatory and immunological markers between severe and nonsevere COVID-19 patients.

Methods: Relevant studies were identified from PubMed, EMBASE, Web of Science, SCOPUS and preprint servers. Risk of bias was assessed for each study, using appropriate checklists. All studies were described qualitatively and a subset was included in the meta-analysis, using forest plots.

Results: Based on 23 studies, mean cytokine levels were significantly higher (IL-6: MD, 19.55 pg/mL; CI, 14.80, 24.30; IL-8: MD, 19.18 pg/mL; CI, 2.94, 35.43; IL-10: MD, 3.66 pg/mL; CI, 2.41, 4.92; IL-2R: MD, 521.36 U/mL; CI, 87.15, 955.57; and TNF-alpha: MD, 1.11 pg/mL; CI, 0.07, 2.15) and T-lymphocyte levels were significantly lower (CD4+ T cells: MD, -165.28 cells/µL; CI, -207.58, -122.97; CD8+ T cells: MD, -106.51 cells/µL; CI, -128.59, -84.43) among severe cases as compared to nonsevere ones. There was heterogeneity across studies due to small sample sizes and nonuniformity in outcome assessment and varied definitions of disease severity. The overall quality of studies was sub-optimal.

Conclusion: Severe COVID-19 is characterized by significantly increased levels of pro-inflammatory cytokines and reduced T lymphocytes. Well-designed and adequately powered prospective studies are needed to amplify the current evidence and provide definitive answers to dilemmas regarding timing and type of anti-COVID-19 therapy particularly in severe patients.

Keywords: CD4+ T cells; CD8+ T cells; COVID-19; SARS-CoV-2; cytokine storm; novel coronavirus.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • CD4 Lymphocyte Count
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • COVID-19 / blood
  • COVID-19 / immunology*
  • Cytokine Release Syndrome / immunology*
  • Cytokines / immunology*
  • Humans
  • Interleukin-10 / immunology
  • Interleukin-6 / immunology
  • Interleukin-8 / immunology
  • Lymphocyte Count
  • Receptors, Interleukin-2 / immunology
  • SARS-CoV-2
  • Severity of Illness Index
  • Tumor Necrosis Factor-alpha / immunology


  • Cytokines
  • Interleukin-6
  • Interleukin-8
  • Receptors, Interleukin-2
  • Tumor Necrosis Factor-alpha
  • Interleukin-10