Biomarkers of cytokine storm as red flags for severe and fatal COVID-19 cases: A living systematic review and meta-analysis

PLoS One. 2021 Jun 29;16(6):e0253894. doi: 10.1371/journal.pone.0253894. eCollection 2021.


Objective: To describe the laboratory parameters and biomarkers of the cytokine storm syndrome associated with severe and fatal COVID-19 cases.

Methods: A search with standardized descriptors and synonyms was performed on November 28th, 2020 of the MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials,, LILACS, and IBECS to identify studies of interest. Grey literature searches and snowballing techniques were additionally utilized to identify yet-unpublished works and related citations. Two review authors independently screened the retrieved titles and abstracts, selected eligible studies for inclusion, extracted data from the included studies, and then assessed the risk of bias using the Newcastle-Ottawa Scale. Eligible studies were those including laboratory parameters-including serum interleukin-6 levels-from mild, moderate, or severe COVID-19 cases. Laboratory parameters, such as interleukin-6, ferritin, hematology, C-Reactive Protein, procalcitonin, lactate dehydrogenase, aspartate aminotransferase, creatinine, and D-dimer, were extracted from the studies. Meta-analyses were conducted using the laboratory data to estimate mean differences with associated 95% confidence intervals.

Data synthesis: The database search yielded 9,620 records; 40 studies (containing a total of 9,542 patients) were included in the final analysis. Twenty-one studies (n = 4,313) assessed laboratory data related to severe COVID-19 cases, eighteen studies (n = 4,681) assessed predictors for fatal COVID-19 cases and one study (n = 548) assessed laboratory biomarkers related to severe and fatal COVID-19 cases. Lymphopenia, thrombocytopenia, and elevated levels of interleukin-6, ferritin, D-dimer, aspartate aminotransferase, C-Reactive-Protein, procalcitonin, creatinine, neutrophils and leucocytes were associated with severe and fatal COVID-19 cases.

Conclusions: This review points to interleukin-6, ferritin, leukocytes, neutrophils, lymphocytes, platelets, C-Reactive Protein, procalcitonin, lactate dehydrogenase, aspartate aminotransferase, creatinine, and D-dimer as important biomarkers of cytokine storm syndrome. Elevated levels of interleukin-6 and hyperferritinemia should be considered as red flags of systemic inflammation and poor prognosis in COVID-19.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Biomarkers / blood*
  • C-Reactive Protein / analysis
  • COVID-19 / complications
  • COVID-19 / mortality
  • COVID-19 / pathology*
  • COVID-19 / virology
  • Cytokine Release Syndrome / diagnosis*
  • Cytokine Release Syndrome / etiology
  • Ferritins / blood
  • Humans
  • Interleukin-6 / blood
  • Leukocytes / cytology
  • Leukocytes / metabolism
  • SARS-CoV-2 / isolation & purification
  • Severity of Illness Index


  • Biomarkers
  • Interleukin-6
  • C-Reactive Protein
  • Ferritins

Grant support

The author(s) received no specific funding for this work.