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Meta-Analysis
. 2021 Jun 29;16(6):e0253894.
doi: 10.1371/journal.pone.0253894. eCollection 2021.

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

Ana Karla G Melo  1   2 , Keilla M Milby  2 , Ana Luiza M A Caparroz  2   3 , Ana Carolina P N Pinto  2   4   5 , Rodolfo R P Santos  2   6 , Aline P Rocha  2 , Gilda A Ferreira  7 , Viviane A Souza  8 , Lilian D A Valadares  9 , Rejane M R A Vieira  10   11 , Gecilmara S Pileggi  12 , Virgínia F M Trevisani  2   13
Affiliations
Meta-Analysis

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

Ana Karla G Melo et al. PLoS One. .

Abstract

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, ClinicalTrials.gov, 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 Grey literature searches and snowballing techniques were additionally utilized to identify yet-unpublished works and related citations.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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Study selection process flow chart.
Fig 2
Fig 2
Forest plots of interleukin-6 (2A and 2B) and of ferritin (2C and 2D) in severe and fatal cases of COVID-19.
See this image and copyright information in PMC

References

    1. World Health Organization 2020. Available from: www.who.int.
    1. Soy M, Atagündüz P, Atagündüz I, Sucak GT. Hemophagocytic lymphohistiocytosis: a review inspired by the COVID-19 pandemic. Rheumatol Int. 2020:1–12. Epub 2020/06/27. doi: 10.1007/s00296-020-04636-y ; PubMed Central PMCID: PMC7315691. - DOI - PMC - PubMed
    1. Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science. 2020;368(6490):473–4. Epub 2020/04/19. doi: 10.1126/science.abb8925 . - DOI - PubMed
    1. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033–4. Epub 2020/03/21. doi: 10.1016/S0140-6736(20)30628-0 ; PubMed Central PMCID: PMC7270045. - DOI - PMC - PubMed
    1. Ramos-Casals M, Brito-Zerón P, López-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet. 2014;383(9927):1503–16. Epub 2013/12/03. doi: 10.1016/S0140-6736(13)61048-X . - DOI - PubMed