TY - JOUR
T1 - Cytokine elevation in severe and critical COVID-19
T2 - a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes
AU - Leisman, Daniel E.
AU - Ronner, Lukas
AU - Pinotti, Rachel
AU - Taylor, Matthew D.
AU - Sinha, Pratik
AU - Calfee, Carolyn S.
AU - Hirayama, Alexandre V.
AU - Mastroiani, Fiore
AU - Turtle, Cameron J.
AU - Harhay, Michael O.
AU - Legrand, Matthieu
AU - Deutschman, Clifford S.
N1 - Funding Information:
MDT is supported in part by the US National Institute of General Medical Sciences, US National Institutes of Health (grant K08 GM 132794). CSC is supported in part by the US National Heart, Lung, and Blood Institute (R35 HL140026); she has received additional grant funding from Roche/Genentech (current) and Bayer (former), and consulting fees from Vasomune, Gen1e Life Sciences, and Quark Pharmaceuticals. CJT's institution, the Fred Hutchinson Cancer Research Center, has held equity in Juno Therapeutics; CJT has received research grants and personal fees for advisory board participation from Juno Therapeutics/Bristol Myers Squibb, during the conduct of the study. He declares fees and stock options in relation to a role on the scientific advisory boards of Precision Biosciences, Caribou Biosciences, Eureka Therapeutics, Myeloid Therapeutics, Century Therapeutics, and ArsenalBio; travel expenses and fees for participation on the advisory boards of Amgen, Novartis, Kite/Gilead, Humanigen, Aptevo, PACT Pharma, AstraZeneca, and Nektar Therapeutics; travel expenses from T-CURX; and research funding from AstraZeneca and Nektar Therapeutics, outside of the submitted work. CJT reports a patent (US patent number 10 653 756; issued May 19, 2020) for the “Identification of CD8+ T cells that are CD161hi and/or IL18Rαhi and have rapid drug efflux capacity for toxicity of CAR-T cells”, for which he receives royalties from the licensee, Juno Therapeutics; a patent pending for “Methods and compositions related to toxicity associated with cell therapy”; a patent pending for “Methods for the treatment of B cell malignancies using adoptive cell therapy”; and a patent pending for “Biomarkers and uses thereof for selecting pancreas immunotherapy intervention”. MOH is supported in part by the US National Heart Lung and Blood Institute (R00 HL 141678). ML discloses research funds from the French Ministry of Health, research support from Shingotec, lecture fees from Baxter and Fresenius, and consulting fees from Novartis. CSD is supported in part by the US National Institute of General Medical Sciences, US National Institutes of Health (R01 GM 121102). He has stock options with Enlivex Therapeutics, outside of the submitted work. CSD reports honoraria from Lippincott Williams & Wilkins (Scientific Editor Critical Care Medicine) and the New York University Department of Anesthesiology (visiting professor); non-financial support for participation in the Bernard-Wiggers Task Force (accommodation) and from the Society of Critical Care Medicine (meeting registration and accommodation); an honorarium, travel expenses, and accommodation from the International Society of Hematology and Thrombosis; and royalties from Elsevier for the textbook Evidence-Based Practice of Critical Care, outside of the submitted work. All other authors declare no competing interests.
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/12
Y1 - 2020/12
N2 - The description of a so-called cytokine storm in patients with COVID-19 has prompted consideration of anti-cytokine therapies, particularly interleukin-6 antagonists. However, direct systematic comparisons of COVID-19 with other critical illnesses associated with elevated cytokine concentrations have not been reported. In this Rapid Review, we report the results of a systematic review and meta-analysis of COVID-19 studies published or posted as preprints between Nov 1, 2019, and April 14, 2020, in which interleukin-6 concentrations in patients with severe or critical disease were recorded. 25 COVID-19 studies (n=1245 patients) were ultimately included. Comparator groups included four trials each in sepsis (n=5320), cytokine release syndrome (n=72), and acute respiratory distress syndrome unrelated to COVID-19 (n=2767). In patients with severe or critical COVID-19, the pooled mean serum interleukin-6 concentration was 36·7 pg/mL (95% CI 21·6–62·3 pg/mL; I2=57·7%). Mean interleukin-6 concentrations were nearly 100 times higher in patients with cytokine release syndrome (3110·5 pg/mL, 632·3–15 302·9 pg/mL; p<0·0001), 27 times higher in patients with sepsis (983·6 pg/mL, 550·1–1758·4 pg/mL; p<0·0001), and 12 times higher in patients with acute respiratory distress syndrome unrelated to COVID-19 (460 pg/mL, 216·3–978·7 pg/mL; p<0·0001). Our findings question the role of a cytokine storm in COVID-19-induced organ dysfunction. Many questions remain about the immune features of COVID-19 and the potential role of anti-cytokine and immune-modulating treatments in patients with the disease.
AB - The description of a so-called cytokine storm in patients with COVID-19 has prompted consideration of anti-cytokine therapies, particularly interleukin-6 antagonists. However, direct systematic comparisons of COVID-19 with other critical illnesses associated with elevated cytokine concentrations have not been reported. In this Rapid Review, we report the results of a systematic review and meta-analysis of COVID-19 studies published or posted as preprints between Nov 1, 2019, and April 14, 2020, in which interleukin-6 concentrations in patients with severe or critical disease were recorded. 25 COVID-19 studies (n=1245 patients) were ultimately included. Comparator groups included four trials each in sepsis (n=5320), cytokine release syndrome (n=72), and acute respiratory distress syndrome unrelated to COVID-19 (n=2767). In patients with severe or critical COVID-19, the pooled mean serum interleukin-6 concentration was 36·7 pg/mL (95% CI 21·6–62·3 pg/mL; I2=57·7%). Mean interleukin-6 concentrations were nearly 100 times higher in patients with cytokine release syndrome (3110·5 pg/mL, 632·3–15 302·9 pg/mL; p<0·0001), 27 times higher in patients with sepsis (983·6 pg/mL, 550·1–1758·4 pg/mL; p<0·0001), and 12 times higher in patients with acute respiratory distress syndrome unrelated to COVID-19 (460 pg/mL, 216·3–978·7 pg/mL; p<0·0001). Our findings question the role of a cytokine storm in COVID-19-induced organ dysfunction. Many questions remain about the immune features of COVID-19 and the potential role of anti-cytokine and immune-modulating treatments in patients with the disease.
UR - http://www.scopus.com/inward/record.url?scp=85095425735&partnerID=8YFLogxK
U2 - 10.1016/S2213-2600(20)30404-5
DO - 10.1016/S2213-2600(20)30404-5
M3 - Review article
C2 - 33075298
AN - SCOPUS:85095425735
SN - 2213-2600
VL - 8
SP - 1233
EP - 1244
JO - The Lancet Respiratory Medicine
JF - The Lancet Respiratory Medicine
IS - 12
ER -