Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes

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; I-2=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.