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

Abstract

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.

Figure 1

Selection of studies ARDS=acute respiratory distress syndrome. CAR T cell-induced CRS=chimeric antigen receptor T cell-induced cytokine release syndrome.

Figure 2

Interleukin-6 concentrations in patients with COVID-19 versus comparison disorders (A) Pooled estimate for each disorder. Markers indicate point estimates and error bars indicate 95% CIs. (B) For individual studies, markers indicate study means and error bars indicate standard deviations. Markers are sized proportionately to the log weight of the study in the analysis. Pooled estimates are represented by the solid bars. The black marking in the centre of the bars indicates the point estimate for the disease. The width of the box is scaled according to the pooled number of participants, whereas the width of the bar indicates the 95% CI. ARDS=acute respiratory distress syndrome. CAR=chimeric antigen receptor. CRS=cytokine release syndrome.

Figure 2

Interleukin-6 concentrations in patients with COVID-19 versus comparison disorders (A) Pooled estimate for each disorder. Markers indicate point estimates and error bars indicate 95% CIs. (B) For individual studies, markers indicate study means and error bars indicate standard deviations. Markers are sized proportionately to the log weight of the study in the analysis. Pooled estimates are represented by the solid bars. The black marking in the centre of the bars indicates the point estimate for the disease. The width of the box is scaled according to the pooled number of participants, whereas the width of the bar indicates the 95% CI. ARDS=acute respiratory distress syndrome. CAR=chimeric antigen receptor. CRS=cytokine release syndrome.

Figure 3

Additional cytokines and biomarkers in patients with COVID-19 versus comparison disorders The figure shows pooled mean estimates for secondary analyses of inflammatory cytokines and markers. Markers indicate point estimates and error bars indicate 95% CIs. ARDS=acute respiratory distress syndrome. CRP=C-reactive protein. CRS=cytokine release syndrome. IFNγ=interferon-γ. IL=interleukin. LDH=lactate dehydrogenase. PCT=procalcitonin. sIL-2R=soluble interleukin-2 receptor. TNFα=tumour necrosis factor-α.

Figure 4

Mechanistic comparison of inflammatory processes in patients with COVID-19 versus ARDS, sepsis, and CAR T cell-induced CRS ARDS=acute respiratory distress syndrome. CAR T cell-induced CRS=chimeric antigen receptor T cell-induced cytokine release syndrome. CRP=C-reactive protein. DAMPs=damage-associated molecular patterns. IFN=interferon. IL=interleukin. LDH=lactate dehydrogenase. PAMPs=pathogen-associated molecular patterns. PCT=procalcitonin. ROS=reactive oxygen species. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. ssRNA=single-stranded RNA. vWF=von Willebrand factor. *Effector function measured by ex vivo functional assays.