A Deep Look Into COVID-19 Severity Through Dynamic Changes in Blood Cytokine Levels

Abstract

An excessive inflammatory response to SARS-CoV-2 is thought to be a major cause of disease severity and mortality in patients with COVID-19. Longitudinal analysis of cytokine release can expand our understanding of the initial stages of disease development and help to identify early markers serving as predictors of disease severity. In this study, we performed a comprehensive analysis of 46 cytokines (including chemokines and growth factors) in the peripheral blood of a large cohort of COVID-19 patients (n=444). The patients were classified into five severity groups. Longitudinal analysis of all patients revealed two groups of cytokines, characterizing the “early” and “late” stages of the disease course and the switch between type 1 and type 2 immunity. We found significantly increased levels of cytokines associated with different severities of COVID-19, and levels of some cytokines were significantly higher during the first three days from symptom onset (DfSO) in patients who eventually required intensive care unit (ICU) therapy. Additionally, we identified nine cytokines, TNF-α, IL-10, MIG, IL-6, IP-10, M-CSF, G-CSF, GM-CSF, and IFN-α2, that can be used as good predictors of ICU requirement at 4-6 DfSO.

Off‐target effects of bacillus Calmette–Guérin vaccination on immune responses to SARS‐CoV‐2: implications for protection against severe COVID‐19

“…Of the 12 cytokines found to have reduced SARS-CoV-2induced secretion following BCG vaccination in our study, nine have been associated with severe COVID-19, namely G-CSF, 16,17 GM-CSF, 18,19 HGF, 18 IL-6, 17,18,[20][21][22][23][24][25] IL-10, [16][17][18][20][21][22][23] LIF, 18 MIP-1b (CCL4), 18 RANTES (CCL5) 18,24 and TNF-a. 17,18,20,24,25 MIP-1b and RANTES (CCL5), however, have also been reported to be lower in severe than in mild cases. 21 Therefore, the reduced SARS-CoV-2induced secretion of these cytokines following BCG vaccination suggests that BCG might protect against severe COVID-19 by suppressing pathological cytokine responses.…”

“…14,15 In our study, the effects of BCG vaccination on cytokine responses are opposite to the immunophenotypes associated with severe COVID-19. Of the 12 cytokines found to have reduced SARS-CoV-2induced secretion following BCG vaccination in our study, nine have been associated with severe COVID-19, namely G-CSF, 16,17 GM-CSF, 18,19 HGF, 18 IL-6, 17,18,[20][21][22][23][24][25] IL-10, [16][17][18][20][21][22][23] LIF, 18 MIP-1b (CCL4), 18 RANTES (CCL5) 18,24 and TNF-a. 17,18,20,24,25 MIP-1b and RANTES (CCL5), however, have also been reported to be lower in severe than in mild cases.…”

“…Effect of BCG vaccination on immune responses to c-irradiated SARS-CoV-2. Volcano and Tukey boxplots depicting differences in cirradiated SARS-CoV-2 (iSARS) stimulation effect (iSARS-iVero response) on whole-blood (a, b) cytokine (n = 50), (c, d) immune cell population (n =17) and (e, f) extracellular marker (n = 17) responses 3 months after randomisation. Differences in iSARS stimulation effect measured by the Wilcoxon signed-rank test comparing the iSARS stimulation effect at 3 months (m3) post-randomisation with the iSARS stimulation effect at baseline (d0).…”

The COVID-19 pandemic — what have urologists learned?

“…Results from a study including 41 hospitalized patients with COVID-19 showed higher plasma concentration of multiple cytokines, such as IL-2, IL-7, IL-10, granulocyte colony-stimulating factor (G-CSF) and tumour necrosis factor (TNF) in patients treated in the intensive care unit (ICU) 51 than in patients in the non-ICU group 48 . In another study, the concentration of numerous cytokines was significantly higher in patients with COVID-19 ( n = 44) than in healthy individuals ( n = 66, P < 0.05) and cytokine levels were shown to be associated with different extents of COVID-19 severity 52 . However, no single definition for the term cytokine storm is widely accepted and the line between a normal and a dysregulated response to a severe infection is blurred 47 .…”

“… 31 ), but the pathophysiological background of AKI is not fully understood. A wide range of severe pathological changes can be found in kidney tissue samples from patients with COVID-19 (refs 41 , 42 , 44 ), but whether this damage is caused by an exuberant systemic inflammatory response 31 , 41 , 48 – 50 , 52 or by a direct cytopathic effect of SARS-CoV-2 (refs 31 , 53 – 55 ) is still unclear. However, physicians should consider COVID-19 as a potential diagnosis for patients showing fever and signs of AKI.…”