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Clinical Trial
. 2021 Jan;109(1):55-66.
doi: 10.1002/JLB.3COVA0820-410RRR. Epub 2020 Sep 15.

Cytokine release syndrome in COVID-19: Innate immune, vascular, and platelet pathogenic factors differ in severity of disease and sex

Aaron C Petrey  1   2 , Fares Qeadan  3 , Elizabeth A Middleton  1   4 , Irina V Pinchuk  5 , Robert A Campbell  1   4 , Ellen J Beswick  2   4
Affiliations
Clinical Trial

Cytokine release syndrome in COVID-19: Innate immune, vascular, and platelet pathogenic factors differ in severity of disease and sex

Aaron C Petrey et al. J Leukoc Biol. 2021 Jan.

Abstract

COVID-19 rapidly emerged as a crippling public health crisis in the last few months, which has presented a series health risk. Understanding of the immune response and biomarker analysis is needed to progress toward understanding disease pathology and developing improved treatment options. The goal of this study is to identify pathogenic factors that are linked to disease severity and patient characteristics. Patients with COVID-19 who were hospitalized from March 17 to June 5, 2020 were analyzed for clinical features of disease and soluble plasma cytokines in association with disease severity and sex. Data from COVID-19 patients with acute illness were examined along with an age- and gender-matched control cohort. We identified a group of 16 soluble factors that were found to be increased in COVID-19 patients compared to controls, whereas 2 factors were decreased. In addition to inflammatory cytokines, we found significant increases in factors known to mediate vasculitis and vascular remodeling (PDGF-AA, PDGF-AB-BB, soluble CD40L (sCD40L), FGF, and IP10). Four factors such as platelet-derived growth factors, fibroblast growth factor-2, and IFN-γ-inducible protein 10 were strongly associated with severe disease and ICU admission. Th2-related factors (IL-4 and IL-13) were increased with IL-4 and sCD40L present at increased levels in males compared with females. Our analysis revealed networking clusters of cytokines and growth factors, including previously unknown roles of vascular and stromal remodeling, activation of the innate immunity, as well activation of type 2 immune responses in the immunopathogenesis of COVID-19. These data highlight biomarker associations with disease severity and sex in COVID-19 patients.

Keywords: .

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Figures

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Graphical abstract
FIGURE 1
FIGURE 1
COVID-19 infected patients have increased plasma proinflammatory cytokines/chemokines as shown by multiplex array, where 8 analytes are significantly increased compared to control plasma (A–H). *P < 0.05 by two samples t-test
FIGURE 2
FIGURE 2
COVID-19 infected patients have increased plasma anti-inflammatory cytokines as shown by multiplex array where (A) IL-10 and (B) IL-1RA are increased significantly compared to control patients and (C) 99% classification power between COVID-19 patients and controls IL-10 receiver operating characteristic (ROC) curve shows that IL-10 classifies COVID-19 infection 99% of the time. *P < 0.05 by two samples t-test
FIGURE 3
FIGURE 3
COVID-19 infected patients have increased plasma factors of vasculitis/vascular remodeling as shown by multiplex array, where 5 analytes are significantly increased compared to control plasma (A–E). *P < 0.05 by two samples t-test
FIGURE 4
FIGURE 4
COVID-19 infected patients have decreased plasma factors (A) macrophage-derived chemokine (MDC) and (B) FLT-3L, and (C) multiple factors associated with severe disease compared to moderate disease (ICU vs. non-ICU). (D) MDC decrease and TNF-α predicting acute-respiratory distress syndrome (ARDS) status 86% of the time correctly. *P < 0.05 by two samples t-test
FIGURE 5
FIGURE 5
COVID-19 infected patients have increased Th2 factors (A) IL-4 and (B) IL-13 and differences between female and male levels of (C) IL-4 and (D) sCD40L that (E) classify biologic sex status 73.5% of the time correctly. *P < 0.05 by two samples t-test
FIGURE 6
FIGURE 6
Discrete clusters of cytokines differ in plasma between (A) control and (B) COVID-19 as shown by Spearman correlation with (C) IL-6 levels able to classify patients with COVID-19 infection 99% of the time
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