Confronting the controversy: interleukin-6 and the COVID-19 cytokine storm syndrome

Abstract

Hypercytokinaemic immune dysregulation in COVID-19 is known as cytokine storm syndrome. Interleukin-6 levels ≥80 pg·mL⁻¹ predict an increased risk of respiratory failure and death, and immunomodulatory therapy is an area of urgent investigation. https://bit.ly/3jq3uJ4

FIGURE 1

Schematic representation of mechanisms by which the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes mild disease in some patients and severe disease in others. In both cases, the virus enters human cells via binding to angiotensin-converting enzyme 2 (ACE2), a transmembrane receptor widely expressed in type II pneumocytes, macrophages, endothelial and other pulmonary cells [24, 25]. a) Mild disease (low incidence of coagulopathy and thrombosis, shorter hospital stay, low critical illness and mortality): these patients have low serum inflammatory cytokines and high tissue reparative growth factors such as epidermal growth factor (EGF), platelet derived growth factor (PDGF), and interleukin (IL)-7 [5]. VEGF: vascular endothelial growth factor. b) Severe disease (high incidence of micro- and macrovascular thrombosis, longer hospital stay, high critical illness, and mortality): many of these patients have cytokine storm, with high serum inflammatory cytokines (such as IL-6, IL-1, IFN-γ) and markers of endothelial activation such as von Willebrand factor (vWF), factor 8 coagulant (F8) and soluble P-selectin (sP-sel), resulting in endothelialitis and microvascular thrombosis [5, 15, 27]. Markedly elevated IL-6 leads to lymphopenia and immunoparalysis which is partially restored by IL-6 blockade [4, 32]. NET: neutrophil extracellular trap; CRP: C-reactive protein.

FIGURE 2

Absolute cytokine levels and their elevation compared to normative values. Depicted are the peak levels for a) interleukin (IL)-6, b) IL-1β and c) tumour necrosis factor (TNF)-α from a Vancouver cohort of 24 critically ill coronavirus disease 2019 (COVID-19) patients. Further, we have represented the corresponding fold difference between cytokine levels observed in the COVID-19 patients and those of healthy controls (i.e. normative values) on the right-sided figure for each cytokine. These normative values can be seen as a horizontal dashed line for IL-6 (value 0.71 pg·mL⁻¹), IL-1β (value 0.064 pg·mL⁻¹) and TNF-α (value 2.23 pg·mL⁻¹). All values were derived from the Simoa HD-1 analyser [13, 33].