The cytokine storms of COVID-19, H1N1 influenza, CRS and MAS compared. Can one sized treatment fit all?

Abstract

An analysis of published data appertaining to the cytokine storms of COVID-19, H1N1 influenza, cytokine release syndrome (CRS), and macrophage activation syndrome (MAS) reveals many common immunological and biochemical abnormalities. These include evidence of a hyperactive coagulation system with elevated D-dimer and ferritin levels, disseminated intravascular coagulopathy (DIC) and microthrombi coupled with an activated and highly permeable vascular endothelium. Common immune abnormalities include progressive hypercytokinemia with elevated levels of TNF-α, interleukin (IL)-6, and IL-1β, proinflammatory chemokines, activated macrophages and increased levels of nuclear factor kappa beta (NFκB). Inflammasome activation and release of damage associated molecular patterns (DAMPs) is common to COVID-19, H1N1, and MAS but does not appear to be a feature of CRS. Elevated levels of IL-18 are detected in patients with COVID-19 and MAS but have not been reported in patients with H1N1 influenza and CRS. Elevated interferon-γ is common to H1N1, MAS, and CRS but levels of this molecule appear to be depressed in patients with COVID-19. CD4+ T, CD8+ and NK lymphocytes are involved in the pathophysiology of CRS, MAS, and possibly H1N1 but are reduced in number and dysfunctional in COVID-19. Additional elements underpinning the pathophysiology of cytokine storms include Inflammasome activity and DAMPs. Treatment with anakinra may theoretically offer an avenue to positively manipulate the range of biochemical and immune abnormalities reported in COVID-19 and thought to underpin the pathophysiology of cytokine storms beyond those manipulated via the use of, canakinumab, Jak inhibitors or tocilizumab. Thus, despite the relative success of tocilizumab in reducing mortality in COVID-19 patients already on dexamethasone and promising results with Baricitinib, the combination of anakinra in combination with dexamethasone offers the theoretical prospect of further improvements in patient survival. However, there is currently an absence of trial of evidence in favour or contravening this proposition. Accordingly, a large well powered blinded prospective randomised controlled trial (RCT) to test this hypothesis is recommended.

Keywords: COVID-19; Cytokine storm; Immune; Inflammation; Interleukin-1; Interleukin-6.

Fig. 1

The potential origin of the COVID-19 cytokine storm A proposed early event in the development of the COVID-19 cytokine storm is the activation of endothelial cells by SARSCOV2 and or the presence of high levels of proinflammatory cytokines chemokines and ROS species. Such activation is associated with increased STAT-3, NFκB and activation of the NLRP3 inflammazome. The net result is the release of proinflammatory cytokines IL-1, TNF alpha, IL-6, IL-8 and reactive oxygen species (ROS) and the subsequent recruitment of macrophages and neutrophils which become an additional source of IL-1, IL-6, TNF alpha, ROS and several damage associated molecular patterns (DAMPS). IL-1 and IL-6 may engage in autoinflammatory signalling via targeting their receptors on endothelial cells leading to a self-amplifying cascade of inflammation and oxidative stress. Increasing levels of PICs and ROS result in loss of NK and CD8 T cell numbers and function increasing macrophage survival further amplifying PIC and ROS production and compromising macrophage efferocytosis. The resulting increase in survival of NET producing neutrophils further adds to pathological levels of PICs and ROS ultimately resulting in the pyroptosis and necrosis of immune cells and widespread tissue damage The resulting release of DAMPs may trigger further activation of immune and endothelial cells which further sustains and amplifies the inflammatory cascade.

Fig. 2

IL-6 signalling Trans IL-6 signalling is initiated via binding with the soluble receptors and IL-6R/sIL-6R and subsequent engagement of the complex with the trans membrane gp130 receptor possessed by a endothelial cells lymphocytes and leucocytes reviewed this engagement results in the activation of STAT-3 which is in turn phosphorylated by JAK kinase resulting in the nuclear translocation of NFKB SOCS proteins are the main inhibitors of IL-6 -STAT-3 signalling in the immune response and plays a major role in preventing a prolonged or over exuberant immune response. In classical signalling both GP130 the IL-6 receptor are membrane bound and the consequences of signal activation are broadly anti-inflammatory in nature.

Fig. 3

Mechanisms underpinning CRS Massive production of TNF alpha and INF gamma by activated T cells activates monocytes and macrophages which in turn produce large amounts of TNF alpha IL-1 and IL-6. These cytokines activate endothelial cells which then increase the production of IL-1 TNF alpha and IL-6 resulting in the production of an autoinflammatory cascade and escalating activation of the coagulation cascade.

Fig. 4

Mechanisms underpinning the development of MAS Increased production of IL-1, IL-18 and secondary IL-6 and TNF alpha inflammation in the context of a viral infection or inflammazome activation upregulates CD8+ T cell and NK activity and proliferation of macrophages. Impaired clearance of the latter in the context of defects in the cytolytic function of CD8+ lymphocytes and NK cells predisposes to chronic macrophage activation resulting in prolonged and excessive production of TNF alpha and IL-1. The latter inducing further increases in the activity of CD8 T cells and NK cells and the development of self-amplifying inflammation, resulting in a cytokine storm.