A review of cytokine-based pathophysiology of Long COVID symptoms

Russell N Low, Ryan J Low, Athena Akrami, Russell N Low, Ryan J Low, Athena Akrami

Abstract

The Long COVID/Post Acute Sequelae of COVID-19 (PASC) group includes patients with initial mild-to-moderate symptoms during the acute phase of the illness, in whom recovery is prolonged, or new symptoms are developed over months. Here, we propose a description of the pathophysiology of the Long COVID presentation based on inflammatory cytokine cascades and the p38 MAP kinase signaling pathways that regulate cytokine production. In this model, the SARS-CoV-2 viral infection is hypothesized to trigger a dysregulated peripheral immune system activation with subsequent cytokine release. Chronic low-grade inflammation leads to dysregulated brain microglia with an exaggerated release of central cytokines, producing neuroinflammation. Immunothrombosis linked to chronic inflammation with microclot formation leads to decreased tissue perfusion and ischemia. Intermittent fatigue, Post Exertional Malaise (PEM), CNS symptoms with "brain fog," arthralgias, paresthesias, dysautonomia, and GI and ophthalmic problems can consequently arise as result of the elevated peripheral and central cytokines. There are abundant similarities between symptoms in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). DNA polymorphisms and viral-induced epigenetic changes to cytokine gene expression may lead to chronic inflammation in Long COVID patients, predisposing some to develop autoimmunity, which may be the gateway to ME/CFS.

Keywords: COVID-19; Chronic Fatigue Syndrome; Dysautonomia; Long COVID; Myalgic Encephalomyelitis (ME); cytokines; neuroinflammation; post-acute sequelae of COVID-19.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2023 Low, Low and Akrami.

Figures

Figure 1
Figure 1
Grading of the Cytokine Release Syndrome. Activation of T cells induces a release of IFN-γ or TNF-α. This process activates macrophages and other immune cells, releasing proinflammatory cytokines. Large amounts of IL-6 are released, which in a positive feedback loop activates T cells and other immune cells. Reproduced from “Cytokine Release Syndrome” by AJ Shimabukuro-Vornhagen, P Gödel, M. Subklewe, HJ Stemmler, HA Schlößer, M Schlaak, et al. 2018 Immunother. Cancer 56 (http://creativecommons.org/licenses/by/4.0/).
Figure 2
Figure 2
Proposed model of pathophysiology underlying CNS-mediated Long COVID symptoms.
Figure 3
Figure 3
Schematic of microglial polarization states and functions. Reproduced from “Targeting microglial activation states as a therapeutic avenue in Parkinson’s disease” by SR Subramaniam and HJ Federoff. (http://creativecommons.org/licenses/by/4.0/).
Figure 4
Figure 4
SARS-CoV-2 induces overwhelming inflammation by directly activating p38 and downregulating the Ang1-7 inhibitory pathway. Reproduced from “The role of antioxidants in the chemistry of oxidative stress: a review” by AM Pisoschi and A Pop. (http://creativecommons.org/licenses/by/4.0/).
Figure 5
Figure 5
Epigenetic mechanisms altering gene expression. Reproduced from “A Scientific Illustration of How Epigenetic Mechanisms can Affect Health.” National Institutes of Health. (Image available for public use).

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