A Cytokine-based model for the pathophysiology of Long COVID symptoms, 2020, Low et al

[Dolphin]

This contains quite a lot of discussion of ME/CFS, including in the abstract.

Source: OSF Preprints Preprint Date: November 12, 2020 URL: https://osf.io/7gcnv

A Cytokine-based model for the pathophysiology of Long COVID symptoms
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Russell Low(1), Ryan J Low(2), thena Akrami(2)

1. Sharp HealthCare and Sharp Memorial Hospital, 7901 Frost Street San Diego, CA 92123(retired).
2. Sainsbury Wellcome Centre, University College London. 25 Howland St, Fitzrovia, London W1T 4JG, United Kingdom.

* Contact: rnl email: rlow52@yahoo.com

Abstract

The Long COVID group includes patients with mild-to-moderate symptoms, in whom recovery is prolonged, lasting months. Here we propose a model for 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. Intermittent fatigue, Post Exertional Malaise (PEM), CNS symptoms with 'brain fog,' arthralgias, paresthesias, and GI and ophthalmic problems can all be attributed to elevated peripheral and central cytokines.

There are abundant similarities between symptoms in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A post-infectious ME/CFS model involving a dysfunctional peripheral and central cytokine inflammatory response and autoimmunity is emerging. 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, Cytokines, Long COVID, Long Hauler, Neuroinflammation

 

[Creekside]

"These dysregulated microglia are hyperreactive
to signals from the peripheral immune system, producing an exaggerated and prolonged
central cytokine response to an otherwise mild immune challenge. The primed
microglia then become resistant to normal regulation, failing to revert to the quiescent state
after inflammation resolution"

That's how I was imagining my disorder even before I knew about ME: the glial cells somehow getting 'stuck' in an abnormal state.

It's really interesting that long-covid victims get PEM so similarly to PWME.

 

[Ravn]

251 references. If nothing else they've put some work into this. Unfortunately over my head so no idea if it makes any sense. But they do seem to have listened to patients about the nature of PEM at least and are not confusing it with post-exertional fatigue. That's always a good start.

Post-exertional Malaise

Severe post-exercise fatigue and malaise (PEM), is one of the most striking and demoralizing symptoms reported by many of the Long COVID patients. One to two days after a mild-moderate exercise session, Long COVID patients experience marked worsening of symptoms with extreme fatigue, malaise, fever, shortness of breath, and neurological deficits. Dysfunctional mitochondria can partially mediate PEM in muscles and brain microglia with less efficient glycolysis. Subsequent lactic acidosis with increasing ROS, and elevated cytokines results in exercise-induced peripheral and central fatigue [156,164].

[...]

We argue that for the COVID-19 patients, the exercise-induced cytokines may trigger a recurrence of symptoms by reinitiating the same feedback loop pathways that caused the initial symptoms. Essentially, symptoms can all be due to peripheral and central cytokine cascades.

[...]

The delay in onset of symptoms following physical or mental stress is also predictable because the cytokines do not cause the symptoms; they just start the process of immune system recruitment and activation that leads to the symptoms. Cancer immunotherapy drugs produce the CRS with an onset of symptoms within a few days of the drug administration [201]. This timing correlates with the delayed onset of Long COVID symptoms after exercise.

CRS=Cytokine Release Syndrome
I quickly googled CRS and many of the results were related to cancer treatment side effects; it appears rituximab can cause this. No idea what to make of that piece of information.

 

[Jonathan Edwards]

251 references. If nothing else they've put some work into this. Unfortunately over my head so no idea if it makes any sense.

It doesn't make any sense because cytokines do not seem to be released either in ME or Covid much. The bit about cancer drugs is incorrect and irrelevant. I am afraid I think this is an advert for a private healthcare facility touting for business selling the same quackery to Long Covid people as toPWME.

 

[Snow Leopard]

Yeah, nah.

Old discarded theories become new again?

I'm a bit bored of this superficial cytokine hype that fails to explain any illness, except the appropriately named cytokine-release syndrome.

The delay in onset of symptoms following physical or mental stress is also predictable because the cytokines do not cause the symptoms;

Who cares then? It's like saying that one of the pieces in your 1200 piece jigsaw puzzle is essential because otherwise your jigsaw would be incomplete - yes it matters, but it is not central...