A Cytokine-based model for the pathophysiology of Long COVID symptoms

[Wishful]

https://osf.io/7gcnv/

I'm posting it here because it involves a lot of discussion about ME and the similarities between the two. I liked this part:

"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"

This was also the first time I read that long-covid victims suffered PEM, similar to what PWME do.

I do hope that ME researchers are taking advantage of funding available for long-covid research. Any research into PEM should qualify.

 

[bensmith]

i def got pem later, months after persistant covid. i think most will resolve and not get pem. i am happy for htem but sad for me, i wish there were millions of me in the us, as that would get more research and attention.

 

[ljimbo423]

Very interesting @Wishful.

Here's the "Highlights, Summary and Abstract". Below is a link to the full paper in PDF form.

HIGHLIGHTS
● Long COVID patients include millions of people worldwide, and persistent symptoms following COVID-19 can continue for months.

● Varied and relapsing symptoms of Long Covid can be attributed to elevated peripheral and central cytokines, generated by an abnormal immune response.

● CNS effects may be due to direct viral invasion or an indirect immune response.

● Dysregulated activation of brain microglia, due to neuroinflammation, can cause centrally mediated symptoms.

● Upregulation of the p38 MAPK pathway by SARS-Cov-2 can be a possible mechanism by which the virus increases cytokine production.

● Progression to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may be possible and could involve development of autoimmunity.

Summary
Dysregulated immune-inflammatory response with elevated peripheral and central cytokines can explain Long COVID symptoms. Hyperreactive brain microglia can modulate a host of CNS-mediated symptoms.

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.

Link to full paper in PDF form

 

[lenora]

Thanks to @Wishful, @ljimbo423 and @Pyrrhus for their kindness in seeking and putting this in a form for us to understand. You're all wonderful at doing that and, I for one, do appreciate it. I know that others do, also. Yes, sadly, I'm afraid that a lot of these "survivors" will be joining us for years to come. Yours, Lenora.

 

[Mohawk1995]

In my "functional physiology" view (my expertise is not in biomolecular science), the two key features that are consistent between Long COVID and ME/CFS are the shut down of energy production (mitochondrial dysfunction) and Neuro-inflammation (Cytokines being most impactful). This accounts for (at least in part) the key functional features these two pathophysiological process can display: Fatigue, PEM, Brain Fog, Unusual Sensations and Pain.

There are other similar disorders sharing this common link like Chronic Lyme disease and Post Concussive Syndrome that I believe have the same two physiologic process at play.

There are others that seem to have more Neuro-inflammatory related physiology including a whole range of pain disorders (Fibromyalgia, CRPS, Migraines) and immune/autoimmune related like MCAS, Polymyositis, MS, Lupus, IBS, Rheumatoid disorders and more. However, even in most of these there is a fatigue component that is likely related to Mitochondrial Dysfunction.

A key point in the practice of medicine and one that is often forgotten is that there must be a match between the functional condition (presentation) of the person and the diagnostic tests results. In other words, one must be able to link the physiological presentation to the test findings. This takes someone who has the clinical experience and knowledge of human physiology and pathophysiology to make the connection.

That is the difference between a non-medically trained person (even the best of research scientists) and a medical provider. Or at least that should be the difference. Unfortunately our medical system has come to the belief (not fact or truth) that diagnostic tests are the only "source of truth". If we can't find a diagnostic test to prove our theory, then our theory is wrong.

Viewing things from a Physical Therapist's point of view, how the patient presents is the pure truth. Diagnostic Tests, when they can be correlated with the patient presentation only confirm the truth and provide further understanding of the problem. I must also be open to the fact that what I think is happening is not accurate. Maybe it is inaccurate because it is not a complete explanation (most often the case) or maybe it is just plain wrong. That still does not negate that the patient presentation is THE TRUTH.

Perhaps if more in medicine would take this approach, we would have better success treating the more chronic and difficult diseases to treat like ME/CFS.

 

[Wishful]

the two key features that are consistent between Long COVID and ME/CFS are the shut down of energy production (mitochondrial dysfunction)

That's not actually consistent. My 'energy level' didn't change when I developed ME. I expect that my mitochondria, at least in most parts of my body, are producing ATP just fine. I think the energy loss is a common downstream effect of ME and other related diseases, but not an essential part of it. Certain events, such as viral infection, can make me feel more physically limited, but I'm not sure whether that involves reduced ATP production; it could be neural dysfunction instead.

 

[lenora]

Or, it could be that ME is present in our bodies many years before it actually manifests itself. I think many things are simply early signs of what is to come....IBS, muscles fatigue and many things of both natures. Viral is involved, but I think that has as much to do with our bodies being overloaded to begin with than anything else.

One thing's certain....this illness does exist and I do believe the medical field is becoming more and more accepting of that by the day.

 

[Pyrrhus]

One thing's certain....this illness does exist and I do believe the medical field is becoming more and more accepting of that by the day.

I do hope you're right that they are becoming more accepting of Long Covid.
Whether that will translate to more constructive research remains to be seen...

 

[Mary]

This was also the first time I read that long-covid victims suffered PEM, similar to what PWME do.

You might want to take a look at this thread about Paul Garner, an epidemiologist with NICE who developed PEM after having COVID. He'd been an athlete before falling ill, very physically active. He's written several blogs about it in the British Medical Journal (there's a link to these blog posts in that thread I just linked), has some interviews on youtube, has been quite a presence advocating for the removal of GET and CBT. I wonder if he may have been a factor in NICE deciding to remove GET from its recommendations for ME/CFS in its new draft guidelines: The new NICE Proposals for the Guidelines are up and SMC gives voice to the Deluded | Phoenix Rising ME/CFS Forums

 

[livinglighter]

Thanks @Wishful for posting this great research paper. I've been waiting for something like this to come out since cytokine storm/breeze has been mentioned as what's possibly causing ME/CFS and Long Covid.