Converging Evidence of Similar Symptomatology of ME/CFS and PASC Indicating Multisystemic Dyshomeostasis , 2023, Marks

Abstract
:
The purpose of this article is to review the evidence of similar symptomatology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-acute sequelae of SARS-CoV-2 infection (PASC). Reanalysis of data from a study by Jason comparing symptom reports from two groups of ME/CFS and PASC patients shows a notably similar symptomatology.

Symptom scores of the PASC group and the ME/CFS group correlated 0.902 (p < 0.0001) across items. The hypothesis is presented that ME/CFS and PASC are caused by a chronic state of multisystemic disequilibrium including endocrinological, immunological, and/or metabolic changes. The hypothesis holds that a changed set point persistently pushes the organism towards a pathological dysfunctional state which fails to reset.

To use an analogy of a thermostat, if the ‘off switch’ of a thermostat intermittently stops working, for periods the house would become warmer and warmer without limit. The hypothesis draws on recent investigations of the Central Homeostasis Network showing multiple interconnections between the autonomic system, central nervous system, and brain stem. The hypothesis helps to explain the shared symptomatology of ME/CFS and PASC and the unpredictable, intermittent, and fluctuating pattern of symptoms of ME/CFS and PASC. The current theoretical approach remains speculative and requires in-depth investigation before any definite conclusions can be drawn.

https://www.mdpi.com/2227-9059/11/1/180

 

I’m not sure that such hypothesising based on a large number of generic symptoms gets us anywhere useful.

It’s easy to fit just about any narrative to any broad collection of symptoms. We need hard biomedical evidence to identify causes.

And I suspect it’s more productive to go from evidence to hypothesis than from searching for evidence to back up an hypothesis. The latter has been tried for decades without much luck.

I hadn’t appreciated that there was such a high symptom overlap between two diseases, though . Interesting.

 

Recent study/thread re thrombosis & Long Covid*. So, seems like a lot of Long Covid may be related to thrombosis.
Apologies for my usual comment re GWAS, but it would be interesting to see GWAS studies in ME/CFS [DecodeME] & Long Covid --- e.g. is there a subgroup of Long Covid which is similar to ME/CFS or a sub-group of ME/CFS?

*https://www.s4me.info/threads/analy...h-post-covid-syndrome-2022.31119/#post-453383

 

Absolutely. I am afraid that to me multi systemic dyshomeostasis sounds about as hand-waving as biopsychosocial.

If a thermostat misbehaves because a wire has come out it is probably more useful to say a wire has come out than to call it dyshomeostasis.

I am also not convinced by symptom score statistics. I had two months of post-covid fatigue but nothing that I would have confused with ME, despite the fact that I would probably have technically qualified as having PEM on a dodgy questionnaire.

 

I like the concept, and hope that it will spread to other researchers. However, a study based on self-reported questionnaires is pretty flimsy. The reported correlations may only be correlations to normal responses of ill people to those questions. My guess is that if they'd included another few groups suffering from colds, flues, maybe food poisoning or other illnesses, they'd see similar correlations, just because that's how such questionnaires work.

 

I agree that using a fancy word doesn't make it more meaningful. I do believe that ME is an abnormal state that adapts to maintain itself. Imagine that the thermal sensor in a thermostat has changed in a way that changes its response to temperature. You can set the control to 21C, but the sensor produces the 21C signal at 23C, so even if double-check the setting (21C) and you open a window in winter, the thermostat will try to keep the room at 23C. It's trying diligently to do its job properly, but it wasn't designed to deal with a defective sensor.

 

The thermostat analogy is indeed a no-brainer, but we can all think of that, and the reasons why it might be right or wrong. It only gets interesting if you have a proposal for what the specific signal error is. Waving hands at 'multi systems' is the opposite of that.

 

At least they're being humble rather than flaunting their hypothesis as nearly proven.

 

This doesn't get us any closer to a solution, but recognizing that it's a *control system* problem is putting us on the right *path* to a solution, I think.

I was under the impression, several years ago, that Nancy Klimas' group understood that and was using network analysis to craft a solution. Then... nothing.

 

This is important but a lot is being lost in the discussion when restricting to ME. What we are seeing in LC would normally fall across the spectrum of chronic illness, from fibromyalgia, IBS, dysautonomia, neurological symptoms and the like. It even includes whatever the quacks mean by "dissociative seizures" and even beyond. I see a lot of what would normally be labeled as "movement disorders" and beyond.

Long Covid isn't just ME, and this isn't what this study is saying, but the big picture is being missed that ME is just one endpoint that shares many others. In my case I didn't even have any significant fatigue until several years and this is a common problem.

I know this is beyond the scope, just lamenting how awful the situation is and how progress is happening at a pace that is so slow it's insulting. The broader issue is the concept of chronic illness, which medicine rejects because it has no theoretical basis for it, and that it's the broader concept that is important, more than the worst case scenario of ME.

And it really looks like we have to do this on our own, which makes it especially important that we do it right, because the medical profession is clearly incapable of this.

 

I saw her as a patient around the time that she was giving speeches on the 'system reset' with the modeling engineer. I don't really know whatever happened?

 

The problem might be that they realized that they didn't know enough about the brain's systems to model it in a worthwhile way. A few days ago I came across a paper reporting on yet another previously unknown organ (or organ part). It's another layer of the meninges, with extra immune cells. The function of that layer can affect the glial cells and thus the rest of the brain and body. It's at least possible that it's a critical part of the feedback loop that maintains the ME state, yet no one has tested it (or modelled it) because no one knew it existed. I'm sure there are other important brain mechanisms still unknown. If you imagine the model of the brain and body that would reveal ME's mechanism, what percentage of the parts of that model are actually known in enough detail to model?

I still think that ME should be treated as a black box problem: vary as many inputs as you can and see what happens. That might narrow down some areas for deeper evaluation (ie. Substance x makes ME reliably worse, and is known to affect microglial deactivation, so try other microglial activators/deactivators). There's also at least a chance of finding a substance that helps, even if no one can explain why.

 

I'm not so sure. There's so much still that we can understand about the inner workings, that simply looking at inputs and outputs feels almost like resigning to one-hand-behind-our-backs. We have some advanced techniques down to the single cell interrogation level, as well as newer modalities of neuroimaging. We just need the will and the resource (to be provided).

Looking back at Jo, Simon et al (2016), highlighted areas #2 and #3 were —

It's only a few years on from 2016, but we've already seen significant technical advancements and new ideas in both these areas. On the technical side, new PET tracers and MRI sequences for microglial activation; multi-colour laser flow cytometers; single-cell transcriptomics; rapid cell deformability assessments, etc. On the findings and hypothesis side, on the background of last year's major MS/EBV finding, we have new concepts to test like "transactivation" of on-board herpesviruses, Covid/LC studies showing dysregulation in monocytes, endothelial dysfunction, etc.

I think these and others will help us refine our theoretical models and get to testing ideas in a more directed approach. From a personal POV also, while I want a cure for me and for all of us, if I had to go through this and observe worse in others, and for much longer, then I really want to know what it was all about. Accidentally finding a helpful drug would feel somewhat unsatisfying. I also think understanding more of these chronic illnesses will open large doors across the medical spectrum: from cardiovascular disease to major mental illness, from cancer to autoimmune disease, from neurodegenerative diseases to O&G. I suspect there will be more than a little overlap when all said and done.

 

I don't think Creekside is suggesting that ME/CFS should *remain* a black box; rather, by *intervening* in a select aspect of the system, whether that is Whole Body, or immune cells, or mitochondria in muscle cells, etc., by varying inputs (e.g., adding a signaling chemical, adding stress, adding supraphysical O2, or eliminating other factors), one will gain understanding of the inner workings of the black box, which is the ultimate goal. Along the way, an intervention might be discovered that improves patients' health without necessarily providing a significant piece of the puzzle - which is better than nothing.

My biggest frustration with the research I've read is that there is very little intervention - most of the effort is spent on observation, wherein the discoveries may prove to be helpful down the line or may prove to be trivial or incidental. It drives me mad that, upon discovering some histological or metabolic abnormality, researchers don't *tinker with it*, right then and there, while they've got the samples and time and keys to the lab. Take it to the next level *now*. Push the oddity in different ways in an attempt to destabilize it and then, from that, gain understanding of its role or its level in the hierarchy of the system.

I realize that this is all fantastically complicated, and there are likely many hurdles to operating in an expedited manner, but... I'm frustrated as f by the glacial pace of this process. I've expected a cure (or explanation of the black box) every month for the last decade or more, and it never arrives. Meanwhile, my condition gets worse with age, and I have less years to be salvaged by a cure. [grumble]

 

Commenting out of context but nailed it -- ME/CFS has a generic symptom --- how can you trace the disease pathology from that ---- try a large GWAS study --- identify the underlying pathology ---