Preprint Abnormal T-Cell Activation And Cytotoxic T-Cell Frequency Discriminates Symptom Severity In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome,'25,Lee

[Jonathan Edwards]

There seems no doubt that ME/CFS of the same sort can be mild/mod or severe. However, I think it is quite plausible that people with a diagnosis of ME/CFS fall into two main groups. One of those (A) may also include quite a range of at least partly unrelated problems. I think it likely that the other one (B) has a single central causal path.

I think it is quite possible that A is more or less always mild/moderate but B goes through to severe.
The result then is that studying severe cases gives meaningful answers but if you study A+B you may get a lemon. I also think that it is quite possible that things that are up or down in B are down or up in A. If we are talking about receptor interactions it is quite common to have two similar looking illnesses with some abnormalities opposite.

 

[V.R.T.]

I would not refer to it as different diseases, but if something is progressing there may be different components of the contributing processes becoming more or less deranged or consequential as things get worse.

See this is totally reasonable and I can absolutely see that being the case. But I got the impression that wasn't what Cliff et al were implying.

 

[V.R.T.]

There seems no doubt that ME/CFS of the same sort can be mild/mod or severe. However, I think it is quite plausible that people with a diagnosis of ME/CFS fall into two main groups. One of those (A) may also include quite a range of at least partly unrelated problems. I think it likely that the other one (B) has a single central causal path.

I think it is quite possible that A is more or less always mild/moderate but B goes through to severe.
The result then is that studying severe cases gives meaningful answers but if you study A+B you may get a lemon. I also think that it is quite possible that things that are up or down in B are down or up in A. If we are talking about receptor interactions it is quite common to have two similar looking illnesses with some abnormalities opposite.

What do you make of the fact they found raised IFNy and CD38 in severe patients? As well as TNF and IL-17 which have come up on here before.

 

[Kitty]

I could imagine a picture where a group of people have a severe type of ME/CFS, and although they don't have severe symptoms all the time, they are very likely to get them at some point in their illness.

Another groups is very unlikely to get them, though they may have significant impairment. I'd fit that one; I reach my 50th ME/CFS anniversary next year and I've never been severe. I've been very ill a few times with crashes, but the bedbound period was relatively short-lived (weeks, not months) and looked more like an acute illness than severe ME/CFS.

 

[V.R.T.]

I could imagine a picture where a group of people have a severe type of ME/CFS, and although they don't have severe symptoms all the time, they are very likely to get them at some point in their illness.

Another groups is very unlikely to get them, though they may have significant impairment. I'd fit that one; I reach my 50th ME/CFS anniversary next year and I've never been severe. I've been very ill a few times with crashes, but the bedbound period was relatively short-lived (weeks, not months) and looked more like an acute illness than severe ME/CFS.

I think the complication is that I don't know how likely those of us who deteriorated severely from intense exercise would have been to become severe without it. I had a lot of viral hits, several head injuries and countless big exertions in the three and a half years before I began pushing myself, and always found my way back to a mild state.

 

[Karen Kirke]

I think it is quite possible that A is more or less always mild/moderate but B goes through to severe.
The result then is that studying severe cases gives meaningful answers but if you study A+B you may get a lemon. I also think that it is quite possible that things that are up or down in B are down or up in A. If we are talking about receptor interactions it is quite common to have two similar looking illnesses with some abnormalities opposite.

Agree. Back in 2016 when the plan for the NIH study was presented in a webinar, my father (a medical researcher) wrote to Nath to urge them to study patients with severe ME/CFS for exactly this reason. His work was in neural tube defects, and if I remember correctly, his group was not getting results when people with, for example, mild spina bifida were included in their sample alongside more severe cases (A+B). They had their breakthroughs when they separated A from B and looked at B.

 

[V.R.T.]

There seems no doubt that ME/CFS of the same sort can be mild/mod or severe. However, I think it is quite plausible that people with a diagnosis of ME/CFS fall into two main groups. One of those (A) may also include quite a range of at least partly unrelated problems. I think it likely that the other one (B) has a single central causal path.

I think it is quite possible that A is more or less always mild/moderate but B goes through to severe.
The result then is that studying severe cases gives meaningful answers but if you study A+B you may get a lemon. I also think that it is quite possible that things that are up or down in B are down or up in A. If we are talking about receptor interactions it is quite common to have two similar looking illnesses with some abnormalities opposite.

Another thought - you have said that the studies you have had advance sight of will bring significant progress but there will likely be more experiments to do before we are in the home stretch. So does it follow that those studies should probably look at severe patients to get the best results? If so it's important those planning the next batch of studies understand this.

 

[Jesse]

There seems no doubt that ME/CFS of the same sort can be mild/mod or severe. However, I think it is quite plausible that people with a diagnosis of ME/CFS fall into two main groups. One of those (A) may also include quite a range of at least partly unrelated problems. I think it likely that the other one (B) has a single central causal path.

I think it is quite possible that A is more or less always mild/moderate but B goes through to severe.
The result then is that studying severe cases gives meaningful answers but if you study A+B you may get a lemon. I also think that it is quite possible that things that are up or down in B are down or up in A. If we are talking about receptor interactions it is quite common to have two similar looking illnesses with some abnormalities opposite.

Will DecodeME be able to classify different groups? For example based on severity or finding sub-types? Will it have enough statistical power?

 

[Utsikt]

There seems no doubt that ME/CFS of the same sort can be mild/mod or severe. However, I think it is quite plausible that people with a diagnosis of ME/CFS fall into two main groups. One of those (A) may also include quite a range of at least partly unrelated problems. I think it likely that the other one (B) has a single central causal path.

I think it is quite possible that A is more or less always mild/moderate but B goes through to severe.
The result then is that studying severe cases gives meaningful answers but if you study A+B you may get a lemon. I also think that it is quite possible that things that are up or down in B are down or up in A. If we are talking about receptor interactions it is quite common to have two similar looking illnesses with some abnormalities opposite.

Could you move from A to B?

Or would anyone that have gone from mild/mod to severe always have had B all along?

Would that mean that those with A can’t get worse?

 

[Jonathan Edwards]

Could you move from A to B?

No, A and B are defined as quite distinct - maybe like rickets and vitamin D resistance or hypoparathyroidism and pseudohypoparathyroidism, or type 1 diabetes and glucagonoma. They may superficially look the same but they may actually involve opposite changes.

 

[Jonathan Edwards]

Will DecodeME be able to classify different groups?

I suspect that once we have data from DecodeME it will be relatively straightforward to crosscheck with much smaller cohorts in away that allows statistically valid subgrouping. It may be difficult to torture more information out of DecodeME data per se.

 

[Kiristar]

It is interesting though that there is such a difference between mild moderate and severe. The conclusions are that these could be two different diseases.

I was mild/moderate for decades until what seemed like a switch flipped to severe. Did I have two different diseases or did some mechanism flip? I'd be interested to here about others who are severe and did they experience a long mild/moderate phase or straight into severe quite quickly.

Has such a survey ever been carried out? I don't believe the mega ME Action survey has published as there might be data in there somewhere.

My disease course was exactly the same as yours. Mild and undiagnosed for 25 years. Then rapidly declining to severe over a 3 to 6 month span after further triggers. I don't believe I have two different diseases, I think it's slowly progressive over an extremely long time span, which makes studying that feature nigh on impossible.

 

[V.R.T.]

Would that mean that those with A can’t get worse?

That could explain why GET doesn't harm absolutely everyone, and there are people who believe it helped them.

 

[Utsikt]

That could explain why GET doesn't harm absolutely everyone, and there are people who believe it helped them.

That’s where my thoughts were going.

 

[Jonathan Edwards]

That could explain why GET doesn't harm absolutely everyone, and there are people who believe it helped them.

It could well do, but it still doesn't require that GET actually did any good for anybody!

 

[Jonathan Edwards]

So does it follow that those studies should probably look at severe patients to get the best results? If so it's important those planning the next batch of studies understand this.

I don't think we can be sure but I am beginning to think that focusing on severe at the expense of numbers if necessary may be sensible. On the other hand, having data on the moderate group might also be a useful comparator, as for the Lee study.

 

[V.R.T.]

It could well do, but it still doesn't require that GET actually did any good for anybody!

Exactly! Just that these people don't deterioate.

 

[Kitty]

That could explain why GET doesn't harm absolutely everyone, and there are people who believe it helped them.

They could be in two categories. Those who're not harmed because they were going to recover anyway, and those who're not harmed irrevocably, and any setbacks during GET weren't so bad they'd be thought of as 'harm'.

An old friend and I might have survived GET quite well at some points in our illness, and my late aunt too. Only at certain points though—e.g., after a lot of enforced rest after first becoming ill—and all of us still have significant impairment. We're not mildly affected, just not severe.

Of course even if we'd got through GET, nobody would have recorded that we hadn't gone on to make a full recovery. We'd never have got beyond a certain point of increased activity, and if we carried on trying because some eejit had convinced us it was possible to build fitness like healthy people, we'd eventually meet that wall head-on and at speed.

 

[Rick Sanchez]

That could explain why GET doesn't harm absolutely everyone,

It`s very interesting.

I definitely feel like I am in this very weird subgroup of MECFS patients (that might be considered none-MECFS in the future). Got progressively more ill as a child, couldn't even pinpoint where it started. Still did sports because my parents forced me, and I was so mild there was no reason to think I was chronically ill. They finally relented when I was basically beaten to a pulp fencing, coming home with marks all over my body and looking completely worn out aged 15.

Then as an adult around 22, after I had been tested for what felt like everything at the time they hired a personal trainer for half a year, and I tried exercising myself healthy for two years afterwards, and whilst I did deteriorate whilst this took place, I honest to God can not say if exercise accelerated my decline at all. I obviously had PEM constantly from the exercise, but sadly at this point I had MECFS for so long I had no idea that you were not supposed to feel like absolute crap a day or two after exercise. My personal trainer always remarked how weird it was that I could never emulate the same performance if I had not had a day of rest. He had to make loads of changes to his program like removing anything resembling cardio, which would absolutely murder me. He simply couldn`t understand why I was not gaining the muscle weight I was supposed to gain. He had never experienced anything like it, although to be fair he used to train elite soldiers.

No matter what I do I slowly deteriorate, and it comes in these bursts where it feels like I have the flu pretty much yearly, which lasts for weeks or months and leaves me permanently worse. If I had been like the patients who get more ill permanently from exercise I would have been bedbound by age 9 from playing football and tennis 4 times a week. Whereas I will probably first approach being something resembling bedbound within a decade, around my mid 40s.

I do feel like the group that gets significantly worse from exercise has to be small, otherwise I feel like we would have a lot more severe patients. The majority of patients seems to have some kind of story of trying to push themselves with exercise.

The worst part is that the only improvement I have ever in twenty five years, was just after taking valaciclovir I got at an MECFS clinic recently (my parents guilt tripped me to go). I thought the idea of anti-virals was idiotic, there was no evidence for it as treatment, but not wanting to insult the kind person at the clinic I obliged and humoured them by taking it. Just after 3 days on it I could feel sleepy for the first time since early childhood, whilst also being able to breathe properly again, it felt like a miracle, like a switch had been pressed. I gradually kept improving, to the point where I was preparing to go back to uni and finishing my studies. I remember having a day where I suddenly just felt so much better. I could increase my daily steps by twice the amount out of nowhere. I was able to read my old jurisprudence text books and actually understand what was written. Then sadly it gradually stopped working after 4-5 months, completely stopping after 9 months or so.

I honestly still think someone could force me to exercise, without permanently accelerating my decline. Of course I am not willing to torture myself to find out though!! I have to little life left as is.

there are people who believe it helped them.

I am in the embarrassing camp where I genuinely believed exercise helped me for a year or two. That was even after at least 13 years with MECFS (although I did not know MECFS existed at that point). This was also despite the fact that I was actually slowly deteriorating yearly. MECFS fluctuates so much in the mild and very mild category that you can convince yourself that pretty much anything works due to how much it fluctuates. Researchers are on to something by only having ´´sicker`` patients in their studies.

TLDR: I apologize deeply for the wall of text, I tried to bold everything related to exercise. Feel free to delete if anyone feels like it is derailing the discussion, I wont take offense.