Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome, 2024, Walitt et al

[Dolphin]

Harvard Health Publishing
Harvard Medical School
DISEASES & CONDITIONS

Is chronic fatigue syndrome all in your brain?
An NIH study expands on a body of research locating objective markers of ME/CFS in the brain, the immune system, the gut, and beyond.
February 28, 2024
By Anthony L. Komaroff, MD, Editor in Chief, Harvard Health Letter

https://www.health.harvard.edu/blog/is-chronic-fatigue-syndrome-all-in-your-brain-202402283020

 

[Jonathan Edwards]

Perhaps, but I was thinking "pragmatic" more in the sense of the larger public discussion of focus

If the larger discussion is more biology, fine. But as Trish points out vanElzakker has friends in persistent virus money gathering. And as Lucibee pointed out, our pragmatism needs to be pointing in the right direction. Encouraging people to go back to the never-ending search for viruses and treating patients with toxic drugs while they are at it is not good for the wider message. Viruses are no better than false beliefs if they do not exist.

 

[Jonathan Edwards]

He is very critical of the neurology interpretation related to the effort preference nonsense, and is critical of the mix of results and interpretation in the paper that doesn't make it clear what was evidence and what was interpretation.

The criticism of the psychological interpretation is good but we need to be critical of the mix of data and interpretation in the immunology just as much. I am probably wrong but so far the main T cell finding seems to be mislabelled in the figure.

 

[duncan]

Brain biopsy is not a terribly good idea!

True, but I think that's where we need to be looking. Looking for a smoking gun the same way with the same methods hasn't been working out so well. Even with post-mortem efforts, I'm concerned how and what they'd look for. At least in post-mortem investigations, though, patients efforts can't be suspect.

I'm not confident CSF samples tell us anything, at least not with metrics calibrated the way they currently are. Serum, of course, even more limited.

Researchers need to infer from patients, and the people asking the questions and building questionnaires aren't doing the best job.

I also think it's a crap shoot in terms of medical discipline. Infectious disease specialist, immunologist, neurologist - they all bring their own baggage.

Patients need to lead this, with the associated experts helping.

That's not likely anytime soon. And I've seen that tanked even when patients tried to build a safety valve into an NIH study. But I'd pay to see that unfold.

Encouraging people to go back to the never-ending search for viruses and treating patients with toxic drugs while they are at it is not good for the wider message. Viruses are no better than false beliefs if they do not exist.

Turning your back on a very possible theory in the search for whatever culprit is at play doesn't seem quite right, either.

 

[Jonathan Edwards]

Turning your back on the search for whatever culprit is at play doesn't seem quite right, either.

OK, but my main contribution to medical science has been the deduction that for autoimmune disease there is no 'culprit' after all, just complex dysregulation. Twenty years later hundreds of thousands of people with about thirty diseases have been successfully treated based on our proof of concept trials. And it looks as if version 2.6 with CAR-T might get permanent cure in those where that has not yet been achieved.

In comparison the persistent pathogen idea looks to me much like the dodo in the Pitt-Rivers Museum in Oxford.

The patients are now leading and I am doing what I can to help by being honest. Within a year we will have powerful genetic data - whether positive signal or not.

Everyone brings their baggage it seems!

 

[duncan]

OK, but my main contribution to medical science has been the deduction that for autoimmune disease there is no 'culprit' after all, just complex dysregulation.

You may be right.

The patients are now leading and I am doing what I can to help by being honest. W

I know you are.

The patients are now leading

I'm not sure that's quite accurate. Nice thought, though.

In comparison the persistent pathogen idea looks to me much like the dodo in the Pitt-Rivers Museum in Oxford.

To a lot of people. Others, not so much.

Everyone brings their baggage it seems!

Agreed.

 

[dave30th]

Everyone brings their baggage it seems!

Ha! Well, I think this is one proposition we can all probably agree on.

 

[dave30th]

Perhaps that colours vanElzakker's response to the NIH study.

that's a good point. But Iwasaki at Yale has also suggested viral persistence or perhaps viral remnants as a possible driver of Long Covid, at any rate.

 

[dave30th]

I am doing what I can to help by being honest.

Jo, I appreciate your honesty and forthrightness very much, independent of whatever issue or difference of opinion is being discussed..

 

[Jonathan Edwards]

I'm not sure that's quite accurate. Nice thought, though.

I am quite sure that the patients are leading.

DecodeME came about largely through the efforts of a member here and is co-run by a member.

The overturn of UK NICE guidelines came from Shepherd, Kindlon, Matthees, all patients.

I am only here because carers got me involved and maybe David T too.

In the UK the current Government Working Party initiative will achieve things because of patients' involvement. It got started because a Health Secretary has a sick relative.

Things may not be quite the same in the US, I realise. But Maureen Hanson and Ron Davis are carers and Lenny Jason is a patient.

Persistent pathogens are important in specific situations. Interestingly, my mother told me that the eradication of the problem of Hepatitis B in renal dialysis units was largely driven by scientists who had renal failure themselves. But it is never good to start out with a preferred theory like viral persistence. We came across the B cell story having no interest in B cells whatsoever. They stuck their noses at us. Talking up minimal evidence for a preferred story is tempting but the downside needs to be considered too.

 

[EndME]

I don't see these results as leading to anything new. The studies on T and B cells are not significant with such a tiny sample.

T cell sequencing I think would be a complete waste of time even if we knew what antigen might be around. There is no evidence of antigen being around so there is nothing to look for. If you sequence the peptides that bind to receptors on T cells cloned out of patients you are likely to find they could be from a million different organisms. It isn't a serious strategy to my mind.

I trust your judgment on a scientific level, but I see some possibility of some nuance to this on the political level. I might be completely wrong and just be far to naive, because I have no understanding on how scientific findings should and can be used politically, which I anyways find quite a disturbing thought to be begin with.

I will try to illustrate what I mean:
For the sake of the argument, I'm assuming that all results in the paper are null results, but that for example the authors interpret the T-cell results to mean that there are big significant differences in pwME. Now it's harder to politically motivate follow-up studies and more funding via null results. However, it's possible to play some sort of political game where one demands follow-up studies if null results are interpreted as findings. These follow-up studies one demands will then be have to be something like large immunological studies so that they aren't focused on the previous null-results, but only tangentially include something like T-cell sequencing. The follow-up work of the T-cell sequencing will then give you null results (or is ideally not done at all) but the immunological studies could reveal something interesting. Sort of using the interpretation of positive data as trojan horse to get actually interesting work funded or just using it to increase annual funding in general. Whether its null results or not matters scientifically, but might not matter politically as long as the demands aren't purely focused on following-up those null-results.

From what I can tell this is how some of the funding for viral persistence was obtained. Vague findings were used to motivate further work. This further work subsequentially doesn't have to be focused on vague previous results once the demand/motivational stage is over.

 

[Kitty]

From what I can tell this is how some of the funding for viral persistence was obtained. Vague findings were used to motivate further work.

It might depend on where you are, and whether the funding is private or public? Private foundations have a lot of discretion, but it's hard to imagine further study based on weak or over-interpreted data would survive scrutiny by a publicly funded research council.

 

[EndME]

It might depend on where you are, and whether the funding is private or public? Private foundations have a lot of discretion, but it's hard to imagine further study based on weak or over-interpreted data would survive scrutiny by a publicly funded research council.

I would certainly think so (but then again how many publicly funded CBT/GET studies have we already seen?) and it seems even the NIH is placing more focus on viral persistence, see for instance these highlights from the Research Opportunity Announcement by RECOVER

 

[dave30th]

maybe David T too

thanks for the shout-out--but I only bugged you for quotes when I wrote my big piece and then nudged you to sign letters. you were already involved!

 

[Jonathan Edwards]

thanks for the shout-out--but I only bugged you for quotes when I wrote my big piece and then nudged you to sign letters. you were already involved!

I meant that maybe you too were led in by the patients, David!
That might also be wrong of course.

 

[dave30th]

I meant that maybe you too were led in by the patients, David

Ah, read it wrong! Yes, absolutely! That's how I got into it--I read the patient critiques of PACE, and that patients could be recovered on measures at baseline, and I thought that can't be right, they must be misinterpreting or something. And when I looked at the trial, I saw they were right. I mean, who would believe that any trial would have outcome thresholds below entry criteria? And then Tom K helped take me through the whole thing.

 

[Jonathan Edwards]

However, it's possible to play some sort of political game where one demands follow-up studies if null results are interpreted as findings.

It is true that just working in a lab on anything often starts off observations that become important.

But the vast majority of the time this sort of strategy just leads to some poor PhD student spending five years feeling they have to repeat some duff results and either faking something to look as if they did or ending up miserable, poor and unemployed.

There aren't many avenues to follow for ME but the avenues of chasing viruses and counting lymphocytes have pretty much been done to death now. Something different is more likely to produce the serendipitous result I think.

From what I can tell this is how some of the funding for viral persistence was obtained.

What viral persistence are you referring to? The findings AIDS weren't vague. Thousands of people were dying. The evidence for Hep B in dialysis wasn't vague, or hep c with haemophilia. Everyone died. In ME there doesn't seem to be evidence of viral persistence.

but it's hard to imagine further study based on weak or over-interpreted data would survive scrutiny by a publicly funded research council.

Sadly, I have a feeling that a very major funder in the UK has done just that, but I won't go into detail. It is all too easy for these things to become memes, like the fashion for 'regulatory B cells' which got masses of funding but probably don't exist.


We just need to up the level of analysis for ME to at least as good as RA or lupus or cancer. We are still a long way off that. The main place where the debate gets real is right here.

 

[Jonathan Edwards]

Ah, read it wrong!

I seem to make a habit of being misreadable!
I have meant to do something about it but my effort preference is all screwed up.

 

[Denise]

I have meant to do something about it but my effort preference is all screwed up.

I think it may actually be that you have "mistaken effort preference beliefs"

 

[Eddie]

This all begs the question: what should we ask the NIH to follow up on? And if there is nothing in the paper that warrants follow up study, what is the next thing they should focus on to find clues?