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

[Denise]

That was not the situation we heard of here.
In the S4ME earlier thread, Brian Vastag came and commented

"Hi, Brian here, just signed up for the forum. Yes, that is all true. Still, NIH is having trouble recruiting. They've run 16 patients through the first visit. The NIH team has contacted about 200 patients who made it through an initial screening phone call and look like they qualify for the study, but they all disappeared and did not return phone calls. If about 10-15% of those people maintained contact and got into the study, that would get us to the 40 patients needed. I understand why people make contact and then disappear but I was surprised that 200 people had done that."

I wonder if we are using language differently.
The paper says that there were 484 inquiries for participation. 267 of those were screened out in initial screening. 217 of those 267 had medical record reviews and a phone interview. 146 of those 217 were excluded after review. 44 people did not complete the review process before COVID shut the study down.

NIIH wanted 40 PwME for the study but couldn't get enough people who met the necessary criteria and didn't have exclusionary factors.
For me, that's different than not be enough people coming forward for the study.

 

[Evergreen]

there are also lots of immune related medications in trial by private individuals and groups that might answer this question before research tbh

If long COVID is like ME/CFS, you will learn nothing until you get to placebo controlled trials, because there's a lot of spontaneous fluctuation up and down. Given that people have had long COVID for max 4 years, there will, again if it's like ME/CFS, be plenty of spontaneous recovery and spontaneous substantial remission. You really won't know until all of that is controlled in a well-run trial.

 

[siobhanfirestone]

If long COVID is like ME/CFS, you will learn nothing until you get to placebo controlled trials, because there's a lot of spontaneous fluctuation up and down. Given that people have had long COVID for max 4 years, there will, again if it's like ME/CFS, be plenty of spontaneous recovery and spontaneous substantial remission. You really won't know until all of that is controlled in a well-run trial.

in all honesty im not sure if there is much spontaneous ME remission, and im certainly not holding out for it
there ARE very good placebo trails ongoing thats what im saying, just not by the NIH lol

 

[Binkie4]

I wonder if we are using language differently.
The paper says that there were 484 inquiries for participation. 267 of those were screened out in initial screening. 217 of those 267 had medical record reviews and a phone interview. 146 of those 217 were excluded after review. 44 people did not complete the review process before COVID shut the study down.

NIIH wanted 40 PwME for the study but couldn't get enough people who met the necessary criteria and didn't have exclusionary factors.
For me, that's different than not be enough people coming forward for the study.

I'm not sure that it's about using language differently.
Brian was concerned about 200 patients who had made contact and got through initial screening who then disappeared and did not return follow up calls. A small proportion of those getting involved would have brought them up to 40. So enough people had come forward and got through first screening.

There was a lot of concern in ME Advocacy groups around 2016 about Walitt's background and somatoform beliefs. Did this affect recruitment? I think it possible indeed likely.

 

[Denise]

There was a lot of concern in ME Advocacy groups around 2016 about Walitt's background and somatoform beliefs. Did this affect recruitment? I think it possible indeed likely.

FWIW - I am one of the one who was very concerned about Walitt (and Saligan and.....)

 

[Binkie4]

Me too!

 

[Hutan]

On the NIH study and this paper potentially being of use to BPS interests and specifically their desired outcome in the new Cochrane Exercise Therapy Review:

They certainly leave the door more than ajar but I cannot see this as being cited in a Cochrane review in a conclusion that says 'Even if the efficacy data look dismal some very clever scientists think it should work so we conclude it probably does'.

Oh, I can imagine that there are plenty of ways for that to happen - 'more research is needed on how to tweak things exactly right, but given the lack of documented harm, patients who want to explore ways to get better should not be denied the GET option'....

This is the NIH's considered opinion of what ME/CFS is:

Altered hypothalamic function leads to decreased activation of the temporoparietal junction during motor tasks, suggesting a failure of the integrative brain regions necessary to drive the motor cortex. This decreased brain activity is experienced as physical and psychological symptoms and impacts effort preferences, leading to decreased engagement of the motor system and decreases in maintaining force output during motor tasks. Both the autonomic and central motor dysfunction result in a reduction in physical activity. With time, the reduction in physical activity leads to muscular and cardiovascular deconditioning, and functional disability. All these features make up the PI-ME/CFS phenotype.

They suggest that the functional disability only results from deconditioning produced by the reduction in physical activity. Of course it's ridiculous, as others have pointed out - most of us could give examples of why this is not true. There's that early Newton study that found that the people with mild ME/CFS were not drastically deconditioned. But there it is.

All that needs to happen for the BPS people to keep winning the Cochrane war is for there to be ongoing disputes about the draft of the new Exercise Therapy Review. So long as that happens, and surely it will, then the 2019 review stands, and continues to be cited. And there's no loss of BPS reputations.

 

[poetinsf]

While on the ski slope yesterday, I was thinking about the finding that the catechol level correlating the symptom severity. Even though there is no such correlation in HV, it could mean that high dopamine/norepinephrine level can provide some protection against MECFS. i.e., high dopamine/norepinephrine individuals are less likely to develop MECFS, and less severe when they do. That seems to be consistent with the finding that the history of depressive disorder being a predisposing factor for Long COVID. It could also explain why I, a recovered patient, get under the weather after a heavy exercise (post-exercise depression) and become vulnerable to PEM.

 

[Hutan]

Have I understood correctly that Wallitt is in charge of a similar study with people with Long Covid? If so, one part of any complaints should be to insist he be removed from all further involvement with ME/CFS or LC.

I see, that’s a big problem. But what would happen if people with ME and LC refuses to participate with him in the lead?

I think this is surely something that US advocacy groups can change. They can point out the poor recruitment response (I'm still not really convinced that it was due to lack of patient interest. I knew the problems with Walitt, but I was still keen to participate, (I would have travelled from another country to be there), and enquired, but had had ME/CFS for just months too long to be eligible. Walitt was doing the screening, so it is possible that something about his manner or the way he described the study did put some people off.)

I think Long Covid advocacy groups and specialist clinics could say to the NIH that they cannot and will not promote studies to their communities while Walitt and his ilk are involved.


I have been thinking that it might be useful to do a Freedom of Information request - I don't know what it is called in the US. A request for copies of communications between Walitt, Nath and other scientists involved in this study. Surely there are some scientists who were really pissed off at having to halt their studies with only e.g. 8 ME/CFS participants contributing data? Maybe there were communications about how the study should be written up? Maybe there were discussions following internal peer review? I'd like to know if anyone said 'maybe exertion preference isn't the best term' and who said 'yes it is'.

It would be interesting to know what Walitt's responsibilities were, if they changed over time and who made those decisions. And to compare that with what the ME/CFS community was told about Walitt's involvement at various points over the years.

Maybe that information wouldn't change much right now, but it would make people accountable for their actions when the history of all this is written.

 

[Simon M]

With time, the reduction in physical activity leads to muscular and cardiovascular deconditioning, and functional disability

Astonishing. Again: why does this not happen in every other limiting illness? And ME-like syndrome would be the norm if this were true.

More pertinently, they collected no evidence that allowed them to plausibly speculate along these lines. What they could easily have done is asked their participants if disability or deconditioning inactivity came first as some kind of sensible check - since the patients were there to see the sequence. But they chose not to. this is not science, it's bar room opining.

 

[duncan]

Do we know who from the NIH that was involved in the ME/CFS study will be involved in the LC effort besides Nath and Walitt?

I worry about a research template of sorts being passed down. There is also the Lyme group. And isn't there a new overarching group that looks at several diseases in tandem?

 

[Eleanor]

They suggest that the functional disability only results from deconditioning produced by the reduction in physical activity. Of course it's ridiculous, as others have pointed out - most of us could give examples of why this is not true. There's that early Newton study that found that the people with mild ME/CFS were not drastically deconditioned. But there it is.

Interesting that muscles are considered to be deconditioned when that's the explanation being offered for a person's disabled state, but the same muscles are considered to be working normally when we're talking about "effort preference" and "mismatch between what someone thinks they can achieve and what their bodies perform”?

 

[Evergreen]

Lots of findings have been critiqued or dismissed on this thread, but I'm interested to know which findings are, well, interesting.

The results below are beyond my powers, but I would really appreciate others' views on them:

In cerebrospinal fluid, the PI-ME/CFS group had statistically significant decreased levels of DOPA, DOPAC, and DHPG (Fig. 6a–c)...These results did not change after excluding data from participants taking central-acting medications.

Metabolomic analysis of cerebrospinal fluid also showed group differences (Fig. 6h). Tryptophan metabolites were among the top 15 differentially expressed and statistically significant after correction for multiple comparisons (Fig. 6i). Decreased glutamate, dopamine 3-O-sulfate, butyrate, polyamine, and tricarboxylic acid (TCA) pathway metabolites were noted in PI-ME/CFS participants (Supplementary Data S14A).

An increase in percentage of naïve and decrease in switched memory B-cells in blood were observed in PI-ME/CFS participants (Fig. 7a, b).

Markers of T-cell activation, PD-1+ CD8 T-cells, were elevated in the cerebrospinal fluid of PI-ME/CFS participants (Fig. 7c)....CD226+ CD8 T-cells were decreased in blood (Fig. 7d) of PI-ME/CFS participants

When stratified by sex, PI-ME/CFS males had increased CXCR5 expression on CD8 + T-cells in cerebrospinal fluid (Fig. 7e). PI-ME/CFS females had increased CD8+ naïve T-cells in blood (Fig. 7f),

 

[JemPD]

Just wanting to re-emphasise this because i'm not sure Elanor's mic drop was loud enough

Interesting that muscles are considered to be deconditioned when that's the explanation being offered for a person's disabled state, but the same muscles are considered to be working normally when we're talking about "effort preference" and "mismatch between what someone thinks they can achieve and what their bodies perform”?

!!!! very interesting indeed...

 

[Lidia Thompson]

The NIH intramural study always looked to me like a camel designed by a committee. A good fMRI study on its own would have been excellent. A serious muscle study like that of Wust on a decent number would have been good. The idea that you can measure everything and solve a problem is never a good approach.

... and it's not going to take him (Rob Wust) anything like 8 years either! ... not if this is anything to go by:

 

[josepdelafuente]

Interesting that muscles are considered to be deconditioned when that's the explanation being offered for a person's disabled state, but the same muscles are considered to be working normally when we're talking about "effort preference" and "mismatch between what someone thinks they can achieve and what their bodies perform”?

hahaha this hadn't even occurred to me, but yea. wow. well spotted. jesus!
I know there are so many other concerning issues with this paper which people have already spotted, but does this thing @Eleanor has spotted not expose the Walitt analysis (maybe not the raw data) as completely ridiculous?
Maybe I'm missing some nuance but it seems like he really is attempting to claim that the data shows the study participants had muscle de-conditioning but also simultaneously didn't have muscle de-conditioning. I mean I know that's what @Eleanor has just said.. but yea.. I'm struggling to get my head around someone actually publishing that.. I must be missing something.

 

[Hubris]

When you think about it, it is really insane the NIH can publish a study where they say the functional disability is caused by deconditioning, yet at the same time claim exercise wouldn't help.

Even without knowing anything about the history or context of ME, how could anyone approve this paper?

 

[Dakota15]

Sharing in here if not already shared.

Live Science: '''It took the rug right out from under my life': Milestone ME/CFS study begins to explain disease, but will it lead to treatments?’'

NPR: 'Clues to a better understanding of chronic fatigue syndrome emerge from a major study'

MedPage Today: "Brain Dysfunction, Immune Abnormalities Seen in Post-Infectious Chronic Fatigue — Deep phenotyping study provides new clues about ME/CFS"

 

[Hoopoe]

When you think about it, it is really insane the NIH can publish a study where they say the functional disability is caused by deconditioning, yet at the same time claim exercise wouldn't help.

Even without knowing anything about the history or context of ME, how could anyone approve this paper?

My guess is that the lack of coherence is due to different authors having different opinions.

 

[FMMM1]

Have I understood correctly that Wallitt is in charge of a similar study with people with Long Covid? If so, one part of any complaints should be to insist he be removed from all further involvement with ME/CFS or LC.

similar study --- as in an fMRI---Long Covid study?
At the very least the study should be conducted in a way which tests whether the fMRI signal is just an artifact e.g. by including people with other diseases (rather than just healthy controls) --- larger umbers ---. But yes, the illogical way this study has been promoted as finding that it's "effort preference", rather than aberrant signalling, doesn't inspire confidence.