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

[Jaybee00]

If no specific antigen(s) was found, how did they end up jumping to the conclusion that “chronic antigenic stimulation” was the cause of the various immune system irregularities?

{mea culpa if this was already addressed in any of the 35 previous pages}

 

[Sean]

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

Yep. Don't ever stop doing what you do so well, @Jonathan Edwards. Your contributions here have injected a big shot of rigour along with huge experience and background knowledge, and helped enormously in keeping it all on track. Also for opening doors within medicine that have previously proved resistant to giving us a fair hearing.

Very grateful for that.

 

[Jonathan Edwards]

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

Somebody finally blew my cover.

 

[Jonathan Edwards]

This all begs the question: what should we ask the NIH to follow up on?

I wouldn't ask them to follow up on anything. I would encourage the NIH to put money into groups with new ideas. They have done so in the past, including CureME. They should do so again.

 

[Jonathan Edwards]

If no specific antigen(s) was found, how did they end up jumping to the conclusion that “chronic antigenic stimulation” was the cause of the various immune system irregularities?

I presume there was no jump. They had concluded that before they started and just used the few bits of data that could support it to go on concluding that. That is the way 90% of science labs work.

 

[Sid]

This all begs the question: what should we ask the NIH to follow up on?

Absolutely nothing, I hope, as long as America's version of Wessley is in charge of our thing over there.

 

[duncan]

Absolutely nothing, I hope, as long as America's version of Wessley is in charge of our thing over there.

This in part is why I earlier suggested the patients need to lead the way. Let the pateints pick the PI and investigation team, and oversee the entire process. Politics and vested interests pervade medical research in many of our institutions. Patients might not be able to erase that, but maybe we can at least help it regain its feet enough to be able to function coherently and fairly.

 

[Kitty]

This all begs the question: what should we ask the NIH to follow up on?

I wondered if there was anything on the diagnostics side. As they wanted participants who'd become ill in a limited time frame the majority of patients were automatically excluded, but why were some people who met that criterion also screened out?

If it was because they had (or might have) been misdiagnosed, there could be something to learn from it. Are there diagnostic errors that could be reduced by more careful application of the criteria? Are there specific conditions that were mistaken for ME/CFS in more than one patient, and/or by different doctors?

(Apologies if is this has already been answered, my reading capacity's a bit limited at the moment).

 

[Evergreen]

I wondered if there was anything on the diagnostics side. As they wanted participants who'd become ill in a limited time frame the majority of patients were automatically excluded, but why were some people who met that criterion also screened out?

If it was because they had (or might have) been misdiagnosed, there could be something to learn from it. Are there diagnostic errors that could be reduced by more careful application of the criteria? Are there specific conditions that were mistaken for ME/CFS in more than one patient, and/or by different doctors?

(Apologies if is this has already been answered, my reading capacity's a bit limited at the moment).

I hear you. I've been quiet for a couple of days because pain flared due to...repetitive prolonged button pressing. The irony. This happens when I play around with data, because my body can't handle the sustained pressing of the CTRL button and the down arrow. Or rather, it builds over a few days and then explodes like a fireball. (And of course if I were in a study like this, I'd be safely home before it peaked.)

Apologies to anyone if I've missed replies.

But to answer your question - it's in Supplementary Data file 2, which I've uploaded to this message.

I've pasted the info below too, but formatting is funny, so you might want to look at the excel file instead.

Supplementary Data 2A: Criteria for exclusion after initial screening* n
Total inquiries 484
Screened out after initial interview 267
Reasons for screen failure
Onset >5 years 176
Onset < 6 months 1
No infection 54
Too sick to travel 16
Not between ages of 18 and 60 16
Cannot pedal bicycle 4
Dropped Out/No Response 2
No formal diagnosis of ME/CFS 23
Unwillingness to have Lumbar Puncture 4
Unwillingness to have MRI 3
Autoimmune disorder 11
Had Cancer 8
Neurological Disorder 5
Concussion/Head Injury 11
Lyme diagnosis 24
Other Diseases 78

Supplementary Data 2B: Criteria for exclusion after review of medical records n
Interviewed by Study Physician 217
Screened out after medical record review 146
Reason for Exclusion
Inflammatory disorder 8
Immunodeficiency 1
Medical sleeping disorder 4
Endocrine disorder 5
Cancer 1
Childhood epilepsy 1
Head injury 6
Hepatitis B 1
Psychosis 5
Severe Depression 2
Severe Anxiety 1
PTSD 2
Onset more than 5 years prior 46
No record of triggering infection 26
No diagnosis of ME/CFS 8
Fatigue not moderately severe 2
Fatigue prior to infection 7
Ongoing treatment for Lyme Disease 10
Excluded Medication Use 9
Dropped out/lost contact 13
MD did not support participation 1
Unwilling to have procedures 3
Cannot pedal bicycle 1
Under review when the pandemic closed the study 44

Supplementary Data 2C: Criteria for exclusion after in-person evaluation n
In-person medical evaluation 27
Excluded after NIH evaluation 10
Withdrawn 2
Cancer 1
Atypical myositis 1
Primary biliary cholangitis 1
Parkinsonism 1
Excluded based on being adjudicated NOT Post-Infectious 4

Supplementary Data 2D: ME/CFS Criteria n
Met 2015 Institute of Medicine Criteria 17
Met 1994 Fukuda Criteria 14
Reasons for Fukuda Exclusions (n=3)
1: No sore throat, lymph nodes, muscle pain, joint pain, or headaches.
2: No sore throat, lymph nodes, muscle pain, joint pain
3: No substantial impairment in short-term memory/concentration, sore throat, lymph nodes, muscle pain, multijoint pain
Met 2003 Canadian Consensus Criteria 9
Reasons for Canadian Consensus Exclusions (n=8)
1: No pain
2: No pain, No autonomic, no neuroendocrine, no immune
3: No neurocognitive, no immune
4: No neuroendocrine, no immune
5: No pain
6: No pain
7: No neuroendocrine, no immune
8: No neuroendocrine, no immune

Edit: Formatting to make it easier to read

 

[Kitty]

But to answer your question - it's in Supplementary Data file 2, which I've uploaded to this message.

Oh, thank you! This ruddy thing's a nightmare to get through.

So most of the exclusions seem not to be due directly to being diagnosed with one condition when they actually have another. I'm not sure about the "other diseases" entry at the bottom of 2A, but it may mean they had co-morbid conditions rather than different ones.

That's useful. I've long thought the stricter criteria, when applied properly, should be reliable enough for practical purposes—it might be a heterogeneous illness, but the picture is quite a distinctive one.

 

[cassava7]

#MEAction have released their analysis of the study: https://www.meaction.net/2024/02/29/meaction-nih-study-response/

NIH’s recent paper on ME/CFS elicited strong reactions from the community. While we recognize the incredible sacrifice of the patient community who gave their health and time to make this study possible, ultimately, we caution against drawing any sweeping conclusions from this study.

The paper draws conclusions based on an atypical cohort that may not be representative of the ME/CFS community, and from a very small sample size, and there are also conclusions drawn in regards to “effort preference” that may not be supported by the evidence.

 

[FMMM1]

This is nonsense but as a necessary upbeat take on a very costly study that was supposed to be groundbreaking it is excusable, and at least a good message to the world.

Insightful -- spent 8 years & $8 million -- some brainstorming & hey presto --- line to take is ---"The study provides irrefutable evidence for the biological basis of the illness---"!

It is possible that the signal patterns are a tell tale sign of whatever is actually stopping PWME from doing things but if so nothing has been discovered about what that is or where it is.

Thank you!

 

[Ravn]

Just wanted to highlight this

NIH spent $8M to gather data from seventeen subjects, chosen in a way that may bias their conclusions—and they structured those conclusions around a core of psychosomatic reasoning. One immediate way to take action is by working on the ME/CFS Research Roadmap research priorities. The public comment period closes on March 8th.

How NIH acts on this community input will matter even more in the light of this recent paper.

https://www.meaction.net/2024/02/29/meaction-nih-study-response/

 

[Dakota15]

Yep, I know what you mean. But in interviews about the paper, Avindra Nath is talking about exactly that - a trial of multiple treatments with one placebo arm, that would simultaneously try to replicate some findings in larger cohorts and test a bunch of drugs - I have the impression he is talking about multiple checkpoint inhibitor drugs but I could be wrong on that. So certainly Nath is talking about treatment trials based on this study.

Apologies if I already shared this @Evergreen, if I hadn't, doing so now.

I asked Nath and Koroshetz following the publication if they are planning to pursue clinical trials now based on their recommendations at the NIH. I received the following replies:

From Koroshetz: "NIH site is best for small, intense studies like the one Avi did. Clinical trials are usually done by the University investigators. Hopefully a University site would take this on.”

From Nath: "I think that (clinical trials) is what needs to be done. But I do not have the resources to do it. I have no say in these matters. I do not control funding. Plus I have lots of restrictions on what I can do.”

 

[Trish]

Not sure whether this Medscape article by Mirian Tucker has been posted.
ME/CFS Experts Express 'Dismay' at Aspects of NIH Study
Miriam E. Tucker
February 28, 2024

She quotes comments from Bateman and Yellman and from Nath.

I thought this section from Nath was interesting (to put it politely) when responding to why they had used the term 'effort preference'

Quote:
According to Nath, "we battled around with ourselves about what is the right term to use. The problem is that it's a subjective sensation…And even the patients who experience it use a variety of different terms to describe it."

But, Nath said, the way he interprets the symptom based on what patients have said is that it's akin to having the flu and not wanting to get out of bed. "It's not like you're not capable of doing it, but your body tells you don't do it…Your body just wants to fight the infection. So, the way I understand their symptoms, that's what's happening to these individuals. They got the infection, their body kind of shut down, and then it never recovered…And we did find some of that reflected in their immune systems."

 

[SNT Gatchaman]

lead author Avindra Nath, MD, Senior Investigator and Clinical Director of Intramural Research at the National Institute of Neurological Disorders and Stroke (NINDS), said that the selection of both recent-onset patients and those who were less severely ill was done in part to avoid the confounding factor of deconditioning.

"We were very careful not to take deconditioned patients. That doesn't mean that small amounts of deconditioning didn't take place, but I don't think it can all be explained by that. For example, we found functional brain abnormality that cannot be explained by deconditioning. And then there were some immune abnormalities. We found naive T cells and B cells were activated, and the anti-programmed death-1 level was elevated. So, there were a number of findings that I think cannot be explained by deconditioning."

But that's not what the paper says. The paper stated —

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.

Physical deconditioning over time is an important consequence.

 

[Trish]

Quote:
According to Nath, "we battled around with ourselves about what is the right term to use. The problem is that it's a subjective sensation…And even the patients who experience it use a variety of different terms to describe it."

But, Nath said, the way he interprets the symptom based on what patients have said is that it's akin to having the flu and not wanting to get out of bed. "It's not like you're not capable of doing it, but your body tells you don't do it…Your body just wants to fight the infection. So, the way I understand their symptoms, that's what's happening to these individuals. They got the infection, their body kind of shut down, and then it never recovered…And we did find some of that reflected in their immune systems."

I think they have invented a 'symptom' and called it effort preference.
It's not a symptom, it's an artefact of false interpretation of an anhedonia test inappropriately used.

I'm really not clear what the 'it' he is describing refers to.
No wonder patients use different ways of describing 'it', if it's a figment of Walitt and Nath's imagination.

 

[EndME]

But, Nath said, the way he interprets the symptom based on what patients have said is that it's akin to having the flu and not wanting to get out of bed. "It's not like you're not capable of doing it, but your body tells you don't do it…Your body just wants to fight the infection. So, the way I understand their symptoms, that's what's happening to these individuals. They got the infection, their body kind of shut down, and then it never recovered…And we did find some of that reflected in their immune systems."

I think I understand what he is trying to say and the message seems understandable for a press release. However, the argument itself doesn't seem to dissimilar to the BPS argument to me. Both can be falsified by the fact that many people recover perfectly well from the acute infectious phase and a couple of days/weeks later develop symptoms (was this something the looked at in the intramural study ?). Of course that is something Nath is perfectly aware of since he is proposing a model of Long-Covid were people recover from the acute infection and days/weeks later develop symptoms (see more info on his proposal here), so this quote seems somewhat out of context (apart from the fact that "effort preference" has never been described as a symptom by anybody and that is has no scientific backing in ME/CFS I'm aware of).

 

[SNT Gatchaman]

In this post from a locked thread —

Nath, who also studies ME/CFS, says that “we think mechanistically they are going to be related.” Researchers suspect that ME/CFS, like some cases of long COVID, could be autoimmune in nature, with autoantibodies keeping the immune system activated. ME/CFS has been difficult to study because it often arises long after a mild infection, making it hard to identify a viral trigger. But with long COVID, Nath says, “the advantage is that we know exactly what started the process, and you can catch cases early in the [development of] ME/CFS-like symptoms.” In people who have had ME/CFS for years, “it's done damage, and it's hard to reverse that.” Nath speculates that for long COVID, if doctors could study people early in the illness, they would have a better chance of reversing the process.

Now that we have the paper, what's the damage? (Not referring to damage by the paper itself!). Surely he can't mean deconditioning because... well... that's reversible.

 

[Evergreen]

Apologies if I already shared this @Evergreen, if I hadn't, doing so now.

I asked Nath and Koroshetz following the publication if they are planning to pursue clinical trials now based on their recommendations at the NIH. I received the following replies:

From Koroshetz: "NIH site is best for small, intense studies like the one Avi did. Clinical trials are usually done by the University investigators. Hopefully a University site would take this on.”

From Nath: "I think that (clinical trials) is what needs to be done. But I do not have the resources to do it. I have no say in these matters. I do not control funding. Plus I have lots of restrictions on what I can do.”

Yes, someone posted in the early pages of the thread that they had heard UCSF (I presume that's University of California at San Francisco?) was considering a trial.

Hopefully any universities considering trials might dig a bit deeper first rather than launching straight in - and they may have to, to get funding.

Just to be clear, I am neither pro-trial nor pro-viral-persistence-theory. My personal stance would be pro-more-digging into the "biological" findings in this and other studies to see which hold water, and then consideration of all the possibilities any that hold water could point to, followed by more digging.

I think premature trials could do more harm than good.