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

[FMMM1]

Yes, but it is even worse than that. People with MS have a validated, socially sanctioned disease. People with ME/CFS, well, we have to deal with crap like this paper. So participants with ME/CFS are carrying a whole other burden of feeling responsible to the ME/CFS community, and justifiable fear that their responses will be misinterpreted, when they participate in research.

I agree fully - in a well understood/validated biomedical disease NIH's approach, in publishing at best a hypothesis paper i.e. without enough data to validate that hypothesis, would have been unfortunate - in a disease like ME/CFS their approach is simply unacceptable.
Walitt seems to be behaving as if they've found something of note - basically they've probably noted an artifact ---!

 

[Dakota15]

[just to quickly interject, I compiled media roundup of the NIH ME Intramural Study below - sharing for anyone browsing through this thread and maybe didn't read]

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'

Science Magazine: ‘Sweeping chronic fatigue study brings clues but not clarity to mysterious syndrome’

STAT News: 'NIH study of ME/CFS points to immune dysfunction and brain abnormalities at core of long-dismissed disease’

New York Times: ''Study of Patients With a Chronic Fatigue Condition May Offer Clues to Long Covid'

Scientific American: 'People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome May Have an “Exhausted” Immune System'

Medscape: ''Deep Phenotyping' Identifies Abnormalities in ME/CFS'

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

Bloomberg: ''Exhaustive Chronic Fatigue Study Points to Infectious Driver'

The Guardian: 'Scientists find link between brain imbalance and chronic fatigue syndrome’

 

[Hutan]

Obesity and stress are said to reduce DOPA levels - the ME/CFS cohort had higher BMIs.

BMI was no different between the two cohorts according to supplementary data 5:
mean (SD) BMI of HVs: 25.8 (3.4) ME/CFS: 25.9 (5.3) p-value 0.9
Was there a subset for this DOPA finding with higher mean BMI?

You are right, I had misremembered. What differed, in the same way as the ages, is the proportions in different categories. There were quite a lot more participants with ME/CFS with a BMI over 30.

 

[RedFox]

After taking some time to read the study, I can conclude there are good parts and bad parts. The NIH was quite thorough and delivered additional evidence that ME/CFS is biological. Many of their findings point to the immune system, others point to the nervous system. On the balance, this study will help increase people's belief in ME/CFS. However, nothing in here will lead to treatments. Their biological findings are mostly not new; they reproduce things others have found, often in larger studies. However, reproducing results is very valuable.

The largest flaw in their study is their conclusions about effort preference. They also fail to discuss PEM. They believe the effort expenditure test explains some of the pathology. The test is literally just pushing buttons rapidly for a reward of up to $8. I believe it just shows that we have limited energy. Some of the participants probably chose not to put much effort into it in order to minimize PEM caused by a long day/week at the NIH. They were wrong to conclude that people with ME/CFS exhibit a lower "effort preference" and their discussion is demeaning to patients.

There are several positives here: Increased awareness and acceptance of ME/CFS, especially in the media. And reproduction of previous results. However, considering that this is the NIH's seminal study on ME/CFS, I would expect to see more, like a clear path to a drug trial.

 

[Evergreen]

You are right, I had misremembered. What differed, in the same way as the ages, is the proportions in different categories. There were quite a lot more participants with ME/CFS with a BMI over 30.

View attachment 21190

Gotcha. That seems like an important difference, potentially, between these tiny cohorts.

I had a look at the diet data yesterday in supplementary data 11. We have diet records for 10 HVs and 11 pwME, and diet history questionnaires for 15 HVs and 17 pwME, so there's just too little to go on. But intake differences that look like they would be worth checking for in much larger datasets are potentially

• lower protein
• higher fat particularly saturated fat
• lower fibre
• higher sodium (but blood sodium same in the full cohorts supplementary data 9)
• lower iron (bit lower in the full cohorts supplementary data 9)
• lower folate (bit lower in the full cohorts supplementary data 9)

in patients compared to controls. I did not restrict myself to statistically significant results as the samples are so small that we could miss something significant, so I looked at anything with a p-value less than 0.1.

Carb and sugar intakes look similar in this tiny comparison, as does caffeine intake.

There are a few things that could be intentional - eg lower gluten intake may mean some patients are avoiding it due to sensitivity, higher fat intake could be ketogenic-diet-inspired, higher sodium intake could have been recommended for orthostatic intolerance.

But others could just be an overall less nutritious diet because of reduced ability to prep and/or eat healthy/fresh/diverse food.

Am sure @Midnattsol would have a lot more insight on the diet data. Forgive me if I've said misleading things - happy to correct if so!

 

[Kitty]

The largest flaw in their study is their conclusions about effort preference.

I have more of a problem with the name than the underlying concept. Even assuming they've understood and applied the test appropriately (and I make no such assumption), the name's inappropriate because it doesn't communicate the prophylactic nature of conscious and subconscious effort preference.

Safeguarding measures dominate the way ill, frail, and disabled people have to live and the choices they have to make. "Preference" is a grossly insulting way to present enormous limitations on people's lives and options.

 

[Sean]

Thank you, @Simon M.

 

[Evergreen]

However, considering that this is the NIH's seminal study on ME/CFS, I would expect to see more, like a clear path to a drug trial.

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.

"We need to validate these findings, but they can be done in the context of a clinical trial," Nath said. There's now enough data to start pinpointing potential therapies, narrowing down which populations of ME/CFS are likely to benefit, and then testing these in trials. Once selected, multiple drugs could even be tested in the same trial, with, for example, four groups receiving different treatments and one receiving a placebo. This could speed up the process, Nath suggested. https://www.livescience.com/health/...xplain-disease-but-will-it-lead-to-treatments

 

[Evergreen]

I find the way Nath and others explain effort preference in interviews much more palatable than how it is written in the paper.

"Their brain is telling them, 'no, don't do it,'" says Nath. "It's not a voluntary phenomenon."
This is a novel observation, says Komaroff, demonstrating that a brain abnormality makes it harder for those with ME/CFS to exert themselves physically or mentally.
"It's like they're trying to swim against a current," he says.
https://www.npr.org/sections/health...chronic-fatigue-syndrome-emerge-from-major-st

 

[Evergreen]

"Preference" is a grossly insulting way to present enormous limitations on people's lives and options.

Exactly. The word "preference" denotes volition. So if you're describing something in someone's brain that they have no control over, which is certainly Nath's interpretation of what they're describing, don't use the word preference. The use of "unfavorable preference" made it even worse. It's so reminiscent of the unhelpful beliefs and fear avoidance model.

Call it an "exertion brake" or something. While people who drive intentionally press the brake pedal, we also have experience of being in vehicles that others are driving - cars, busses, trains - and feeling the brake, and grinding to a halt.

 

[duncan]

I find the way Nath and others explain effort preference in interviews much more palatable than how it is written in the paper.

"Their brain is telling them, 'no, don't do it, " says Nath. It's not a voluntary phenomenon." "This is a novel observation, says Komaroff, demonstrating that a brain abnormality makes it harder for those with ME/CFS to exert themselves physically or mentally."

A brain abnormality of volition?? Of perceived reward??

Patients' brains - which is them - are telling them not to do it because they feel like shit. It's a symptom cluster. Exhaustion, depleted energy, weakness, cognitive freefall, headaches, balance issues, poisoned sensation like a constant toxin or acid, dizziness, pain....what don't they understand? Moreover, patients know there is a very real risk associated with pretty much every thing involving any exertion. They literally never know what might propel them into PEM, so they've learned to be cautious. We may have cognitive issues, but we're not brain dead.

Sugar coating won't make what appears to me as a fundamental and deeply flawed misunderstanding any more palatable. For me, it just smacks of patronizing.

And this "brain abnormality" is BS.

 

[Jonathan Edwards]

So certainly Nath is talking about treatment trials based on this study.

Except that this study provides no basis for such trials. It shows no evidence for a need to 'clear antigen' even if checkpoint inhibitors were good for that which I doubt.

 

[Keela Too]

If as Nath said (quoted from above), “the brain is telling them don’t do it”, then I can see only one reason to label the effect “effort preference”.

IMO this name was a blatant attempt to blame patients.

The effect observed would surely be more accurately described as “effort inhibition”, if they were describing what Nath has described, and not trying to lay blame!

 

[Evergreen]

Yep. My understanding is that Nath is going on indirect evidence - perhaps some of these findings:

Markers of T-cell activation, PD-1+ CD8 T-cells, were elevated in the cerebrospinal fluid of PI-ME/CFS participants

PD-1, a marker of T-cell exhaustion and activation, was elevated in the cerebrospinal fluid of PI-ME/CFS participants.

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). Two PI-ME/CFS participants had detectable antibody secreting B-cells in cerebrospinal fluid;

in order to conclude

The finding of possible immune exhaustion suggests that immune checkpoint inhibitors may be therapeutic by promoting clearance of foreign antigen.

Alternatively, perhaps he's thinking of trials of neuro drugs:

Immune dysfunction leads to neurochemical alterations that impact neuronal circuits, which may be another point of intervention.

I get the sense that as far as Nath is concerned, they didn't find the smoking gun, but they did find the smoke, and that's good enough to try something.

My hope is that others will dig deeper.

 

[Lucibee]

My concern is that saying “There’s nothing [physically] wrong with your muscles.” gives a huge amount of rope to those trying to gain ground with their psychosomatic/functional disease theories.

I hear what you are saying but the opposite - suggesting that there is something wrong with muscle metabolism or there are hidden viruses - gives a huge amount of rope to private physicians selling toxic medications like antivirals etc..

I wasn't suggesting saying the opposite... (although if there is persistent/reactivated virus then antivirals may well be helpful to some). It just seems that the press have gone out of their way to get positive quotes about this study, particularly from those who are supported by the patient community, and yet there are so many obvious caveats.

Also, it seems that is precisely what this paper does do (giving "a huge amount of rope to private physicians selling toxic medications like antivirals etc"). The unqualified suggestion that there is "persistent antigen" that requires removal is just the sort of thing that quack physicians will be leaping all over.

You've already acknowledged earlier in this thread that use of checkpoint inhibitors could well be counterproductive. I would agree. Taking the brakes off a system that could well lead to autoimmunity doesn't seem terribly sensible. The data on which this is based is sketchy at best - the PD-1 CD8+ subgroup data are poor and the analysis suspect (just look at the scatter graph and overlap - comparing means in that context seems somewhat meaningless).

If they do test this in a combination therapy trial (CBT/GET + CI + something else (Ampligen?)), as suggested at the end of the discussion, it looks like it is set up to fail. An opportunity to say, "see, it was deconditioning all along" maybe? Where have we seen that before?

I think what is happening at NIH is similar to what happened with PACE - a need to appease competing theories: in PACE it was White's GET vs Sharpe's CBT; in NIH, it's Walitt's Effort Preference deconditioning theory vs Nath's (?) persistent antigen leading to immune dysfunction theory, with a sprinkling of central mechanisms to tie the two together.

Mashing these theories together seems to be done more to favour the researchers than to do anything to find a valid treatment path for patients.

 

[siobhanfirestone]

Except that this study provides no basis for such trials. It shows no evidence for a need to 'clear antigen' even if checkpoint inhibitors were good for that which I doubt.

hard agree, at worse these drugs also CAUSE autoimminity in rare cases. This is a potential disaster

 

[siobhanfirestone]

I wasn't suggesting saying the opposite... (although if there is persistent/reactivated virus then antivirals may well be helpful to some). It just seems that the press have gone out of their way to get positive quotes about this study, particularly from those who are supported by the patient community, and yet there are so many obvious caveats.

Also, it seems that is precisely what this paper does do (giving "a huge amount of rope to private physicians selling toxic medications like antivirals etc"). The unqualified suggestion that there is "persistent antigen" that requires removal is just the sort of thing that quack physicians will be leaping all over.

You've already acknowledged earlier in this thread that use of checkpoint inhibitors could well be counterproductive. I would agree. Taking the brakes off a system that could well lead to autoimmunity doesn't seem terribly sensible. The data on which this is based is sketchy at best - the PD-1 CD8+ subgroup data are poor and the analysis suspect (just look at the scatter graph and overlap - comparing means in that context seems somewhat meaningless).

If they do test this in a combination therapy trial (CBT/GET + CI + something else (Ampligen?)), as suggested at the end of the discussion, it looks like it is set up to fail. An opportunity to say, "see, it was deconditioning all along" maybe? Where have we seen that before?

I think what is happening at NIH is similar to what happened with PACE - a need to appease competing theories: in PACE it was White's GET vs Sharpe's CBT; in NIH, it's Walitt's Effort Preference deconditioning theory vs Nath's (?) persistent antigen leading to immune dysfunction theory, with a sprinkling of central mechanisms to tie the two together.

Mashing these theories together seems to be done more to favour the researchers than to do anything to find a valid treatment path for patients.

well said, as someone with a background working with the CLEAR immune dysfunction that is CAUSED by HIV (i worked in S. Africa with clinicians but not a clinician or med worker), this is maddening to see. 0 evidence of dormant or reactivated viruses here and also terrible terrible work done in the NIH study to even demonstrate this tbh......long covid will present the needed data tbh

 

[Simon M]

I find the way Nath and others explain effort preference in interviews much more palatable than how it is written in the paper.

I think there might be 2 things going on here.
1. Effort preference, which means nothing and is a null test for the study population.
2. The separate rather odd fadings about lack of central fatigue (as shown by transcranial magnetic stimulation), which might mean something. I haven't read this part of the paper yet. The paper tries to combine the 2 concepts, which I don't think holds up as several people have said.

Nath's explanation might apply to finding 2 - I don't know.

but I think we should get all our ducks in a row before coming to too many conclusions.

Thank you so much @Simon M for clarifying a very confusing situation. Would it be OK for your analysis to be used by those writing to people at NIH, and possibly writing to the journal that published it, to complain about the publication? I think it would be very helpful to have it spelled out so clearly.
I would like Nath to be asked how it came about that such misuse of a test and invention of a false hypothesis came about and why noone had insisted the whole invented and unevidenced premise of effort preference be removed from what is meant to be a biomedical science paper.

Thank you, @Trish. This is a public forum so people can use it any way they wish. Though I hope others will check the arguments first.

But also see my comment at the start of this post. I think it might be premature to write to the NIH.

 

[Jonathan Edwards]

I get the sense that as far as Nath is concerned, they didn't find the smoking gun, but they did find the smoke, and that's good enough to try something.

The sample is too small to tell if they found anything in fact. And if they did it seems to me more like an 'odd smell' rather than smoke. It might just as well be the smell of cold damp ash.

These labels like 'activation marker' and exhaustion marker' are highly dubious at best. I fail to see how something can be an activation marker (marking increase in activity) and an exhaustion marker (showing loss of activity). And if the cells are exhausted I would expect using a checkpoint inhibitor to achieve nothing. If they activated then the situation might get worse.

 

[siobhanfirestone]

The sample is too small to tell if they found anything in fact. And if they did it seems to me more like an 'odd smell' rather than smoke. It might just as well be the smell of cold damp ash.

These labels like 'activation marker' and exhaustion marker' are highly dubious at best. I fail to see how something can be an activation marker (marking increase in activity) and an exhaustion marker (showing loss of activity). And if the cells are exhausted I would expect using a checkpoint inhibitor to achieve nothing. If they activated then the situation might get worse.

i think the theory is
Pd-1 receptors are found more in t cells that are used by t-regs to limit immune activation and try and prevent self-attacks on cells/tissues etc. There is also associated molecules that i dont understand, nor do i know how they tested for but they did not in this paper.
You do something that lowers this/inhibits = releases t cells to fight magical "viruses" they didnt even test for
Agonists are actually being trialed in autoimmunity atm, i could not find results: https://www.ncbi.nlm.nih.gov/pmc/ar...imary human,event in many autoimmune diseases.