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

Jonathan Edwards said:
The journal Nature that had a reputation for quality is a thing of the distant past. This is par for the course I am afraid.
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you have mentioned t cell populations in LC and ME patients before, is there anything meaningful in this data other than "immune cells are activated in this population indicating something is happening maybe" - which we have heard a million times but no one seems to be able to work out the god damn specifics
They mention the distinction in immune signals between men and women, whilst interesting is 17 patients really in any way meaningful here?
 
Cognitive testing:

The 15 neuropsychological tests that were performed are called: WTAR, HVLT-R Learning , Grooved Pegboard Dominant , Grooved Pegboard Nondominant, WAIS-IV Symbol Search, WAIS-IV Coding, WAIS-IV Digit Span, HVLT-R Delayed Recall, BVMT-R Learning , Wisconsin Card Sorting Persverative Responses, COWA, Animal Fluency, PASAT, BVMT-R Delayed Recall.

The only test that seemed to show any difference at all (but not remotely statistically significant) was HVLT-R Learning.

These tests were all performed once, .i.e. without (delayed) repetition (so doesn’t assess something like “cognitive PEM”, if that were to exist and if that even is the right characterisation of what patients describe as “cognitive PEM/brain fog”).

It would still be interesting to know what the time duration was during which these tests were performed, i.e. over multiple days or one after the other in a given time frame. I cannot see that information or missed it.

The authors mention that there was no "differential degradation of performance over time" but it's unclear to me what that means. In the supplementary material they only mention that "More limited testing was also performed before and 48 hours after exercise stress in the CPET cohort. Performance on the BVMT and TOVA did not change for either group 48 hours after CPET.".

It also means that the Simple Reaction Time (SRT) and Number Vigilance Test (NVT), which were recently significant in a LC study, were not performed. I would however think that some of the above tests could be at least somewhat comparable though and that, that could provide some more insights on what the "brain fog" terminology might mean in LC and/or ME/CFS. I don't think anybody has ever figured out how to accurately describe and test for the transient "brain-fog" phase many people experienced during the earlier variants of acute Covid, but if such a test exists, it might be worthwhile seeing whether it is similar to one of the above tests.
 
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A muted response from Chris to Science Media Centre

Prof Chris Ponting, Chair of Medical Bioinformatics, University of Edinburgh, said:

“This long-awaited publication describes results from an exploratory study of 17 people with post-infection ME/CFS who match by age, sex and body mass index with and 21 healthy volunteers. The NIH investigators undertook deep phenotyping of their cells and molecules, and the autonomic, cardiorespiratory and central nervous systems. The long-awaited results show that people with post-infectious ME/CFS have different amounts of molecules in cerebrospinal fluid, muscle and blood, and immune cells in blood, relative to healthy control individuals. As they acknowledge, the data is useful to investigate correlations, but is unable to highlight causes of ME/CFS, and will be helpful to reprioritise future, more mechanistic, experiments. These should involve more than the 17 cases participating in this study, and should include people with ME/CFS without an infection prior to onset, and people who have been diagnosed for more than 5 years, the maximum for this study.”
 
siobhanfirestone said:
is there anything meaningful in this data other than "immune cells are activated in this population indicating something is happening maybe"
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No. I don't see anything significantly new here.

siobhanfirestone said:
They mention the distinction in immune signals between men and women, whilst interesting is 17 patients really in any way meaningful here?
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No, not as more than a possible pointer. But if there is a major difference in pathways in men and women it could show up with such small numbers.

Take the analogy of inflammatory oligoarthritis in young adults. Take a random sample of 17. They will likely consist of 11 women, of which 7 have early rheumatoid and 4 seronegative spondarthropathy and 6 men of which 1 has early rheumatoid and 5 spondarthropathy. Rheumatoid is a B cell disease, spondarthritis is a T cell disease but they can look identical. Around 1975 Moll and Wright worked out that they are two separate pathways with only spondarthritis linked to nail lifting. So maybe 3 out of 11 women (27.3%) would have nail changes and 4 out of 6 (66.6%) men.
 
Andy said:
one defining feature of PI-ME/CFS was an alteration of effort preference, rather than physical or central fatigue, due to dysfunction of integrative brain regions
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For this to be credible, we need an explanation for PEM and relapses. If our body was fine and the problem is with effort preference (or even central perception), why if we choose to do stuff regardless:
1. We get PEM - is that then purely a brain phenomenon (this is possible)?
2. We get relapses.

For me, if I choose to ignore my feelings of tiredness etc, as I did when I tried CBT, I would feel terrible and could do less. I chose to continue doing stuff, my legs would give way, and I had a relapse, able to do far less: I eventually recovered from that relapse (had plenty more since), but how does brain dysfunction explain this?

Did they follow-up on the biology of the participant who reported it took her months to recover from a CPET? I'm struggling to relate the findings to my experience of ME (and I think the experience of many others).

Andy said:
with consequences on autonomic functioning and physical conditioning
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Nice work by Brian Wallit.
 
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https://www.statnews.com/2024/02/21...ephalomyelitis-chronic-fatigue-syndrome-news/
For a disease that just decades ago was relegated to a dusty corner of science — and reduced to an issue women made up — the paper is a milestone, albeit one based on a small sample of patients. Using many different analyses, researchers confirmed that there are clear biological markers of illness. Namely, there’s a protracted immune response that exhausts T cells. No matter how much the body tries to fight whatever bug is in its system, it can’t win.

This inflammation is what makes people feel like they’re constantly battling a flu, researchers say. ME/CFS patients also had abnormal functioning in a part of their brain that governs effort. “When they are asked to exert themselves, it doesn’t light up as much,” said Anthony Komaroff, a professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. “It’s like trying to swim against a current.”
 
Braganca said:
https://www.statnews.com/2024/02/21...ephalomyelitis-chronic-fatigue-syndrome-news/
For a disease that just decades ago was relegated to a dusty corner of science — and reduced to an issue women made up — the paper is a milestone, albeit one based on a small sample of patients. Using many different analyses, researchers confirmed that there are clear biological markers of illness. Namely, there’s a protracted immune response that exhausts T cells. No matter how much the body tries to fight whatever bug is in its system, it can’t win.

This inflammation is what makes people feel like they’re constantly battling a flu, researchers say. ME/CFS patients also had abnormal functioning in a part of their brain that governs effort. “When they are asked to exert themselves, it doesn’t light up as much,” said Anthony Komaroff, a professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. “It’s like trying to swim against a current.”
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this statement does not follow "No matter how much the body tries to fight whatever bug is in its system, it can’t win.", it could also be some form of internal autoimmune or autoimmune like issue. We simply dont know from this
 
Simon M said:
A muted response from Chris to Science Media Centre

Prof Chris Ponting, Chair of Medical Bioinformatics, University of Edinburgh, said:

“This long-awaited publication describes results from an exploratory study of 17 people with post-infection ME/CFS who match by age, sex and body mass index with and 21 healthy volunteers. The NIH investigators undertook deep phenotyping of their cells and molecules, and the autonomic, cardiorespiratory and central nervous systems. The long-awaited results show that people with post-infectious ME/CFS have different amounts of molecules in cerebrospinal fluid, muscle and blood, and immune cells in blood, relative to healthy control individuals. As they acknowledge, the data is useful to investigate correlations, but is unable to highlight causes of ME/CFS, and will be helpful to reprioritise future, more mechanistic, experiments. These should involve more than the 17 cases participating in this study, and should include people with ME/CFS without an infection prior to onset, and people who have been diagnosed for more than 5 years, the maximum for this study.”
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Just the right tone
 
This paper is a complete joke and evidence for the NIH's semi-fraudulent behavior in regards to ME/CFS. If somebody would tell you to make an effort primarily to show effort, but, to not actually find answers, that is approx. what you would get. The fact that Fukuda criteria were used is simply unbelievable. It took the NIH 8 years to come up with this garbage. I bet once again, US advocacy groups wll fail to stand up, once again it shows that people in the community arguing that 'the NIH gets it, but their hands are tied' can't be taken very seriously and are part of the problem.
 
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Simon M said:
For this to be credible, we need an explanation for PEM and relapses. If our body was fine and the problem is with effort preference (or even central perception), why if we choose to do stuff regardless:
1. We get PEM - is that then purely a brain phenomenon (possible)?
2. We get relapses.

For me, if I choose to ignore my feelings of tiredness etc, as I did when I tried CBT, I would feel terrible and could do less. I chose to continue doing stuff, my legs would give way, and I had a relapse, able to do far less: I eventually recovered from that relapse (had plenty more since), but how does brain dysfunction explain this?
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I am not clear how effort preference differs from central fatigue but someone may be able to clarify that.

Effort preference is clearly a bad term and hopefully will gain no traction. But I don't have a particular problem with the general sort of model they propose.

Let us say that an infection, in these cases, or possibly some other pattern of stimuli, that might be a snowballing of sub threshold stochastic events (as I think is true of autoimmune disease), leads to a shift in perhaps a CD-1 T cell population. That population, let us say, is involved in interaction with nerve pathways through ACh and maybe cytokines in controlling a programmed defence response that shuts down exertion capacity not just during acute infection but for some time after. Maybe it is normally a few days but for EBV or Q fever can be months. And in ME/CFS it never shuts off.

This defence mechanism might work on the basis that signals preventing exertion gradually drop off, allowing a bit more activity, but the pathways are re-engaged if activity rises too quickly. We know that very rapid return to muscle activity leads to muscle cell death - quite extensive. The defence mechanism would be tuned to keep levels below that as far as possible. And it could have a time course that ran into days, in the way that our biological clocks do, so that jet lag lasts a week. If the mechanism involves a feedback loop that can trip positive, you get a snakes and ladders effect where you can go right back to the bottom line for months.
 
But part of the problem in ME is that your effort preference during activity is to KEEP EXERTING. When I had moderate ME I could feel relatively normal during activity and crash afterwards. Now I have severe ME and I have to stop myself from walking too far or being on feet for long. If I do continue to walk I’ll hit a weakness wall after five mins or so, and afterwards will be in PEM for rest of day from being out. But until I hit that wall I feel kindof ok and better than while in bed sometimes bc of the mental distraction and enjoyment of being upright and outdoors.
 
Well, that seems pretty disappointing, as expected. I can't believe Nath talked this paper up this much. And I can't believe it took so many years to write up something so utterly vague.

As someone with a history of head injuries I find the conclusions worrying. It seems like if their theory is correct that would be hard to treat. Plus Wallit's statement about how much we perceive we can do is total bollocks, unless my laymans understanding is incorrect. How could the fact I can't hold something relatively heavy out in front of me without incurring muscle fatigue and eventually PEM be caused by my perceptions of what I'm capable of? Outside of BPS nonsense that is.
 
Beth Pollack, a research scientist at the Massachusetts Institute of Technology, noted that, in the years after participating, four of the 17 patients “spontaneously recovered” from the condition, which she said is “not typical of ME/CFS.”

Both she and Dr. Scheibenbogen also pointed out that the study did not find some medical signatures of the condition that have been documented by other research. For example, it did not find that patients performed more poorly on cognitive tests or that they had neuroinflammation.


“These are well-established pathologies and really central to ME/CFS,” Ms. Pollack said, adding “so this did not address everything, and it contradicted some things that we know.”

Study of Patients With a Chronic Fatigue Condition May Offer Clues to Long Covid - The New York Times (nytimes.com)
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If there are no cognitive issues in ME/CFS, what's to stop us patients from hopping on a wheelchair and getting back to work or school? I'm a PhD dropout and my brain feels inflamed and legs aching just by trying to read this paper.
 
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