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

[Binkie4]

Edited: I'd also like to know which out of the 4/17 patients that recovered met which criteria. That could be revealing. (@EndME)

I too was curious about 4 out of 17 recovering. It's not a ratio that is even close to anything that I've seen before.

 

[Jonathan Edwards]

100% of ME patients met the IOM criteria, 82% met the Fukuda Criteria and only 53% met the Canadian Consensus Criteria.

So at least we should perhaps be less concerned that the patients didn't have PEM. The low CCC rate is puzzling as you say but I have always thought CCC was too
complicated. Nevertheless, one might expect 'barn door' ME cases to likely fit CCC.

Since none of the patients in this study seemed to have orthostatic intolerance,

Is this correct though? They may have demonstrated no haemodynamic changes but orthostatic intolerance in ME does not seem to be closely correlated to a particular haemodynamic change. I suspect in many cases it occurs with normal pulse and BP. OI is a much more general symptom.

But something which always worried me about this study is that anyone with what I would call moderately severe current ME - by which I mean something quite a bit worse than my experience with Longish Covid - might be keen initially to volunteer for this study but once they knew what was involved would likely back off. If I had significant OI there is no way I would agree to take part.

 

[butter.]

I looked at the cohort characteristics a bit more. 100% of ME patients met the IOM criteria, 82% met the Fukuda Criteria and only 53% met the Canadian Consensus Criteria.

Fatigue is necessary in all criteria. Now the discussion becomes a bit more involved because PEM is a necessary symptom in the IOM criteria as well (it’s not necessary for Fukuda).

Now after a post-infectious onset the only criteria that have to met in the Canadian Consensus Criteria are (the illness duration of at least 6 months has automatically been met by all patients in this study):

• Fatigue
• PEM*
• Two or more Neurological / Cognitive Manifestations from a list of symptoms
• At Least One Symptom From Two of the Following Three Categories (autonomic, neuroendocrine, immune) from a list of symptoms

The IMO criteria furthermore requires patients to either have orthostatic intolerance or cognitive impairment. Since none of the patients in this study seemed to have orthostatic intolerance, this means they have all had to have had cognitive impairment (I will look at the study data at a later time point to see if this can actually be verified by their data when they assessed subjective cognitive impairment).

So where do the 47% come from that don’t met the Candian Consensus Criteria? The most logical explanation would be that they don’t have at least one symptom in at least 2 categories from the list of symptoms in the autonomic, neuroendocrine, immune list of symptoms in the CCC (I'm working under the additional assumption that people with cognitive impairment in the IMO criteria will have at least 2 cognitive symptoms in the CCC list). There's a caviat* to this mentioned below.

Fukuda is of course extremely vague. It requires fatigue and at least 4 symptoms from the following list: substantial impairment in short-term memory or concentration, sore throat, tender lymph nodes, muscle pain, multi-joint pain without swelling or redness, headaches of a new type/pattern/ severity, unrefreshing sleep, post-exertional malaise lasting more than 24 hours.

Since allegedly all patients had PEM (with the caviat * mentioned below) and cognitive impairment (assuming it aligns with "substantial impairment in short-term memory or concentration") as well as unrefreshing sleep are also a necessary symptom of the IMO criteria this automatically means that 18% of patients didn’t have another symptom of the above list (i.e. 18% didn't have a concurrent occurrence of any of the following symptoms: sore throat, tender lymph nodes, muscle pain, multi-joint pain without swelling or redness, headaches of a new type/pattern/ severity).

*The caviat to this discussion is PEM. The IMO criteria aren’t specific to what PEM exactly is or how long it should last, so some subtle differences could arise there when applying different criteria in the above discussion, it’s not necessary in Fukuda but has to last more than 24 hours to count as one of the symptoms and in the CCC there should be a pathologically slow recovery period – usually 24 hours or longer. It should be noted that in none of the above criteria is a delayed onset necessary.

A whole different question would be who actually assessed these patients and what is their rigor and background. Someone that uses the CCC might be far more rigorous and might not classify something as PEM, whilst others do. Apart from the fact that patients couldn't be sick for longer than 5 years and had to have an infectious onset, I cannot understand who you start off with over 400 patients and only end up studying 8 patients that meet the CCC. Do you have some more details on how the recruitment and assessment worked @B_V ?

Edited: I'd also like to know which out of the 4/17 patients that recovered met which criteria. That could be revealing.

I think the thing that stands out to me the most is that there was not a single patient with POTS. Unless pwPOTS were conciously excluded, which would be hard to justify, this really makes no sense.

Either some of these patients had POTS and it did not show up (can happen with TTT), they were conciously excluded or something is really off here. I don't think you can grab 17 ME patients out of a sample without one having POTS easily. POTS is an objective finding, PEM wasn't back then and isn't now (unless you think iCPET is circumstantial evidence that makes PEM plausible). I find it curious this did not pop up.

 

[Jonathan Edwards]

I too was curious about 4 out of 17 recovering. It's not a ratio that is even close to anything that I've seen before.

But it was a group of people feeling robust enough to spend a week having tests - which is not representative.

 

[Hubris]

Edited: I'd also like to know which out of the 4/17 patients that recovered met which criteria. That could be revealing. (@EndME)

I too was curious about 4 out of 17 recovering. It's not a ratio that is even close to anything that I've seen before.

A quarter of patients recovering and no POTS is a huge red flag. This is why you can't let "FND" minded people select patients. 8 years down the drain.

 

[EndME]

Is this correct though? They may have demonstrated no haemodynamic changes but orthostatic intolerance in ME does not seem to be closely correlated to a particular haemodynamic change. I suspect in many cases it occurs with normal pulse and BP. OI is a much more general symptom.

But something which always worried me about this study is that anyone with what I would call moderately severe current ME - by which I mean something quite a bit worse than my experience with Longish Covid - might be keen initially to volunteer for this study but once they knew what was involved would likely back off. If I had significant OI there is no way I would agree to take part.

I completely agree that OI in ME seems to more complicated than haemodynamic changes, however the IOM criteria define the orthostatic intolerance criteria in ME as "Orthostatic intolerance—patients develop a worsening of symptoms upon assuming and maintaining upright posture as measured by objective heart rate and blood pressure abnormalities during standing, bedside orthostatic vital signs, or head-up tilt testing." In this study no such values in objective heart rate differences were seen (at least when compared to controls).

Unless I'm missing something these patients wouldn't have had OI as it is defined as in the IOM criteria (or there are differences in recruitment results and study results, which should probably be further investigated or at least mentioned).

 

[Hubris]

A quarter of patients recovering and no POTS is a huge red flag. This is why you can't let "FND" minded people select patients. 8 years down the drain.

I don't think FND doctors are evil masterminds, they might be genuinely fascinated by this mysterious illness where people say they are tired and decide not to do things even though they clearly can.

But when someone is psych minded like this, they see what they want to see and hear what they want to hear.

They might claim the patients fit the IOM criteria, but I simply don't believe it. You can't trust someone like that to select the patients and the fact nobody has POTS (the most common objective finding), as well as a quarter of the patients recovering suggests this was basically a FND study.

 

[poetinsf]

Greater activation in the HVs suggests that they are attending in detail to their slight failures, while the PI-ME/CFS participants are accomplishing what they are intending.

I couldn't parse this sentence that sounded paradoxical. Then I realized after reading subsequent paragraph that it basically was blaming pacing for the under-performance:

Conscious and unconscious behavioral alterations to pace and avoid discomfort may underlie the differential performance observed.

In other words, the parietal junction was not activated because the patients avoided exerting.

Too much focus on fatigue and none on PEM. The "potential" pathophysiology was the wildest speculation I've ever seen. The only thing that I found interesting in this paper was about the catechol level correlating to the fatigue level. There has been something about forced alertness that counteracted PEM in my experience and the catechol level seems to point to that direction.

 

[Lucibee]

We don't even know quite what it is protecting against in 'flu and it may well be unneeded there too.

Likely it's to conserve energy. Fighting against organisms that are trying to hijack your cells to their own ends is an energy intense enterprise. There are good reasons to get rest when the body is going through that onslaught.

We have to be very sure that any "central mechanism" is redundant or misfiring for no reason at all before we start trying to muck about with it.

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.
It's back to the "just push through and you'll be fine" mentality. That somehow you have to reprogramme your central mechanisms to overcome the deconditioning.

And of course they are now combining it with immune profiling and "deep phenotyping", because it lends credence to their theory that it is the "central mechanism" that is causing all this chaos and is leading to disruptions in biological functioning. Maybe, just maybe, it's the other way around?!

 

[Binkie4]

But it was a group of people feeling robust enough to spend a week having tests - which is not representative.

Exactly. It is not a group that is representative of people with a ME diagnosis which is why the selection criteria is so important.

 

[Jonathan Edwards]

"Orthostatic intolerance—patients develop a worsening of symptoms upon assuming and maintaining upright posture as measured by objective heart rate and blood pressure abnormalities during standing, bedside orthostatic vital signs, or head-up tilt testing."

OK, but this IOM statement is no good. Measurements of heart rate and BP are not measures of 'worsening of symptoms'. This is typical of the ramshackle way these criteria get devised. We are told that all patients satisfied IOM, so presumably the assessors did not take this statement literally and just asked about OI - more symptoms on standing. That seems to me in the spirit of a fair understanding of ME. They then failed to find technical POT or orthostatic hypotension and I am not that surprised about that. Partly because I suspect they only occur in a minority and partly, as I posted, that I suspect anyone with significant OI would not want to volunteer.

 

[siobhanfirestone]

as someone with long covid who is newish to fucking understanding the shit storm (and life saver) that is the immune system
I am so sorry that Me patients have to put up with this collosal bullshit. Its why i refuse an ME diagnosis and only accept long covid.
We know patients who are literally doing chemo in bed alone in the hopes they will get better. This is not on them, its on the fucking psycho-babble bastards and bad studies like this
Today has been rough

 

[Ash]

Likely it's to conserve energy. Fighting against organisms that are trying to hijack your cells to their own ends is an energy intense enterprise. There are good reasons to get rest when the body is going through that onslaught.

We have to be very sure that any "central mechanism" is redundant or misfiring for no reason at all before we start trying to muck about with it.

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.
It's back to the "just push through and you'll be fine" mentality. That somehow you have to reprogramme your central mechanisms to overcome the deconditioning.

And of course they are now combining it with immune profiling and "deep phenotyping", because it lends credence to their theory that it is the "central mechanism" that is causing all this chaos and is leading to disruptions in biological functioning. Maybe, just maybe, it's the other way around?!

This is my preferred explanation.

 

[Kitty]

Likely it's to conserve energy.

That, and protecting the herd from infection, perhaps?

 

[Andy]

A whole different question would be who actually assessed these patients and what is their rigor and background.

"Case adjudication
Clinical information from the visit was compiled and reviewed by a Case Adjudication panel. Adjudicators were all recognized clinical experts in ME/CFS (Lucinda Bateman, Andy Kogelnik, Anthony Komaroff, Benjamin Natelson, Daniel Peterson). Each adjudicator performed their own independent review to assign both ME/CFS case status and temporality of ME/CFS onset to an infection. When discrepancies arose between adjudicators, a case adjudication meeting was convened. Adjudicators had to unanimously agree that a participant developed ME/CFS after a documented infection for a case to be considered adjudicated and included in the analyses. Positively adjudicated participants were also invited to return for an additional 10-day long exercise stress visit."

I've seen it pointed out that Komaroff is also a peer reviewer of the paper.

 

[Tom Kindlon]

Very disappointing:
$8M NIH study used some of the very broad and inappropriate thresholds* that are part of the Reeves et al (2005) criteria that I thought had been consigned to history . Note: these are either/or *not* all

*Though thankfully the SF36 emotional functioning element was dropped

We used information from the SF-36, MFI and Symptom Inventory to classify subjects empirically according to the 3 main dimensions of CFS: functional impairment (SF-36), fatigue (MFI) and accompanying symptoms (Symptom Inventory). We defined substantial reduction in occupational, educational, social, or recreational activities as scores lower than the 25th percentile of published US population [11] on the physical function (≤ 70), or role physical (≤ 50), or social function (≤ 75), or role emotional (≤ 66.7) subscales of the SF-36. We defined severe fatigue as ≥ medians of the MFI general fatigue (≥ 13) or reduced activity (≥ 10) scales.

https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-3-19

To be considered an adjudicated case, participants were required to be unanimously considered to be a case of PI-ME/CFS by the protocol’s adjudication committee, meet at least one of three ME/CFS criteria (1994 Fukuda Criteria64, 2003 Canadian Consensus Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome65, or the Institute of Medicine Diagnostic Criteria66), have moderate to severe clinical symptom severity as determined by having a Multidimensional Fatigue Inventory (MFI) score of ≥13 on the general fatigue subscale or ≥10 on the reduced activity subscale, and functional impairment as determined by having a Short-Form 36 (SF-36) score of ≤70 on physical function subscale, or ≤50 on role physical subscale, or ≤75 on social function subscale.

https://www.nature.com/articles/s41467-024-45107-3

https://twitter.com/user/status/1760354491134603286

 

[Hubris]

"Case adjudication
Clinical information from the visit was compiled and reviewed by a Case Adjudication panel. Adjudicators were all recognized clinical experts in ME/CFS (Lucinda Bateman, Andy Kogelnik, Anthony Komaroff, Benjamin Natelson, Daniel Peterson). Each adjudicator performed their own independent review to assign both ME/CFS case status and temporality of ME/CFS onset to an infection. When discrepancies arose between adjudicators, a case adjudication meeting was convened. Adjudicators had to unanimously agree that a participant developed ME/CFS after a documented infection for a case to be considered adjudicated and included in the analyses. Positively adjudicated participants were also invited to return for an additional 10-day long exercise stress visit."

I've seen it pointed out that Komaroff is also a peer reviewer of the paper.

How is it possible that with those people selecting patients none of them have POTS? Something doesn't add up.

 

[Creekside]

I read the article, and while I don't like the term "effort preference", to me it fit with my experience that my body is capable of exertion, but my willingness to exert is reduced by ME, through a biological mechanism. It's not a psychological problem that you can simply "push through", because the circuits of the brain that allow you to "push through" are malfunctioning. Sadly, the wording in the paper is so vague that the proponents of psychological causes will view it as supportive of their theories. I hope there will be follow-ups on verifying the physical differences in brain function.

 

[Jonathan Edwards]

Likely it's to conserve energy. Fighting against organisms that are trying to hijack your cells to their own ends is an energy intense enterprise.

Possibly but I am not sure that is so likely. Fighting a micro-organism is largely a matter of things like cloning up some lymphocytes and maybe replenishing some proteins made by the liver. I don't think we really know. It might be a mechanism for keeping you away from infecting too many other people carrying your family genes!

We have to be very sure that any "central mechanism" is redundant or misfiring for no reason at all before we start trying to muck about with it.

Yes, but over forty odd years of research every attempt to find something wrong peripherally has come up with not much or nothing. We get regular claims of finding things but they rarely if ever pan out.

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.. It also makes it a pushover for BPS people to argue back - 'What, these patients say there is evidence of mitochondrial damage in their muscles? Fact is nobody has found anything.' The more people say there are 9000 papers proving ME is physical the easier it is to raise an eyebrow and say - 'yes, well there would be wouldn't there'.

The point of emphasising central protective signals is that we know that in common illnesses central protective signals can make it impossible to even stand up when there is nothing to find wrong with muscles or circulation or whatever. For that reason the argument that it must be just a belief of being ill doesn't wash.

If what we need to do is focus on the way lymphocytes talk to brains then we should be happy to say so. And this study points in that direction as have so many before. The fact that the authors cannot understand the implications we can try to forget about.

 

[Simon M]

Credible mechanism for how 'effort preference' issues could explain PEM & relapses?

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

I queried how simply pushing overriding 'effort preference' could explain both PEM and relapses, where it seems (particularly for relapses) our body behaves as it is broken (e.g. legs giving way), as opposed to the problem being faulty brain signaling.

I don't have a particular problem with the general sort of model they propose.

[Posits an infection could lead to a shift in an immune cell population eg CD-1 T cells that migth control] 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.

@Jonathan Edwards - are there any known programmed defence responses (beyond the sickness response)?
ADDED: whoops, covered already:

we know that in common illnesses central protective signals can make it impossible to even stand up when there is nothing to find wrong with muscles or circulation or whatever.

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.

If I've understood right, you are proposing a mechanism involving the immune system and the brain that could lead to a relapse lasting months. So that the rest of the body is 'normal' but the regulator is faulty. Like ot being able to open the door of a stopped washing machine becaue the door lock thinks it is still going?