The Concept of ME/CFS, 2024, Edwards

Another review -- by Ruud Raijmakers, Radboud University Medical Center, Nijmegen, Netherlands

https://www.qeios.com/read/W3Q720

"Without agreeing or disagreeing with the claims that were made, I tried to offer some counterclaims/queries to spark a scientific discussion."


Just picking out these two somewhat related ones:

"I like the paragraph on patient-initiated research and where it has brought the field. Are you at all afraid of a biased approach with these developments? Or do you feel the bias lies in the academic research that has been done up until then?

"Could the author elaborate on psychological intervention studies after the PACE trial that found benefit for some patients? Could it not be of use for some patients on the fatigue spectrum?

"Ref 17 does not scientifically support the strong claim that is made. "


Ref 17 is the Anomalies paper by White et al. criticizing the NICE guideline.


Raijmakers question about bias as an either-or issue I think may expose a lack of understanding of what bias is. Or maybe they just wanted to give you an easy opportunity to elucidate with some examples?


Reminded me of a couple of questions/ suggestions I had but wasn't able to write up in time.

Just one question now re ref 17: Why did you reference the Anomalies paper instead of its rebuttal by Barry et al?


I think in general some additional references and explanations would be helpful -- even if you think that's all too obvious for people you intended to get interested.

You could also name S4ME as a place where pwME/CFS engage in thorough discussions on research?

Anyway, it's good to see professionals with different background commenting on your article. To me that seems an exceptional chance to get some basic things across to people who haven't been aware of these before and are open to learn even if that includes reviewing some of their taken-for-granted assumptions.


Edit: Typo 1st line ('Preview' -> review)
 
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Jonathan Edwards said:
I have posted responses to reviewers.
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They're very good. But I don't see a response to Marku Partinen's review, which contains, for example, this statement: "However, people woth ME/CFS may get much better by rehabilitation. They ,may be able to return to work or to go back to school ME/CFS is not "chonic", but it is, unfortunately, often a longstanding illness."
 
Raijmaker is the researcher who suggested that CBT was helpful for Q-fever fatigue syndrome (and that it has been proven to be helpful for CFS) despite his data showing that there was no long term benefit (see here, for example). While he has published from the BPS camp, I do wonder if he might be a bit more open to biological causes of post-infection fatiguing illnesses than some. His engagement with the Concept paper therefore is possibly a win for the relatively neutral stance taken by Jonathan.

An excerpt from Raijmakers' comment:
Could the author elaborate on psychological intervention studies after the PACE trial that found benefit for some patients? Could it not be of use for some patients on the fatigue spectrum?

Ref 17 does not scientifically support the strong claim that is made.

The author suggests specialised multi-disciplinary care for ME/CFS patients. Would specialised centres be an option? And would you say that these centres should specialise solely in ME/CFS or also in other adjacent syndromes like post-viral fatigue syndromes (given the recent surge in post-COVID cases)? Where does the GP come in, or does the author feel that ME/CFS (perhaps especially the severe cases) needs specialist care?
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And Jonathan's reply:
I am not aware of studies since PACE that provide reliable evidence for usefulness of psychological intervention. All the studies to date suffer from the basic design fault of open label treatment with subjective outcome measures. In other branches of internal medicine the format is considered of no use, other than in specific situations where bias can be mitigated. Authors of trials of psychological intervention argue that it is too difficult to overcome the bias problem. But you cannot admit that your method is unreliable and then ask people to treat it as reliable because you cannot do better! In my view the a priori likelihood of psychological therapy being useful in ME/CFS is low and the inadequately designed studies so far suggest that CBT performs less well in trials than one might expect from a run of the mill placebo response from an ineffective treatment. In other words, we have no evidence for anyone benefitting over and above disease natural history. And the longer term PACE data showed no difference in disease course with any of the arms.

In view of the above and the content of reference 17 being a complete denial of these problems by PACE authors and associates I would argue that it supports my contention very adequately! The critique of the NICE process in paper 17 shows a total lack of understanding of trial methodology. If anything, NICE was too lenient because it used GRADE, which relies on a pseudo-arithmetic scale for grading reliability as a surrogate for direct reasoning. None of the trials to date reach basic reliability requirements and so should score zero for evidence quality.

In your last comment I think you may have misread what I said about ‘multidisciplinary care’. I pointed out that, when applied in the absence of any treatments with a reliable evidence base, the ‘MDT’ is largely a means to diffuse responsibility and pass the buck (I am trained and accredited in rehabilitation so am familiar with the context). We need physicians to make safe diagnoses. Delegation to an experienced nurse makes sense for practical support but I don’t see that needing the tag ‘multidisciplinary’.

I think I have probably answered most of your other questions in the paper. I think we need specialist care, if only to allow academic physicians to make progress with research. I personally think that ME/CFS patients should have access to general clinics in a specialty such as rheumatology just as patients with rheumatoid or spondylitis do. Triage to specialised clinics makes sense but is not the only model. When I started out in the 1970s the situation for RA was rather as it is now for ME/CFS. We had little idea of disease mechanism and no very useful treatment. Through regular follow-up of large numbers of cases we could do research and now we have highly effective therapies. I cannot see how any progress will be made if ME/CFS is handled in primary care. There seems to be a belief nowadays that we have a recipe for everything and patients can just be shunted to the right pigeon hole. I think there is a much longer road ahead before we get to that point. We need to go back to recognising our ignorance.
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Jonathan Edwards said:
I have added a reply.
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Thank you! That's very good, and it's amazing to me that people are still making these claims in public for the efficacy of rehabilitation at this point.

You said in your reply:

Jonathan Edwards said:
Post-infectious fatigue, as I have indicated in other replies, is a different concept, even if it may apply to the same patient in some cases. Many patients and physicians make a link to infection but there is no stereotyped time relation of the sort recognised in rheumatic fever or Reiter's syndrome, which makes the relation much more tenuous and subject to coincidence.
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I'm wondering if I've misunderstood you. Don't you think that most cases of ME/CFS are triggered by viral infection?
 
Sasha said:
I'm wondering if I've misunderstood you. Don't you think that most cases of ME/CFS are triggered by viral infection?
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I am very uncertain about that.
It used to be said that rheumatoid arthritis was often triggered by infection or trauma but it probably isn't. When I asked people about lag between infection and ME/CFS onset the results were pretty variable. It may well be that infection is often the straw on the camel's back so to speak but I am not convinced that chasing viruses will tell us much about the illness.

There is currently a big push to include ME/CFS in 'post-infective syndromes' and I worry that that is mostly driven by very naive immunology bound up with 'cross-reactivity' and such-like.
 
Jonathan Edwards said:
I am very uncertain about that.
It used to be said that rheumatoid arthritis was often triggered by infection or trauma but it probably isn't. When I asked people about lag between infection and ME/CFS onset the results were pretty variable. It may well be that infection is often the straw on the camel's back so to speak but I am not convinced that chasing viruses will tell us much about the illness.
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Interesting. I've always thought of my ME as post-viral but I started feeling a bit rubbish for a couple of months, though still able to live life as normal, and then got a flu-like illness that really scuppered me and a second that made me bed-bound for years. Lately, I've been really done in by what were probably two Covid infections (no test results available). It never even occurred to me that the whole thing wasn't post-viral.

So if viruses are only the straw that breaks the camel's back, does that say something about what kind of camel it is?

There is currently a big push to include ME/CFS in 'post-infective syndromes' and I worry that that is mostly driven by very naive immunology bound up with 'cross-reactivity' and such-like.
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Maybe I've not been paying attention but is this notion that viruses probably aren't one of the causes of ME/CFS novel? I don't recall seeing it before. If the field is going the wrong way in terms of seeing it as a post-infective syndrome, do you need to be writing a new paper? :)
 
Sasha said:
Don't you think that most cases of ME/CFS are triggered by viral infection?
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Jonathan Edwards said:
I am very uncertain about that.
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When it comes to infections, would it be more accurate to say ME/CFS is 'associated with' rather than 'triggered by' infection?

There appears to be an association, possibly a strong one, but stating that one triggered the other suggests we understand the chain of events. We don't; we're making an assumption because the two sometimes coincide.
 
Sasha said:
Maybe I've not been paying attention but is this notion that viruses probably aren't one of the causes of ME/CFS novel?
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We have discussed the uncertain relation between a viral 'trigger' and ME/CFS for a good while but I must admit that my current scepticism was in part raised by trying to enunciate the 'Concept of ME/CFS' clearly and realising that the relation to 'post-viral fatigue syndrome' is likely to be more complicated than a lot of people assume. Some of the people commenting on my article are clearly wedded to an idea of ME/CFS as 'post-infective' but I not at all sure that works.

My own experience of post-EBV and post-covid illness is that I was exhausted and felt that I might have a sense of what ME/CFS is like but I never had episodes I would call PEM or crashes. I just felt that I had never quite got better from the acute phase. Lots of people with ME/CFS report sudden worsening after the apparent trigger infection has long gone.
 
Jonathan Edwards said:
We have discussed the uncertain relation between a viral 'trigger' and ME/CFS for a good while but I must admit that my current scepticism was in part raised by trying to enunciate the 'Concept of ME/CFS' clearly and realising that the relation to 'post-viral fatigue syndrome' is likely to be more complicated than a lot of people assume. Some of the people commenting on my article are clearly wedded to an idea of ME/CFS as 'post-infective' but I not at all sure that works.

My own experience of post-EBV and post-covid illness is that I was exhausted and felt that I might have a sense of what ME/CFS is like but I never had episodes I would call PEM or crashes. I just felt that I had never quite got better from the acute phase. Lots of people with ME/CFS report sudden worsening after the apparent trigger infection has long gone.
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We have shedloads of people catching Covid, which we know can trigger an ME-style Long Covid. Does this give us a chance to catch the biology in action?
 
Sasha said:
We have shedloads of people catching Covid, which we know can trigger an ME-style Long Covid.
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I think we need to be careful about what we know here.

Maybe one person in five has long-lasting fatigue after Covid - maybe for three months or more - many of which might seem to fit criteria for ME/CFS if the questions are put badly in a questionnaire, but on careful analysis not really qualify.*

We also know of hundreds (out of the above millions) who seem to have a pretty classic ME/CFS picture, some severe enough to be bed bound. But there were going to be thousands of people getting ME/CFS in the last five years anyway.


It may well be that post-viral fatigue as a whole, and ME/CFS, share a common pathway problem but it may also be that the mechanism behind that problem is quite different in the two situations. In one case it might be an essentially normal hypothalamic response through nerve or endocrine pathways. In the other it might be an entirely abnormal signal feeding in to the same pathway.

* If rheumatoid arthritis was diagnosed purely on symptoms over the phone a large majority of people giving the 'right' answers to questions given as a questionnaire would not in fact have RA. It would be a bit like trying to identify grasses from a handbook without pictures just by described features. Unless you are very expert it is pretty unreliable.
 
Jonathan Edwards said:
We have discussed the uncertain relation between a viral 'trigger' and ME/CFS for a good while but I must admit that my current scepticism was in part raised by trying to enunciate the 'Concept of ME/CFS' clearly and realising that the relation to 'post-viral fatigue syndrome' is likely to be more complicated than a lot of people assume. Some of the people commenting on my article are clearly wedded to an idea of ME/CFS as 'post-infective' but I not at all sure that works.
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I agree there is overlap between PVFS and ME. However, I think there is still evidence connecting ME with infection (even if most post-infectious cases are not ME/CFS).
For instance,
  • I think 17% of DecodeME subjects (all with a diagnosis) reported their illness began with lab-confirmed viral GF and almost all respondents reported PEM (even though most had had it for a substantial time, i.e. it wasn't simply a protacted post-viral fatigue).
  • The Dubbo study (posted by me earlier in this thread somewhere) showed the symptom pattern developing from fatigue and acute-illness type symptoms to a wider pattern over several months.
  • In DecodeME The biggest factor distinguishing the different onset types (glandula fever/infectious mononucleosis, other infectious, not infectious and not known) was age, which was almost certainly a reflection of onset age. (Added: there was a different on onset age pattern for those who reported infectious onset compared with those, he reported no infectious onset. This is unpublished and unchecked, but I hope this will be explored further at some point.)

Your concept paper has pointed out the hole in the simple post-infectious view (the apparent recovery curve for CFS cases seen from 6 months to 24 months also looks odd). But I think there is still evidence for an infectious onset. Though lumping all (or even a large chunk) of LC with ME/CFS is not yet justified, IMO.

Jonathan Edwards said:
My own experience of post-EBV and post-covid illness is that I was exhausted and felt that I might have a sense of what ME/CFS is like but I never had episodes I would call PEM or crashes. I just felt that I had never quite got better from the acute phase. Lots of people with ME/CFS report sudden worsening after the apparent trigger infection has long gone.
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A close relative of mine has long covid. Speaking on the phone over several months, I didn't know if she had what I do. When we were finally able to meet, I had no doubt this was ME, because I know the illness and I know her. This includes PEM. and crashes. Of course, I don't know how typical she is, but I do know some else well who recently got long covid and again, I am sure she has the same thing that includes PEM and goes well beyond exhaustion.(And sounds very different from what you have just described.)

This is just trading anecdotes, but perhaps points to a mixed population post-infection. I'm not sure any studies have looked for this.
 
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I think two factors are at play that affect our ability to understand ME/CFS as a post-acute infection syndrome: the recognition of acutely asymptomatic viral infection; the subclinical / latent period.

The latter I recognised in my own history, only in hindsight. Once strange symptoms started to occur and were apparent, they were relatively mild rather than disabling initially and they were intermittent — interspersed with asymptomatic periods. There was a slippery slope of 5-6 months where I continued to try and live live normally, but in hindsight I was obviously inducing (mild) PEM and lowering my baseline, until I ultimately crashed out to severe.

I expect stories similar to that are not uncommon, and while I have evidence of prior acutely asymptomatic Covid, most people would not, so you get the "must be stress at work", "I hurt my neck", "I banged my head" or any number of other things that are closer in time to the definitive major symptom presentation.
 
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