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)

 

I have posted responses to reviewers.
I don't see any need to change the paper?

 

I thought your reply to Ruud Raijmakers was especially well done. Thank you for writing it.

 

Very good responses to all reviewers. In my view the paper does not need any changes. As responded, a number of reviewers didn't seem to understand the concept of the concept.

 

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."

 

Partinen did not officially review. He commented on a review.
But I will have another look.

 

Thanks! I hadn't realised it wasn't a review. I just hate to see that kind of baseless stuff left to stand.

 

I have added a reply.

 

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:

I'm wondering if I've misunderstood you. Don't you think that most cases of ME/CFS are triggered by viral infection?

 

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.

 

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?

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?

 

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.

 

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.

 

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?

 

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.

 

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.

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.

 

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.

 

I'm not sure if I am being temporarily thick (as often happens!) but what is GF?