Why is it so often said that almost nothing is known about ME/CFS?

And we're glad you did - excellent summary.

2-day CPET (with 48 hours inbetween) seems to be the best biomarker for now - but they've always been small studies and have seemingly struggled to get traction. Does anybody know if there's anybody trying to replicate on larger numbers and (just as important) trying on other diseases to demonstrate drop off on the second day is unique to ME/CFS?

 

The quote from the CCC has the heading:

Post-exertional malaise and/or Fatigue:

I think this has, unfortunately, been poorly written. It could be interpreted as

(Post-exertional malaise) and/or (Fatigue):

which is how you have interpreted it, or as

Post-exertional (malaise and/or Fatigue):

which is how I think the rest of the following text implies it should be interpreted and how I think @JaimeS is interpreting.

 

I don't believe so, but I am a research novice.

IMO, NKC comes closest to validation, with over a dozen (small!) studies showing low function in pwME. If someone were to write a meta-analysis paper, they might be able to say something by now. But you'd have to take it through that meta-analysis process, in which studies are eliminated as not being applicable (for various possible reasons). You may find you have to eliminate a lot of them.

Everything else is:

1) Unreplicated, or only replicated once or twice
2) Replicated using the exact same patient cohort, which is problematic
and/or
3) Too small

 

Yes, though I def see how that could be unclear.

 

Even then, it's hard to argue that NKC function would be a valid biomarker for ME/CFS given reduced NK cell function is also seen in depression:

• Reduced natural killer cell cytotoxicity in depression but not in schizophrenia
• Reduced natural killer cell activity in major depression: neuroendocrine implications
• Major Depressive Disorder, Alcoholism, and Reduced Natural Killer Cell Cytotoxicity

(Now, that might be to be expected given the increasing suspicion that certain types of depressive disorder may themselves be neuroimmune in nature - however, it suggests to me that NK cell dysfunction doesn't provide a biomarker that would distinguish an ME/CFS patient from a patient with MDD. And given the selection problems with ME/CFS studies it also leads us to have to ensure that the studies that found reduced NK function did sufficient screening to exclude MDD patients)

 

But also did the studies finding reduced NK function in major depression ensure they excluded ME/CFS patients?

 

Maybe we should start a list of studies with 50+ subjects? No Oxford, no psychology, no subjective questionnaires.

 

That wikipedia link doesn't include the disease Acute Flaccid Myelitis. Which to my mind resembles some cases of Severe ME in children? It appears that there may be an enterovirus connection, though it's only been found in a few cases.

 

This is indeed the biggest and most contentious issue with the CCC. It's also the reason why the London Revised criteria were created, and why many of the specialists who wrote the CCC went on to write the ICC.

It's generally considered that the criteria requires post-exertional malaise or post-exertional fatigue, and that this is separate from the general fatigue criteria. I think they were probably trying to capture the idea of rapid fatiguability after exertion (think the latest hand-grip hand strength test) as well as the delayed and prolonged decline in aerobic metabolism (as per the CPET).

The problem is that this could too easily be interpreted as simply an increase in fatigue after exertion. Which may be present in most patients, but doesn't take into account the full breadth of symptom worsening.

I think that it's possible these patients may be experiencing PEM on day one, so they repeat their results. I'd be interested to see if these patients experience the rapid weakness that the HGS test attempts to show instead, or if they don't have that, either.

 

I think you must be right 'Post-exertional (malaise and/or Fatigue)' given the context seems most likely what was intended.

So 'post-exertional malaise and/or fatigue and/or pain' should be interpreted as 'post-exertional (malaise and/or fatigue and/or pain)'.

Effectively saying at least one from from the following list

• post-exertional malaise
• post-exertional fatigue
• post-exertional pain

 

Thinking about this, in detail, for probably the first time, the is a difficulty about the concepts of post-exertional fatigue and pain. What counts as "post" and what counts as "exertion"? It should surely be "abnormal or unexpected post-exertional fatigue or pain".

If you are running a marathon, not that I have, by the time you get to twelve miles you are probably feeling a degree of fatigue and pain. You have already run some distance so it is post that exertion, but is still prior to the remaining exertion. These are difficult ideas. It is different to the malaise which there is no reasonable reason to expect to be related to exertion.

 

x gazillion.

 

That’s slight fudging is why some people don’t like ccc criteria and the fudging is worse in Nice Criteria which don’t mention pain as post exertion effect. I think how my ME presents post exertion is nothing like excess fatigue and I dislike the conflation. I think it’s much better expressed as global exacerbation of symptoms with it understood that there is a lot of distressing symptoms associated with the illness. Having as NICE do, fatigue, PEF and at minimum one additional symptom eg insomnia or headaches, I think is inaccurate characterisation or capturing of what I regard as classic ME. We had long discussion on PEM when Jason was doing his new questionnaire on it.

 

How much we know about ME could be plotted on a range, spectrum, or continuum, depending on your science/medical background, and who your audience is.

From a pwME point of view who is a bit sciency, but not tons, I maintain we know
enough to see ME is biomedical. Diagnosis of MS combines a few tests. Why not ME? Dr. Lily Chu lists tests that in combination certainly show abnormalities: the 2day CPET, tilt table, neuropsychological testing, brain imaging, and NK cell function/numbers.

As a pwME it is frustrating to repeatedly read we know very little about ME, or there are no tests that show abnormalities. We know some, and we can do some tests in
combination. However, despite these first important steps, we hear almost nothing is known. As I said earlier, it depends who your audience is; what's their perspective?Biomedical researchers know some, but are also aware there is MUCH more to learn. PwME know some progress has been made, but there is much more to learn. The uninformed, however, may interpret no testing available, unknown entity etc. as MUS; that there is nothing to learn. I think it depends who is speaking, and who is listening.

 

I agree. Another example would be EDS. Genes have been found for many types (seven?), but some of those genes have an unclear relationship to collagen.

There’s a very large group, the hypermobile group, most of whom still have no gene identified (although it has an autosomal dominant form of inheritance, so the genes are following Mendelian rules so it seems not that hard—yet hasn’t been found, but I don’t think there’s many researchers, much funding, or many studies here, either), and is thought to be likely to end up in several categories eventually.

Plus there’s the split-off diagnosis for people who don’t quite fit the new stricter criteria but have associated symptoms, so clearly don’t have just benign joint hypermobility.

 

Low NK cell function is seen in a lot of conditions.

It’s not a specific biomarker.

However, there’s precedent for using non-specific biomarkers in combination with clinical picture and differential diagnosis, in other diseases when specific biomararkers don’t yet exist, as part of a diagnostic process.

Think about autoimmune diseases, where they use elevated SED and increased ANA, even though these are found in many different diseases (including some of different categories, such as infection).

The problem I am hearing said in webinars from people who use this experimentally is they worry there aren’t enough labs that know how to do it, doctors don’t know how to order it (I think you have to use a vague code and then specify the test), and there’s a time constraint for getting the samples to the lab, because it can’t be frozen.

I don’t think any of those problems are things that can’t be solved.

 

Thank you @Londinium, for specifying a 2day CPET with 48 hours in between. Wish I had done that one, instead of a 2 day back to back, which was very difficult to do.

 

I think I recall reading that Workwell has a case control series with many non-ME patients that is coming out in a paper soon.

 

...or several other things. Including emotional trauma and physical trauma -- anything that would induce a flood of cortisol -- as in severe, severe stressor -- can knock out NKCs. Or so says some pretty preliminary research that looks credible at first glance.

That's not a bad idea. We're basically saying a very rudimentary meta-analysis. Find out just how deep a hole we're in.

[Edit: I wonder if anyone who worked on the IOM report already has such a list? They did review 9K studies, after all.]