Trial Report Plasma exchange therapy for the post COVID-19 condition: a phase II, double-blind, placebo-controlled, randomized trial, 2025, España-Cueto+

I was not suggesting that it is or it isn't placebo, sorry if I came off wrong here. I was merely interested in their opinion

Regarding the study you shared, the main author recently shared (at 31:54) that they believe that their "soft" outcome measures (as you also address with IA) was the issue for their high placebo response and that this was their problem (and the drug might or might not have actually shown a response). I believe she also mentioned during another moment in this conference that they are planning a new trial with better outcome measures Here, she discusses the 6 year follow up, you mentioned and a pilot study with daratumumab.

 

Thanks for sharing. So this is a badly (automated) transcript of what Rekeland says:

My understanding is not that she's suggesting that this was the problem in their study but rather that outcome measures is something that one generally has to be very careful about and that others aren't careful enough especially in a naturally fluctuating disease. "Soft" outcome measures are obviously a problem in all studies and so is choosing the right outcome measures and certainly some outcome measures can be more affected by "placebo-like" things than others, but in the Fluge and Mella trials weren't pretty much all outcome measure null, including step count etc?

 

Hmm, I am quite sure she mentioned that they believe they had too soft outcome measures (that also did not account for natural fluctuations in symptoms severity) and thus they are using more objective ones in their new trial. Maybe it was at some other point during the conference...

One thing I forgot to mention is that if I remember correctly, she also shared that she believes that just the fact of having somebody "taking care" of the participants every X months (don't remember, sorry) could have increased their placebo response rate.

 

Yes and i seem to remember different reported improvement rates at different hospitals during RTX (which would also rather suggest that it isn't the treatment that is being effective rather than that Fluge and Mella are better at getting a desired response). But none of that means that the treatment possibly had an effect. It just serves to explain the observed effects across both groups.

Placebo-effect, regression to the mean, natural recovery, Hawthorne like effects (possibly particularly relevant in ME/CFS where seeing a caring physician can be particularly rare), adapted behaviour in responding to subjective outcome measures (possibly taught as part of the trial), selection bias, outcome measures that show improvement despite treatments having no efficacy, no long-term follow-ups, publication bias, reporting bias, biased statistical analysis can all affect trial outcomes.

In ME/CFS drug trials Hawthorne like effects are quite possibly a lot stronger than in other conditions because patients will less often be met by a "compassionate doctor" than for example cancer patients, whilst subjective outcome measures in unblinded trials have created the largest mess for patients.

I seem to remember @Jonathan Edwards mentioning that he thinks there's reason to believe in some efficacy of RTX in Systemic Lupus erythematodes, despite it being hard to show via studies (unless I've misunderstood). I'm sure, as always it's the details, of which I'm unable to understand any, that matter and perhaps it all has to do with certain antibody profiles for which there is no evidence that they matter in ME/CFS, but perhaps it would be useful to know why such a scenario likely doesn't apply to ME/CFS?

 

Antibody titres in individual people vary widely. Lots of normal people, maybe all, have some low levels of autoantibodies and a few have high levels to some self antigens.

In the past noise type differences have often not repeated, although some seem consistent. Differences between patient groups and controls can arise for all sorts of confounding reasons. Probably the most usual is not doing all assays blind on the same plates and getting artefacts from lab variation. Another likely possibility is that patients are more likely to have various other illnesses even if at low level whereas healthy intros tend to be 'super healthy' people with no complaints. That is where disease controls are useful.

But if 60% of patients have levels above an arbitrary cut off and 51% of normal controls do it is pretty hard to say you have pathogenic antibodies.

 

Yes but that is basically saying that the other predisposing factor is what causes the problem because the antibodies are just part of the normal immunoglobulin spectrum, just as factor VIII is part of our normal clotting mechanism. It becomes meaningless unless there is very good evidence in patients for these antibodies mediating a change. You can always tweak an assay to produce a result with this sort of thing. And the bottom line is that we don't actually have any evidence of a specific clinical problem that would be explained by any of these antibodies. The patients don't have renal ischaemia or hypertension. So the assay evidence is against a relevance in patients.

For the reasons I have given. As we have discussed the antibodies are clearly not sufficient. In the absence of evidence of another factor there isn't really a viable theory. The results are all over the place, as someone has pointed out. I don't see anything that really makes this theory fly. Moreover, the same theory implicating these antibodies in various other diseases has been raised several times over twenty or thirty years. And nothing has come of it as far as I am aware. If an antibody can be claimed to explain all sorts of different diseases there isn't a well worked out hypothesis.

If anything I would expect antibodies like this either to block receptors - in which case there would be no tachycardia response at all - or stimulate, leading to severe hypertension and permanent tachycardia. The POT situation doesn't seem to fit with either.

I just don't see this getting on the starting line, and I have seen dozens of theories like this over the years.

 

I wouldn't fully discard the idea of them being allosteric modulators - which could fit POTS quite nicely, wouldn't you think?

 

Why stretch things to something so obscure. And I cannot honestly say that would make sense in terms of POT either. POTS with an S seems to me a very doubtful concept. Normal people get tachycardia on standing. The evidence that tachycardia on standing is a good pointer to any specific condition seems doubtful.

I just cannot get enthused about a theory that is typical of a pervasive naive approach to autoimmunity that includes ideas like molecular mimicry and triggering by viruses and a complete lack of understanding of detailed effector mechanisms. And these. are antibodies that occur in exactly the same sort of levels in normal people.

OK, one has to admit that one cannot be entirely sure that the Pope didn't have a Chinese great-great-great-great-grandmother but the reasons for thinking so are not strong.

 

Nice presentation by Prof Fedorowski on POTS, discussing that it's not purely tachycardia as has been said for many years, in case you're interested and curious

 

Simply linking to a youtube-presentation of 30+ minutes mid-thread might not be the best way to get your point across. I don’t think it’s reasonable to expect anyone to spend their very limited energy and time watching it in order to even know what your argument is.

 

The argument is probably that Federowski and others are well aware that POTs is more than just tachycardia, which is why they use things such as the Malmo POTS score or repeat the well-known phrase "POTs is named after its most benign symptom" but I think that possibly misses the crucial point that there might be a lack of indication that POTS is a meaningful descriptor to begin with or when whatever topic is currently being hyped is used to explain the ethology without any evidence for it, be it GPCR-aabs, microclots or whatever is up next.

 

I looked at a few minutes. I got the impression of a man in an Ivory Tower lost in make believe. If POTS isn't what it was supposed to be that would fit - nobody is very clear what it means!

 

Along the same lines of your argument, you will have to forgive me that my energy I too limited to spend it on regurgitating the intricacies of POTS. I am not sure whether I misunderstood the previous poster or not, but I cannot spend my energy on discussing whether a set of symptoms that I (as well as many others) as a previously young, fit and healthy person experience (and effectively treat with cardiovascular medication) since suffering from LC is "doubtful" as a concept or not.

Spot on.
In the second half, I am not sure whether you're talking about semantics regarding the name "POTS"? Whether POTS should be used to explain certain hypotheses, I doubt, but saying that "POTS with S as a concept is doubtful" is wild to me.

Alright, I will leave you with that impression then, please forgive me that I do not have the energy to discuss our different POV in this case.

 

My impression is that it is abundantly clear to most that there is a form of orthostatic intolerance in ME/CFS, that is yet to be unravelled and properly understood, that induces horrible symptoms in relation to being upright and causes a great amount of disability.

What is less clear is whether an HR increase of ≥30 bpm (in the absence of orthostatic hypotension) carries significant weight in the unravelling of this orthostatic intolerance in ME/CFS or whether it rather adds to the confusion. In an unscrewed cohort it is clear to carry no meaning, it less clear whether it might or might not be a meaningful descriptor in people that are experiencing symptoms of orthostatic intolerance (for example people part of the Efgartigimod POTS study), with there being evidence to both sides. There is a great and easy to understand essay on this topic https://mecfsskeptic.com/the-problems-with-pots/. What it is supposed to mean in the context of LC is probably even less clear to me, given the far greater heterogeinty. If POTS was the meaningful descriptor that could be effectively treated with cardiovascular medication, one would think it should be fairly easy to show this within a clinical trial (for example using a somewhat similar setup as the Efgartigimod study of which Federowski was an advisor), precisely because in that case it should simplify everything.

That doesn't mean that people aren't suffering and experiencing physiological symptoms in relation to being upright, both in ME/CFS and LC. They are.

That is similar to how a critique of Fukuda criteria doesn't mean that one doesn't believe that these patients aren't suffering and experiencing these symptoms but rather that one believes that criteria with a larger focus on PEM could be a better approach. Of course Federowski seems to sit a bit on the other side of the fence where he believes that POTS is the more meaningful descriptor than say ME/CFS according to CCC (and as a consequence of which he recommends exercise as treatment for it) and until someone comes up with a proper proof someone can always argue their own position where the words of an internet nobody carry no weight.

 

After 27:08 !

 

I think we might be talking about different things here? In my response to "POTS is a doubtful concept" I was considering POTS as a set of symptoms (as linked above) that occur as part of ME, LC and other illnesses. Not as something that is imperatively and solely linked to ME.

And in cases in which it is not, exercise does seem to be an efficacious therapy. Which is why he as a cardiologist recommended it - somewhat ignorantly in the context of ME. I would argue anybody that experiences POTS is "screwed", be it as a co-morbidity of ME or of something else?

What he also highlights is that as orthostatic intolerance is also seen (as oscillating BP as we know) the traditional simplified definition of > 30 bpm without hypotension might be oversimplified in fact? (which is why they use different, extended diagnostic criteria)

Could you please repeat what you mean with the last part regarding effective treatment and clinical trials? Sorry about the brainfog.

Thank you for the link, I will check it! And in general, thank y'all for the discussions

 

Presenting your argument and opinion can hardly be classified as ‘regurgitation’. If you don’t have the capacity to go into details, just say so. By just linking a video you’re essentially telling people to ‘read up on it’, and you’re straying close to be perceived as saying that people are wrong because they are uninformed. I’m not saying that this was your intention, I’m talking purely about perception here.

Nobody here has claimed that suffering from LC is ‘doubtful’ in any way, shape or form. Some have challenged if POTS is a useful clinical concept in its current form. They have not challenged if the symptoms are real or debilitating.

The road to hell is paved with good intentions..
This is not a good look. If you’re willing to include unfounded recommendations of something you don’t even know what is, I seriously question the validity of the entirety of your paper. The only appropriate thing would have been to say ‘I completely dropped the ball, I will correct the work and learn from this mistake.’

 

What I am meaning, and I think EndME is also saying is that although everyone is aware of a cluster of symptoms it is unclear that they have much to do with orthostatic tachycardia.

I think someone up thread made the point that lots of these syndromes are poorly defined - including hEDS, MCAS, POTS and maybe ME or ME/CFS. For me there is a crucial difference between the ME/CFS concept, which is purely a syndrome based on commonly associated features and the others which all invoke some sort of speculated causation or pathology. (ME is maybe like the others if you assume it implies inflammation.) We don't have good reason to think that chronic disabling symptoms of the sort seen in ME/CFS and indeed in many people given the diagnosis of 'POTS' have anything to do with collagen genes, mast cell abnormalities or indeed a tendency to tachycardia on standing.

Suggesting this is not 'wild'. Most of my medical colleagues would just raise their eyebrows and dismiss all of these categories as make believe. (The few 'experts' who champion these syndromes are very unimpressive in science terms.) My position is different, however. I am spending up to half of my waking day working on issues related to ME/CFS, gratis, because I think the illness desperately needs some serious thought. The people on this forum are amazing as a team to work within in that regard. Whether it is digging out papers or giving personal symptom accounts or criticising logic or whatever, the discussions here are, in my past experience, exactly what is needed to break a log jam in a biomedical problem. I think most people on the forum would see that the basis of the POTS concept is shaky. ME/CFS Skeptic has laid out the arguments very nicely in a blog.

 

Just want to say how hugely grateful I am to you for this. I'm sure we all are. You make such a tremendous difference in the world for us.

 

Nor have I said that anybody was doubting LC, I believe you have misunderstood my sentence (which is about POTS as a co-morbidity of LC), mate.

And regarding the second point, I addressed it above, regarding his ignorance about exercise and ME and exercise as a therapy for POTS per se?