Plasmapheresis to remove amyloid fibrin(ogen) particles for treating the post‐COVID‐19 condition, 2023, Garner et al

[EndME]

Plasmapheresis to remove amyloid fibrin(ogen) particles for treating the post‐COVID‐19 condition


Background
The post‐COVID‐19 condition (PCC) consists of a wide array of symptoms including fatigue and impaired daily living. People seek a wide variety of approaches to help them recover.

A new belief, arising from a few laboratory studies, is that 'microclots' cause the symptoms of PCC. This belief has been extended outside these studies, suggesting that to recover people need plasmapheresis (an expensive process where blood is filtered outside the body). We appraised the laboratory studies, and it was clear that the term 'microclots' is incorrect to describe the phenomenon being described. The particles are amyloid and include fibrin(ogen); amyloid is not a part of a thrombus which is a mix of fibrin mesh and platelets. Initial acute COVID‐19 infection is associated with clotting abnormalities; this review concerns amyloid fibrin(ogen) particles in PCC only.

We have reported here our appraisal of laboratory studies investigating the presence of amyloid fibrin(ogen) particles in PCC, and of evidence that plasmapheresis may be an effective therapy to remove amyloid fibrin(ogen) particles for treating PCC.


Authors' conclusions
In the absence of reliable research showing that amyloid fibrin(ogen) particles contribute to the pathophysiology of PCC, there is no rationale for plasmapheresis to remove amyloid fibrin(ogen) particles in PCC. Plasmapheresis for this indication should not be used outside the context of a well‐conducted randomized controlled trial.


https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD015775/full

Old-timer Garner reads his first microclot studies. Completely useless work. By the end of year Putrino, Iwasaki and Polybio should be able to tell us what role microclots, if any, play in Long-Covid.

 

[Andy]

A new belief

This belief

Note the language. In my opinion, a professional, and more normal, way to have described it would have been as a hypothesis.

 

[Solstice]

Note the language. In my opinion, a professional, and more normal, way to have described it would have been as a hypothesis.

Mustn't blame him, he's used to publishing ideas.

 

[Hutan]

I started out skeptical, but I actually don't mind this review. The main text is a lot better written than the summary quoted above.

I mean, I don't think it amounts to much more than what we have done on the forum - looking at the literature and saying 'there's a lot of problems, we can't tell if micro clots are a real thing, and there's no basis for people to undergo plasmapheresis at this time'. But, this is Cochrane, so their opinion counts for something. I think it may help doctors who don't have time to look at the literature to provide good advice to their patients.

They planned to use the Chalder Fatigue Scale as one of the outcomes, so that's not great. But, for the parts I've read, and aside from the summary with its preference for 'beliefs', it's pretty reasonable.

Edit - if anyone from Cochrane is reading this, there are typos in the declaration of conflicts of interest.

 

[cassava7]

It is certainly interesting to see Cochrane react this quickly to a proposed treatment for long Covid, presumably under the impulse of Prof Garner, compared to their dragging their feet on the review of exercise for CFS.

 

[Trish]

I had a quick read through. I think, as Hutan says, they have come to much the same conclusion as in our discussions here, namely that there's not sufficiently robust evidence that microclots have anything to do with LC specifically, that the published research is of mostly poor quality, and that no properly conducted trials of plasmapheresis treatments have been done yet.

It seems far too early to be doing a Cochrane review except perhaps to damp down the enthusiasm in some quarters promoting this treatment.

Now Garner, how about doing a similar review of the non-existent evidence for what you are promoting around the world as curing you of both ME/CFS and LC.

 

[Jonathan Edwards]

This looks very solid and timely to me. The fact that Paul Garner's name is on it is irrelevant as far as I am concerned. The author list also includes Greg Towers who is nobody's fool and I think contributed to the detailed debunking of XMRV.

We needed the establishment community to come out with something like this because the micro clot story was being spread around via Twitter in such a way that large numbers of people are likely to have been fleeced for unproven and dangerous treatment. If anything it should have come out six months ago. My attempts to get haematologists to give clear opinions ended up with excuses for not saying anything in public. Towers at least does not take that position.

I don't really mind the term belief because the idea is being sold as a belief.

The only thing I would quibble with is their view that these are not clots. They are not thrombi but the term clot includes any fibrin containing deposit in a tube. These are fibrin-containing deposits in tubes. The real point, which I think is their motivation, but not well thought through, is that these are not clots in the sense of lumps circulating in people. They are lumps that have formed in tubes after the blood has been processed - at least as far as I can see.

 

[Hoopoe]

I think the use of "belief" damages the credibility of the review. It comes across as biased and is the kind of language used by people who are secretly thinking that the illness is all in the mind.

 

[Jonathan Edwards]

I think the use of "belief" damages the credibility of the review. It comes across as biased and is the kind of language used by people who are secretly thinking that the illness is all in the mind.

It may do but it may also quite appropriately point out that the microclot idea is all in the mind of some 'scientists'.

 

[EndME]

I think the message of the review is relatively sound. But their conclusion is really just what everybody on social media and doctors have been saying for the past 2 years as well. It would have been far more useful to actually do a study to see what role these clots play, either proving its role or disproving its role, than doing a study to say "we don't know what role it plays" which is what we've known for the past 2 years.

"There is no scorn more profound, or on the whole more justifiable, than that of the men who make for the men who explain. Exposition, criticism, appreciation, is work for second-rate minds". - G.H. Hardy

People don't go for triple therapy of HELP apheresis because the evidence supports it, they go for it because they are desperate, have tried everything else and because doing nothing certainly isn't supported by the evidence.

 

[Jonathan Edwards]

It would have been far more useful to actually do a study to see what role these clots play, either proving its role or disproving its role, than doing a study to say "we don't know what role it plays" which is what we've known for the past 2 years.

That would be true if there was reasonably good evidence they are really there in greater amounts in patients. This review is saying that so far there isn't enough evidence that this is a real phenomenon to even spend money on investigating. Basically the people who have claimed these clots are of interest need to do better studies or at least better described studies.

I would not recommend funding a grant on micro clots on present evidence. The bits in the tubes don't play any role because they are in the tubes. And nobody knows if there are any bits in people. Apart from a few reports of 'Covid toe' that on checking didn't seem to amount to anything above regular bad toes I don't know of evidence of micro clotting in people.

 

[EndME]

That would be true if there was reasonably good evidence they are really there in greater amounts in patients. This review is saying that so far there isn't enough evidence that this is a real phenomenon to even spend money on investigating. Basically the people who have claimed these clots are of interest need to do better studies or at least better described studies.

I would not recommend funding a grant on micro clots on present evidence. The bits in the tubes don't play any role because they are in the tubes. And nobody knows if there are any bits in people. Apart from a few reports of 'Covid toe' that on checking didn't seem to amount to anything above regular bad toes I don't know of evidence of micro clotting in people.

These studies are currently happening, perhaps it would have been more useful to wait for these new results. Iwasaki, Putrino, Rob Wüst, VanElzakker, Dupont, Dalton and others are currently all conduction microclot studies. So they were at least convinced by the evidence they've seen to quickly test this hypothesis.

I also think that the studies weren't too convincing, but it's a rather simple thing to actually test this hypothesis (I don't think the group in SA will produce different evidence by themselves, apparently they haven't been able to). I don't think people will refrain from a therapeutic treatment on that basis of lack of evidence, when the lack of evidence has been very apparent for years.

 

[rvallee]

Wow the summary is frankly unprofessionally written. And the shamelessness of calling this a belief when the woo Garner pushes literally requires it. They talk nonstop about beliefs, it's literally their whole thing. So clearly the issue is not belief so much as whether they hold particular beliefs or not.

But it's been a long time since I've seen much about this. Like most supplements and possible treatments, it died out after it became evident that even if there is something to the hypothesis, the treatment is not effective. This means very little for the hypothesis, which still warrants research, but so far all grants have been rejected and so the blame for the poor quality of evidence is quite obvious.

Funding more research is their eternal answer when it comes to their own research, even though it's been massively over-researched despite having no merit whatsoever. These people are hypocrites.

And that's the difference with quacks who keep pushing their failed pseudoscience: when the treatments don't work, the patient community moves on. I've recently seen someone who said they deteriorated after it, but it could simply because of the exertion of going to and through the treatment. I think it's the only mention I've seen of HELP in the last year.

Cochrane continues their tradition of overfocusing on nonsense and ignoring what actually matters: why are patients so motivated to try unproven treatments. Which is the case for the entire biopsychosocial evidence, they are all unproven and entirely based on belief. These people are not serious.

 

[Jonathan Edwards]

These studies are currently happening, perhaps it would have been more useful to wait for these new results. Iwasaki, Putrino, Rob Wüst, VanElzakker, Dupont, Dalton and others are currently all conduction microclot studies. So they were at least convinced by the evidence they've seen to quickly test this hypothesis.

I do not see it as ethical to wait for studies we have no reason to think will be much better than the ones so far when the story is still being put in to journal reviews as if it should be taken seriously and the treatment sharks have cover. I am afraid that the fact that people who do science by Twitter are convinced makes me even less likely to take it seriously. We live in a time in which real science and virtual sciencebabble can be hard to distinguish.

 

[EndME]

I do not see it as ethical to wait for studies we have no reason to think will be much better than the ones so far when the story is still being put in to journal reviews as if it should be taken seriously and the treatment sharks have cover. I am afraid that the fact that people who do science by Twitter are convinced makes me even less likely to take it seriously. We live in a time in which real science and virtual sciencebabble can be hard to distinguish.

I believe that there's reason to hope that these studies will indeed be better (and provide evidence in either direction) in particular as they are looking at evidence in vivo, rather than just handpicking some biased 2D measures of 3D objects in test tubes, which could be an artefact of anything. I don't know what this new data will tell us, but I think in either way by the end of 2023 the situation might be different.

I completely agree with the Twitter sentiment.

 

[Hoopoe]

Just to make things clear I think the conclusion "Plasmapheresis for this indication should not be used outside the context of a well‐conducted randomized controlled trial." is very sensible.

 

[Lidia Thompson]

This a response from Nico Pretorius and Asad Khan to the above-mentioned paper:

Critical Reflections on the Cochrane Review of Long Covid Research
https://nicopretorius.substack.com/p/critical-reflections-on-the-cochrane

 

[Trish]

I think they make a reasonable point about Cochrane reviews normally being for estabished treatments where there are multiple studies to review, not early stage research on small samples. I was confused too by the Cochrane team's reference to plasmapheresis rather than HELP apheresis.

 

[SNT Gatchaman]

However, the main thrust of these studies was not centred on microscopy; the images served merely as supportive data. Therefore, it is peculiar that the review overlooks critical findings and statistical analyses derived from proteomics - notably, the discovery of a significant increase in α(2)-antiplasmin, as evidenced in the Pretorius 2021 and Kruger 2022 studies.

I think the microscopy images did dominate discussion however — they certainly did on social media. With the initial paper we were interested in the proteomics findings being significant. (As above in this thread and others, findings need to be replicated with different techniques in vivo).

Paul Garner, a co-creator of the Cochrane Reports, has been open about his personal journey of recovery from Long Covid, attributing his recovery to psychological rather than biomedical factors. He has shared his experience in detail and promoted this perspective publicly.

While Garner's personal story is certainly valuable as an anecdote, it must be considered in the context of his professional role. As a co-author of the Cochrane Review, the potential influence of his personal experience on the interpretation of research findings cannot be ignored.

I think we would agree with that.

Another potential source of bias could stem from the choice of reviewers. The Cochrane review appointed a neuropsychiatrist (Alan J Carson) and a systematic reviews expert (Ingeborg Welters) as 'independent' peer reviewers. However, their professional affiliations and research perspectives should also be scrutinized for potential alignment with the views of the report's authors, which could inadvertently influence the objectivity of the review. While the peer review process is designed to ensure rigor and validity, the independence of reviewers is paramount to avoid any inclination towards confirmation bias.

The paper states —

​

The following people conducted the editorial process for this article:

• Sign-off Editors (final editorial decision): Dr Paul Hine, CIDG; Professor Lise J Estcourt, Cochrane Haematology
• Managing Editor (selected peer reviewers, collated peer reviewer comments, provided editorial guidance to authors, edited the article): Dr Deirdre Walshe, CIDG;
• Copy Editor (copy editing and production): Lisa Winer, Cochrane Central Production Service;
• Peer reviewers (provided comments and recommended an editorial decision):​

◦ Ingeborg Welters, MD/PhD, University of Liverpool, Liverpool, UK; Professor Alan J Carson, University of Edinburgh (clinical/ content review)
◦ Mohamad Whdan (consumer review)
◦ Marty Chaplin, Statistical Editor (CIDG) (statistical review)
◦ Ina Monsef, Cochrane Haematology, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany (search review)
​

Haematologists are well-founded peer reviewers for the basic science aspects of this research. What expertise does Alan Carson bring? To cover this solitary line?

On another side, pathophysiology may relate to disturbances in homeostatic mechanisms in the brain (Lemogne 2023).

Which references Why the hypothesis of psychological mechanisms in long COVID is worth considering (2023, Journal of Psychosomatic Research)

 

[Lidia Thompson]

Here's a thread on twitter from Nico Pretorius on the issue: