Preprint Increased circulating fibronectin, depletion of natural IgM and heightened EBV, HSV-1 reactivation in ME/CFS and long COVID, 2023, Liu, Prusty et al

[Jonathan Edwards]

This paper is too complicated for me to unravel but I have a thought that some others might sort out - I rarely get let down by PWME. Fibronectin circulates in plasma and gets included in fibrin clots as I understand it. So measuring it is serum, which is plasma that has clotted and had the clot removed, may not reflect circulating levels. It might reflect some abnormality of clotting I suppose, but since people with ME do not seem to suffer with clotting that much (DVT, pulmonary embolus) I am not sure what to make of that.

 

[V.R.T.]

I think it's also a question of funding and putting in the work of replicating and refining the candidate biomarkers. If that had been done we might have a decent biomarker by now.

It's the same with treatments probably. The orthostatic issues are low hanging fruit and that we don't have good proven treatments for that aspect yet might just be an issue of nobody putting in the work to make it happen (or not having funding to do so).

ME/CFS research gets so little funding that it's hard to do anything at all.

Also, you speak to BPS sympathetic doctors?

Agreed, funding and replication studies are desperately needed

And I avoid them like the plague after the one I was speaking about.

 

[EndME]

This paper is too complicated for me to unravel but I have a thought that some others might sort out - I rarely get let down by PWME. Fibronectin circulates in plasma and gets included in fibrin clots as I understand it. So measuring it is serum, which is plasma that has clotted and had the clot removed, may not reflect circulating levels. It might reflect some abnormality of clotting I suppose, but since people with ME do not seem to suffer with clotting that much (DVT, pulmonary embolus) I am not sure what to make of that.

To add to that levels of cellular Fibronectin are usually extremely low in plasma and only trace amount of it are detactable in plasma. So it isn't clear to me whether the measurements are mainly statements about cellular of plasma fibronectin. Plasma levels of cellular fibroncetin are known to increase if there are problems in the body, I don't know if the same applies to plasma fibronectin.

 

[Hutan]

edit: also nice to see more evidence that ME/CFS and LC, molecularly, are somewhat overlapping but distinct. I think this is becoming clear. Nice to see things in alignment across many groups and biological angles.

Thanks for your post @DMissa. I agree with it, except this point.

I don't think we have yet seen good evidence that ME/CFS-like Long Covid is different to ME/CFS. By 'ME/CFS Long Covid', I mean persisting symptoms compliant with a PEM-inclusive ME/CFS diagnostic criteria. Often all sorts of things are lumped into 'Long Covid', and of course ME/CFS is different to lung injury, or physical damage or PTSD resulting from treatment for a very severe Covid-19 infection, for example.

As others have noted, it's important to distinguish between the impact of a recent infection (which we would see in both people who have had a Covid-19 infection and have no persisting symptoms, as well as in people with ME/CFS-like Long Covid) and Long Covid. We have seen some evidence of this impact lasting for a surprisingly long time. A lot of studies don't have healthy post-infection controls, often making it difficult to know if a purported biomarker is simply a marker of a recent infection.

I'd be interested to see any evidence that strongly supports the idea of ME/CFS-compliant Long Covid being materially different to ME/CFS after a range of illnesses.

If anyone wants to continue this discussion, rather than take this thread off track, we have a thread here:
Is Long Covid a type of ME/CFS? Discussion thread

 

[SNT Gatchaman]

I couldn't determine the disease duration for the ME patients, vs the known 4 yr max LCs. Perhaps some ME are longer duration? Also if ME patients were diagnosed following sub-acute onset during 2020-23, then some may have been asymptomatic/test-negative Covid.

ME/CFS patient cohort: ME/CFS patients, and gender- and age matched healthy controls were diagnosed at the outpatient clinic at the Charité Universitätsmedizin, Berlin and Technische Universität München (TUM) between 2020 and 2023. Diagnosis of ME/CFS in all patients was based on the 2003 Canadian Consensus Criteria and exclusion of other medical or neurological diseases that may cause fatigue by a comprehensive clinical and laboratory evaluation.

Some of the patient samples were also collected at University of California San Diego with signed informed consent under UCSD IRB Project #140072, “The UCSD Metabolomics Study”.

 

[EndME]

I couldn't determine the disease duration for the ME patients, vs the known 4 yr max LCs. Perhaps some ME are longer duration? Also if ME patients were diagnosed following sub-acute onset during 2020-23, then some may have been asymptomatic/test-negative Covid.

Yes. Some ME/CFS patients might also have LC+ME/CFS. Furthermore those patients called HC, never underwent a Covid test, so it isn't even clear how they differ from the no LC group.

 

[SNT Gatchaman]

Furthermore those patients called HC, never underwent a Covid test, so it isn't even clear how they differ from the no LC group.

I think at least some may have pre-dated the pandemic.

For long COVID studies, additional healthy controls were used from the population-based Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB) Cohort

That seems to have recruited "between December 2013 and April 2015" (ref)

 

[Hutan]

The paper claims the following:

A. Evidence for frequent HSV-1 and EBV reactivation in both ME/CFS and LC
B. Experimental reasoning for cellular damage as a result of herpesvirus dUTPase proteins
C. ME/CFS patients have altered autoimmune features , possibly due to the depletion of natural IgM within primary hematopoietic organs
D. Fibronectin protein shows altered expression and immune response patterns that correlate with disease severity

A. Evidence for frequent HSV-1 and EBV reactivation in both ME/CFS and LC
278 patients, 6 months after Covid-19; 149 patients with no LC, 107 with mild LC, 22 with severe LC;
31 healthy controls;
77 ME/CFS
The researchers looked for IgG responses to dUTPases.
The results are given in Figure 1B. I think it's fair to say that there is less reactivation in the 31 healthy controls, but similar amounts of reactivation in the ME/CFS, LC, and, interestingly, in the 149 patients who had had a Covid-19 infection but didn't have LC. For each virus, there were a lot of people in each group who had no sign of reactivation.

B. Experimental reasoning for cellular damage as a result of herpesvirus dUTPase proteins
I had a lot of problems with HSV-1 reactivation after developing ME/CFS, perpetually having cold sores until I had a very long course of valacyclovir. I'm therefore predisposed to believe in the idea of herpes viruses reactivating either as a cause or a result of ME/CFS. But given the lack of evidence in A, the lack of a clear differentiation of response between the groups to the dUTPase proteins of the three viruses, I don't think there's a strong foundation here to build a theory based on reactivation.

It is possible that some of the things that Prusty's group has observed are true and useful findings, that is, perhaps it isn't good for mitochondria or the cytoskeleton when a herpesvirus has reactivated. Still, any theory involving dUTPase proteins or the reactivations in general has to cope with the fact that many people with ME/CFS and LC don't show signs of EBV/HSV-1/HSV6 reactivation. It might be a timing thing - perhaps they would during PEM?

C. Autoimmunity
The paper suggests that chronic HSV-1 and EBV infections lead to autoimmunity, with two papers cited in evidence. The authors considered the possibility that such autoimmunity might be causing ME/CFS symptoms and mitochondrial dysfunction.

They did a study of 17 ME/CFS and 13 controls - applying their IgG to mitochondria in various types of cells. The data from this study is presented poorly and it and the text is unconvincing in terms of there being significant differences. Maybe there is something there somewhere, but this paper does not provide evidence of a difference.

They did some mass spectroscopy on the IgG with bound immune complexes from 12 controls and 15 ME/CFS patients. The authors report finding three proteins reduced in the ME/CFS IgG: fibronectin; alpha 2 macro globulin and serotransferrin. Figure 2d, Extended fig 3d. Extended 3d is more useful to look at. Fibronectin is the only one that looks fairly convincing. The likelihood that lots of molecules were tested in the mass spectroscopy needs to be considered.

They did another small study (12 ME/CFS; 3 controls) looking at IgM levels against 120 auto antigens. There does seem to be some separation of severe ME/CFS from the rest and some of the mild/moderate ME/CFS from the rest, but the number of controls is just way to small to know for sure. Fibronectin is one of the proteins that is reported to differentiate the groups, along with collagen, cyctochrome C, EBNA1, CRP. I have a number of questions about what is actually being presented, for example, the PCA chart seems to show individuals scattered all over the place, without any clustering. It would be good to have this study replicated with well-sized cohorts and clear reporting. Figs 2e, 2f, Extended Fig 4a-b.

The authors say that IgM against fibronectin (IgM-IFN) might be a natural IgM with scavenging and protection functions, and that reduced levels of this IgM could cause autoimmunity. They note that a correlation between higher circulating fibronectin and decreased IgM responses against fibronectin has been documented in trypanosoma infection (which is not the first time that trypanosoma has been mentioned in the same sentence as ME/CFS).

They did another small study (7 severe ME/CFS, 5 Long Covid, 5 healthy controls) reported later in the paper finding IgM-FN1 in healthy controls but not in the patient groups. (Extended fig 5e). It's not very convincing due to the size of study and possible selection biases, and an inadequate presentation of the results They then did a bigger study (63 HC; 66 Me/CFS; 55 no LC; 63 mild LC; 22 severe LC). In this one, they didn't find any difference in IgM-FN1 between healthy controls and ME/CFS. And all of the post-Covid-19 groups, including those with no LC had lower levels of IgM-FN1 and IgG-FN1. Fig 3a-d. I'm afraid it isn't looking very convincing as a cause of ME/CFS and/or LC.

D. Circulating fibronectin
The authors suggest that a lack of fibronectin within immune complexes (i.e. bound to the IgG, IgM, IgA) and the resulting accumulation in the blood 'can indicate lack of protection against certain pathogenic infections'. So, they looked at levels of circulating fibronectin in serum.
ME/CFS 66 patients; 63 healthy controls
They report finding significantly higher levels in ME/CFS (Fig 2g-h), and that levels were positively correlated with severity (Fig I-j).
Below, the chart - red controls, blue severe ME/CFS, yellow mild/moderate ME/CFS. Levels do seem to be a bit higher in severe ME/CFS, but there is a lot of overlap.


They then looked at the Long Covid patients (Fig 2k) - red healthy controls, blue healthy post-Covid-19, yellow mild LC, pale blue severe LC. This is even less convincing. I don't think it can be said that all three of the post-Covid-19 groups, including the healthy people, have different fibronectin levels. I'm not sure how many people were involved in this study, it's not in the results, but might be in the Methods.


I haven't got to the discussion yet. Maybe there is something in here, but it is buried in small studies that are often reported without clarity. There's clearly been a lot of work done and some creative thinking, and I really appreciate that. I think for future papers, it would be better if the authors concentrated on reporting the results of just one well-powered study, or a few related investigations.

 

[EndME]

I think at least some may have pre-dated the pandemic.



That seems to have recruited "between December 2013 and April 2015" (ref)

That is correct. I guess I got a little bit confused with the selection of different patients. Thanks for correcting me.

 

[Hoopoe]

 

[chillier]

The paper claims the following:

A. Evidence for frequent HSV-1 and EBV reactivation in both ME/CFS and LC
B. Experimental reasoning for cellular damage as a result of herpesvirus dUTPase proteins
C. ME/CFS patients have altered autoimmune features , possibly due to the depletion of natural IgM within primary hematopoietic organs
D. Fibronectin protein shows altered expression and immune response patterns that correlate with disease severity

A. Evidence for frequent HSV-1 and EBV reactivation in both ME/CFS and LC
278 patients, 6 months after Covid-19; 149 patients with no LC, 107 with mild LC, 22 with severe LC;
31 healthy controls;
77 ME/CFS
The researchers looked for IgG responses to dUTPases.
The results are given in Figure 1B. I think it's fair to say that there is less reactivation in the 31 healthy controls, but similar amounts of reactivation in the ME/CFS, LC, and, interestingly, in the 149 patients who had had a Covid-19 infection but didn't have LC. For each virus, there were a lot of people in each group who had no sign of reactivation.

B. Experimental reasoning for cellular damage as a result of herpesvirus dUTPase proteins
I had a lot of problems with HSV-1 reactivation after developing ME/CFS, perpetually having cold sores until I had a very long course of valacyclovir. I'm therefore predisposed to believe in the idea of herpes viruses reactivating either as a cause or a result of ME/CFS. But given the lack of evidence in A, the lack of a clear differentiation of response between the groups to the dUTPase proteins of the three viruses, I don't think there's a strong foundation here to build a theory based on reactivation.

It is possible that some of the things that Prusty's group has observed are true and useful findings, that is, perhaps it isn't good for mitochondria or the cytoskeleton when a herpesvirus has reactivated. Still, any theory involving dUTPase proteins or the reactivations in general has to cope with the fact that many people with ME/CFS and LC don't show signs of EBV/HSV-1/HSV6 reactivation. It might be a timing thing - perhaps they would during PEM?

C. Autoimmunity
The paper suggests that chronic HSV-1 and EBV infections lead to autoimmunity, with two papers cited in evidence. The authors considered the possibility that such autoimmunity might be causing ME/CFS symptoms and mitochondrial dysfunction.

They did a study of 17 ME/CFS and 13 controls - applying their IgG to mitochondria in various types of cells. The data from this study is presented poorly and it and the text is unconvincing in terms of there being significant differences. Maybe there is something there somewhere, but this paper does not provide evidence of a difference.

They did some mass spectroscopy on the IgG with bound immune complexes from 12 controls and 15 ME/CFS patients. The authors report finding three proteins reduced in the ME/CFS IgG: fibronectin; alpha 2 macro globulin and serotransferrin. Figure 2d, Extended fig 3d. Extended 3d is more useful to look at. Fibronectin is the only one that looks fairly convincing. The likelihood that lots of molecules were tested in the mass spectroscopy needs to be considered.

They did another small study (12 ME/CFS; 3 controls) looking at IgM levels against 120 auto antigens. There does seem to be some separation of severe ME/CFS from the rest and some of the mild/moderate ME/CFS from the rest, but the number of controls is just way to small to know for sure. Fibronectin is one of the proteins that is reported to differentiate the groups, along with collagen, cyctochrome C, EBNA1, CRP. I have a number of questions about what is actually being presented, for example, the PCA chart seems to show individuals scattered all over the place, without any clustering. It would be good to have this study replicated with well-sized cohorts and clear reporting. Figs 2e, 2f, Extended Fig 4a-b.

The authors say that IgM against fibronectin (IgM-IFN) might be a natural IgM with scavenging and protection functions, and that reduced levels of this IgM could cause autoimmunity. They note that a correlation between higher circulating fibronectin and decreased IgM responses against fibronectin has been documented in trypanosoma infection (which is not the first time that trypanosoma has been mentioned in the same sentence as ME/CFS).

They did another small study (7 severe ME/CFS, 5 Long Covid, 5 healthy controls) reported later in the paper finding IgM-FN1 in healthy controls but not in the patient groups. (Extended fig 5e). It's not very convincing due to the size of study and possible selection biases, and an inadequate presentation of the results They then did a bigger study (63 HC; 66 Me/CFS; 55 no LC; 63 mild LC; 22 severe LC). In this one, they didn't find any difference in IgM-FN1 between healthy controls and ME/CFS. And all of the post-Covid-19 groups, including those with no LC had lower levels of IgM-FN1 and IgG-FN1. Fig 3a-d. I'm afraid it isn't looking very convincing as a cause of ME/CFS and/or LC.

D. Circulating fibronectin
The authors suggest that a lack of fibronectin within immune complexes (i.e. bound to the IgG, IgM, IgA) and the resulting accumulation in the blood 'can indicate lack of protection against certain pathogenic infections'. So, they looked at levels of circulating fibronectin in serum.
ME/CFS 66 patients; 63 healthy controls
They report finding significantly higher levels in ME/CFS (Fig 2g-h), and that levels were positively correlated with severity (Fig I-j).
Below, the chart - red controls, blue severe ME/CFS, yellow mild/moderate ME/CFS. Levels do seem to be a bit higher in severe ME/CFS, but there is a lot of overlap.
View attachment 19802

They then looked at the Long Covid patients (Fig 2k) - red healthy controls, blue healthy post-Covid-19, yellow mild LC, pale blue severe LC. This is even less convincing. I don't think it can be said that all three of the post-Covid-19 groups, including the healthy people, have different fibronectin levels. I'm not sure how many people were involved in this study, it's not in the results, but might be in the Methods.
View attachment 19803

I haven't got to the discussion yet. Maybe there is something in here, but it is buried in small studies that are often reported without clarity. There's clearly been a lot of work done and some creative thinking, and I really appreciate that. I think for future papers, it would be better if the authors concentrated on reporting the results of just one well-powered study, or a few related investigations.

Great commentary @Hutan . I think the most compelling work in the paper is on dUTPase effect on cytoskeleton and mitochondrial morphology - it's just that it has nothing to do with ME. It should probably be in a separate paper that whole section feels tenuously connected to everything else.

Plasma levels of cellular fibroncetin are known to increase if there are problems in the body

This is interesting - don't suppose you have a source for this/ is it known why this would be the case?

This paper is too complicated for me to unravel but I have a thought that some others might sort out - I rarely get let down by PWME. Fibronectin circulates in plasma and gets included in fibrin clots as I understand it. So measuring it is serum, which is plasma that has clotted and had the clot removed, may not reflect circulating levels. It might reflect some abnormality of clotting I suppose, but since people with ME do not seem to suffer with clotting that much (DVT, pulmonary embolus) I am not sure what to make of that.

Does it need to be that changes in fibronectin or microclots as reported elsewhere has to = coagulopathy? If memory serves they did thromboelastography in one of the pretorius microclots papers and it was normal, and presumably if standard clotting assays prothrombin time etc were abnormal this would have long been known about.

If they're real it seems likely microclots are a generic thing seen in many conditions diabetes, RA, presumably acute infections and so on, and perhaps the same is the case with fibronectin or natural IgM (which they're seeing after covid infection generally it seems). Could these things be a general marker of inflammation or of the immune system fighting something like itself/pathogen/commensal, and is there any established marker that is known to correlate with all these conditions generally?

 

[EndME]

Great commentary @Hutan .
This is interesting - don't suppose you have a source for this/ is it known why this would be the case?

Does it need to be that changes in fibronectin or microclots as reported elsewhere has to = coagulopathy? If memory serves they did thromboelastography in one of the pretorius microclots papers and it was normal, and presumably if standard clotting assays prothrombin time etc were abnormal this would have long been known about.

Yes, there's actually even quite a few studies on this subject. It has been shown that blood plasma levels of cellular fibronectin increase after major trauma resulting in vascular tissue damage, after inflammation, in other diseases such as atherosclerosis, ischaemic heart disease, inflammatory arthritis and stroke https://www.sciencedirect.com/science/article/abs/pii/S0022214303000428,https://www.ahajournals.org/doi/full/10.1161/01.STR.0000131656.47979.39,https://www.sciencedirect.com/science/article/abs/pii/S0021915000004901,https://academic.oup.com/rheumatology/article/38/11/1099/1783296#google_vignette.

I think I might have to go through Prusty's preprint again to understand at what points in time he is able to detect cFibronectin, when pFibronectin or when it's just the collection of the two. Since the main message of the paper are fibronectin levels and a response to this, it seems sensible to me to understand what type of Fibronectin is actually being measured.

Since you mentioned RA. The levels in RA seem lower than in some of the above diseases, the last study I cited looked at that. It isn't much evidence, but it shows that there seems to be no uniformity amongst diseases.

What I find a bit unusual is that he finds different levels in men and women, even in HC. Isn't that something that was discussed somewhere on this forum to not be consistent with other studies?

 

[SNT Gatchaman]

Does it need to be that changes in fibronectin or microclots as reported elsewhere has to = coagulopathy? If memory serves they did thromboelastography in one of the pretorius microclots papers and it was normal, and presumably if standard clotting assays prothrombin time etc were abnormal this would have long been known about.

In Dec last year we had two good papers, looking at hypercoagulability in the acute and long-Covid situation.

Transcriptional reprogramming from innate immune functions to a pro-thrombotic signature by monocytes in COVID-19 (2022, Nature Communications)
Analysis of thrombogenicity under flow reveals new insights into the prothrombotic state of patients with post-COVID syndrome (2022, Journal of Thrombosis and Haemostasis)

I haven't re-read recently so I don't know if basic clinical assays might have been normal in the post-Covid paper, although I think elevated d-Dimers are common acutely.

The first paper (acute) had this passage —

A question that remains to be answered is the driver(s) of the described circulating monocyte dysfunction. Ex vivo isolated monocytes from moderate COVID-19 patients are pro-thrombotic while maintaining some innate immune functions. However, secondary pathogen sensing ex vivo triggers a switch in COVID-19 monocyte gene expression signature and functionality from canonical innate immune functions to pro-thrombotic phenotype. It remains to be determined whether any soluble factors in the microenvironment contribute to this reprogramming, or even the direct infection of monocytes by SARS-CoV-2, which has been previously suggested.

Fibronectin is important in coagulation. This paper even suggests very important —

Fibronectin maintains the balance between hemostasis and thrombosis (2016, Cellular and Molecular Life Sciences)

Among other things, fibronectin does interact with monocytes, so possibly this could be such a soluble factor in the microenvironment, eg —

Plasma fibronectin can affect the cytokine profile and monocytes/macrophages function in addition to predicting the prognosis of advanced sepsis (2022, The FASEB Journal)
Elevated Fibronectin Levels in Profibrotic CD14+ Monocytes and CD14+ Macrophages in Systemic Sclerosis (2021, Frontiers in Immunology)
Fibronectin‐adherent monocytes express tissue factor and tissue factor pathway inhibitor whereas endotoxin‐stimulated monocytes primarily express tissue factor: physiologic and pathologic implications (2007, Journal of Thrombosis and Haemostasis)

 

[EndME]

Well it seems like I'm not the only one confused by the selection of patients. According to the above Tweet from Prusty either severe LC patients or HC are taken from the Charite, none of which is stated as such in the paper, or did I miss something (perhaps a LC & ME/CFS overlap that is non-specified which would be horribly bad data representation)?

 

[Simon M]

About the results: "Finding of increased circulating FN1 and depletion of (n)IgM-FN1 as a biomarker for the severity of both ME/CFS and long COVID has an immediate implication in diagnostics

I agree that this is an unsubstantiated claim.

More generally, why do we need a biomarker for severity? Severity. is its own thing.

And the fact that fibronectin 1 levels can’t distinguish mild and moderate cases of ME from healthy controls strongly indicates the molecule isn’t playing a major role in the illness.

If the claim is actually that it can identify ME, but only in severe cases, then they need to show comparisons with other diseases it might be confused with. It’s likely that people with many severe chronic illness (and the deconditioning it brings) will have lots of biomolecules that differ from healthy controls.

I just don’t get the concept of a “biomarker for severity”.
as far as I can tell, fibronectin1 has many roles aside from clottin, some of which are poorly understood, so I’m not sure how helpful a clue the association is with ME.

 

[EndME]

I agree that this is an unsubstantiated claim.

More generally, why do we need a biomarker for severity? Severity. is its own thing.

And the fact that fibronectin 1 levels can’t distinguish mild and moderate cases of ME from healthy controls strongly indicates the molecule isn’t playing a major role in the illness.

If the claim is actually that it can identify ME, but only in severe cases, then they need to show comparisons with other diseases. It might be confused with. It’s likely that people with any severe chronic illness (and the deconditioning it brings), will have lots of biomolecules that differ from healthy controls.

I just don’t get the concept of a “biomarker for severity”.
as far as I can tell, fibronectin1 has many roles aside from clottin, some of which are poorly understood, so I’m not sure how helpful a clue the association is with ME.

I'm probably heavily biased since I don't belong to the mild/moderate group, but I wouldn't have a problem with a biomarker for severity. That would be an outstanding finding, if it indeed measures more than inactivity. Long-Covid patients haven't been sick for too long so a marker might not have to reflect a chronification. Hard to say if you don't know what cohorts he is referring to at which points in time and to what they are compared. Even if there's overlap with other diseases it at least proves that the disease exists (unless it just shows something like you had a Covid infection at some point in time, which some of his data suggested, since then the BPS boys and girls can again argue that your illness is a hysteria to having been sick). I'm not expecting a marker to straight away be something central to the disease, anything no matter how far downstream it is, would already be a substantial improvement.

Is this even a biomarker for severity though?

I have a big problem with inconsistently and randomly splitting up patients differently in different experiments and comparing them to different people in different scenarios until you get a result, without presenting any analysis of what is done. Is this just a monkey with a typewriter type situation?

The graph of a ROC analysis (instead of an actual analysis) was posted by him on Twitter with cohorts that are apparently different to those in the study. This graph is also not part of the preprint. So possibly there's still a lot of data analysis happening in the background that I can't see. I would certainly hope so. Perhaps we'll hear Scheibenbogen comment on these findings soon, especially if she's supplying new data for more analysis. She seems to be very level headed.

 

[AknaMontes]

I really think we need to absolutely stop all fundraising for research into ME, stop participating, and stop spreading calls for donations and participation on social media UNLESS the research is focussed on properly checking out one of the already known potential biomarkers - whether it's Prusty's or another one, provided it's likely to be affordable and practical. If we don't, this circus of small studies that nobody replicates or scales up will go on draining resources and getting nowhere. Meanwhile children are locked up in psych wards in a living hell, families threatened with FII and care proceedings, and people who are Very Severe are suffering preventable malnutrition. It's all because there is no biomarker. They need to identify that and then they can go back to the useful and fascinating playground of pushing back the frontiers of knowledge that may or may not lead to treatments. Focus was perfectly possible in finding vaccines, why not this? PwME need to start saying no. No more money until the researchers get their eyes back on the ball.

 

[Simon M]

I wouldn't have a problem with a biomarker for severity. That would be an outstanding finding, if it indeed measures more than inactivity. Long-Covid patients haven't been sick for too long so a marker might not have to reflect a chronification.

That's a big caveat, hence the need for disease controls.

Even if there's overlap with other diseases it at least proves that the disease exists

But how do we know if it is a disease marker rather than an inactivity marker? I'm sure that's what BPS sceptics would argue.

I'm not expecting a marker to straight away be something central to the disease, anything no matter how far downstream it is, would already be a substantial improvement.

Regardless of biomarker status, any biomolecule associated firmly with the illness would be helpful.

But BP argues on Twitter that we should take Fibronectin 1 more seriously than other biomarkers because of its biology.

Is this even a biomarker for severity though?

Yes, that is the overarching issue! I've been watching biomarker claims come and go since 1996 so I'm looking for something way more impressive than we have so far, starting with independent replication. The field has a biomarker claim problem, IMO.

 

[AknaMontes]

I'm probably heavily biased since I don't belong to the mild/moderate group, but I wouldn't have a problem with a biomarker for severity. That would be an outstanding finding, if it indeed measures more than inactivity.

Indeed, in terms of saving lives and preventing horrible suffering for the families and children who are Severe and Very Severe it would have a big impact. It would be enough to be going on with. It should be straightforward enough to clarify if the marker was related to inactivity simply by comparing with controls who are inactive for some other reason? Whether his claim is over-inflated or not, and it sounds as though it is, if the test suggested is quick and cheap, perhaps combined with another potential one someone else has found, surely that should be scaled up urgently. How do we make sure that happens and what very limited funding there is doesn't continue to go on small studies that end up going nowhere but that thoroughly tests the potential biomarkers already found?

 

[Sid]

That's a big caveat, hence the need for disease controls.

Yep. But recruiting sick controls who are as inactive as us is very challenging. I don’t know anyone who moves as little as me. Even people with cancer seem more active than me.