Using a percentile here somewhat downplays it. On the Qeios page for these stats, it says this paper is ranked number 1 out of 8 for papers of a similar age from Qeios.
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Preprint A Proposed Mechanism for ME/CFS Invoking Macrophage Fc-gamma-RI and Interferon Gamma, 2025, Edwards, Cambridge and Cliff
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New comment on paper from Brett A Lindbury. I think this a professor at ANU.
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Review of: "A Proposed Mechanism for ME/CFS Invoking Macrophage FcγRI and Interferon Gamma"
Thank you for the invitation to assess this review by Edwards _et al_. The proposals behind the review involving Fc-gamma receptors, cytokines (particularly IFN-gamma), and the implications for T-cell : B-cell : Macrophage interactions (and interplay...
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Woolie
Senior Member
Just thought I'd pitch in here: I've done a couple of trials of mycophenolate to treat my autoinflammatory (periodic fever) symptoms. I get flu-like episodes where my inflammatory markers go up (e.g, CRP). Since mycophenolate is supposed to inhibit production of CD4+ and CD8+ t cells (which are sometimes elevated for me when I'm really sick), it would seem to be a reasonable thing to try.
Each time I tried it, it made me feel awful. A different kind of awful to my usual awful. I felt really listless and just wanted to sleep. My usual symptoms are more like burning, with aching glands and feeling like I've got the flu. I decided I preferred that to the listless feeling!
So a couple of take-aways for me there. First, it made me realise how good we are at "reading" our bodies. It was very clear to me that this feeling was entirely different from my "episodes". The BPS idea that we're all having somatic halluncinations is just madness. Second, you can't just think "suppress the inflammation", you've got to think in a more nuanced way about the specific mechanism that is causing the inflammation and address that.
The journey continues...
Each time I tried it, it made me feel awful. A different kind of awful to my usual awful. I felt really listless and just wanted to sleep. My usual symptoms are more like burning, with aching glands and feeling like I've got the flu. I decided I preferred that to the listless feeling!
So a couple of take-aways for me there. First, it made me realise how good we are at "reading" our bodies. It was very clear to me that this feeling was entirely different from my "episodes". The BPS idea that we're all having somatic halluncinations is just madness. Second, you can't just think "suppress the inflammation", you've got to think in a more nuanced way about the specific mechanism that is causing the inflammation and address that.
The journey continues...
Jonathan Edwards
Senior Member (Voting Rights)
Thanks for the heads up.
Do people think this comment is fair?
Another comment to consider is the view, under the section “Evidence for Nervous System Involvement”, that, “No consistent macroscopic or microscopic structural changes have been found in the brain,…”. I do not think that this is correct and would recommend reviewing the primary MRI, fMRI, etc. studies and systematic/scoping reviews on the topic (for example, Nelson T, Zhang LX, Guo H, Nacul L, Song X. Brainstem Abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Scoping Review and Evaluation of Magnetic Resonance Imaging Findings. Front Neurol. 2021 Dec 17;12:769511. doi: 10.3389/fneur.2021.769511).
The review in question is not very high quality - a rag-bag of findings with rather naive interpretation, to my mind. But I admit that studies have claimed to find changes. I was hoping the word 'consistent' would cover 'at least not yet consistently replicated'. The most recent studies (local to Lidbury) by Barnden and colleagues are probably what triggered the comment. My reading of our analysis here was that we thought these were relatively high quality studies but could do with replicating and were not necessarily easily interpretable in terms of role in the illness.
I am also not quite clear what he disagrees with in terms of the relation to viral symptoms. I think I might ask for clarification.
Jonathan Edwards
Senior Member (Voting Rights)
Hi @Woolie ,
Very much agree on both counts.
We started making progress with autoimmune rheumatic disease when we started using very specific biologics targeting individual cytokines or cell populations. Ironically, mycophenolate also hits antibody levels so may be a very useful element of a combination Ig reducing protocol but on its own it is pretty disappointing in any disease I have treated - and is hard to take as you say.
The journey continues, but I am optimistic that we will make headway now, in a way I have not been before. I suspect our little hypothesis here is off target, but working out where it is off target and why might lead to something better.
hotblack
Senior Member (Voting Rights)
Maybe it’s a tonal thing? A lot of the paper is rightfully clear about what is not known, so sentences which seem to more firmly discount an area perhaps stand in contrast to that?
I’m not sure ‘consistent’ alone conveys that uncertainty.
The paper referenced had a little discussion here in this thread here in this thread
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Woolie
Senior Member
Hi @Jonathan Edwards!
I think the problem with this review is that it selected only studies that mentioned terms related to the brain stem by name. Studies that didn't find anything in that region might not mention any such terms so they are not included in the review. Therefore, we have no idea how many null effects are out there. Also, some studies are likely to have performed hundreds or even thousands of tests, so we have no idea how many of these outcomes might have been false positives. We also don't get much of an idea about the specificity of the brain stem findings (is the brain stem implicated to a greater degree than other structures, or is it just one of a shopping list of structures identified?).
Another problem is that volumetric and functional connectivity measures will reveal differences between a clinical group and healthy controls for reasons that are often quite boring. For example, the degree of physical activity the person has participated in over the last few months is likely to affect volumetric measures, and in fMRI the degree of discomfort they feel on the day is likely to affect functional connectivity measures. So positive findings do not always indicate causal primacy for the brain.
When I read that comment, I had the same reaction as you. I think 'no consistent... changes' conveys the current situation of some possibly interesting findings among plenty that are 'grasping at straws' in small cohorts - but no replicated findings. Perhaps I'm not remembering something, but I can't remember anything compelling yet when it comes to structural brain changes.
Joan Crawford
Senior Member (Voting Rights)
Many thanks for sharing this work @Jonathan Edwards. Please thank your colleagues too. I've been away on leave so not have time/internet access to comment until now. I find your paper clear and straightforward to read so far which is excellent. I will keep reading with interest.
Forgive me if this has been covered - one thing that came to mind in relation to age profile and female predominance is the impact during the teenage years of the fluctuating effects of the menstrual cycle. As this varies throughout the month perhaps this is a risk factor / exacerbator for the development and maintenance of ME symptoms? Furthermore, many woman with ME report a significant improvement in ME symptom reduction during pregnancy when hormone levels are, as I understand it, more stable.
I was wondering if this fits or has any relevance to what you are proposing.
Forgive me if this has been covered - one thing that came to mind in relation to age profile and female predominance is the impact during the teenage years of the fluctuating effects of the menstrual cycle. As this varies throughout the month perhaps this is a risk factor / exacerbator for the development and maintenance of ME symptoms? Furthermore, many woman with ME report a significant improvement in ME symptom reduction during pregnancy when hormone levels are, as I understand it, more stable.
I was wondering if this fits or has any relevance to what you are proposing.
Sasha
Senior Member (Voting Rights)
If this theory is correct, would PwME be considered as immunocompromised? Or if we were on one of the proposed treatments?
I'm wondering whether that classification would help us get some kind of special treatment in GP surgeries, hospitals etc. to protect us against infection as standard, or whether that doesn't happen for anyone these days. For years, I've had to phone ahead to make protective arrangements but it's always difficult.
I'm wondering whether that classification would help us get some kind of special treatment in GP surgeries, hospitals etc. to protect us against infection as standard, or whether that doesn't happen for anyone these days. For years, I've had to phone ahead to make protective arrangements but it's always difficult.
boolybooly
Senior Member (Voting Rights)
There have been a lot of findings regarding changes in brain and brain stem morphology in ME/CFS.
Voxel morphometry is, as I understand it, an empirical metric. Rather than list them all here I prefer to cut out the middle man and include a link to google scholar for "voxel morphometry ME/CFS", below.
Google Scholar
Jonathan Edwards
Senior Member (Voting Rights)
Yes, @Woolie, all those things are relevant.
I am keen to play down unreplicated suggestions of neuroinflammation and suchlike (the review refers a lot to van Elzakker and Younger) but I think the Barnden group studies shouldn't appear to be brushed aside entirely. If I put in a reference it will be to Barnden, not the Nelson review. I think it might make he balance better it I added a clause about possible evidence of functionally relevant remodelling. For various reasons I have not opened up on brain aspects here but a gentle'watch this space' comment might be justified.
I am keen to play down unreplicated suggestions of neuroinflammation and suchlike (the review refers a lot to van Elzakker and Younger) but I think the Barnden group studies shouldn't appear to be brushed aside entirely. If I put in a reference it will be to Barnden, not the Nelson review. I think it might make he balance better it I added a clause about possible evidence of functionally relevant remodelling. For various reasons I have not opened up on brain aspects here but a gentle'watch this space' comment might be justified.
Jonathan Edwards
Senior Member (Voting Rights)
We do not go in to this amount of detail but note that both the two X chromosomes and the ongoing exposure to sex hormones are known to be relevant. We cite a review by a colleague of Jo's that is very insightful. Menstrual cycles may certainly be relevant but are hard to disentangle from other aspect of sex hormone levels.
Jonathan Edwards
Senior Member (Voting Rights)
I don't know of any good reason or evidence for thinking pwME/CFS are immunocompromised. That was an idea that came from comparing it to AIDS and calling it CFIDS I think. I don't see any basis for it much. Treatments might compromise, though.
Jonathan Edwards
Senior Member (Voting Rights)
Yes, but are any of them likely to be replicable and valid? I want to avoid 'lots of studies' and stick to findings that we are reasonably confident in.
Utsikt
Senior Member (Voting Rights)
From the comment by Lidbury:
But I’ve spoken to multiple patients that got covid, got better for up to a few months, and then crashed without any apparent additional infections, and have now been diagnosed with CCC ME/CFS. I’ve also seen the same in people that eventually recovered within a year or two of their onset.
I got PEM, fatigue, OI, etc. from the start of the covid infection that probably kicked off my ME/CFS. I was not hospitalised, but wouldn’t call the initial infection «mild».
But I’ve spoken to multiple patients that got covid, got better for up to a few months, and then crashed without any apparent additional infections, and have now been diagnosed with CCC ME/CFS. I’ve also seen the same in people that eventually recovered within a year or two of their onset.
boolybooly
Senior Member (Voting Rights)
What can I say? 'Twas ever thus, ME/CFS MRI studies have been typically underpowered since forever. I wait for DecodeME with fingers crossed.
"A systematic review of neurological impairments in myalgic encephalomyelitis/ chronic fatigue syndrome using neuroimaging techniques."
S. Marshall-Gradisnik et al. Published: April 30, 2020. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232475
IMHO the small MRI studies can't be discarded but there is no definitive consensus on regions apart from brainstem blood flow abnormalities which crops up regular as clockwork.
"Brainstem Abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Scoping Review and Evaluation of Magnetic Resonance Imaging Findings." Zhang et al. https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2021.769511/full
We all want increased cohort sizes. CFS criteria are nebulous and ME/CFS research cohorts need to be refined either by molecular signature or by PEM response to exercise challenge. LC cohorts are not as fuzzy due to a clear history of infection.
Personally I would include small MRI studies under "suggestive findings" and would not discard them because there are just too many people coming to similar conclusions pointing at the brainstem and autonomic system, which given my subjective experiences makes sense.
VanElzakker's combined MRI PET studies are interesting and his vagus model a worthy muse. I think neuroinflammation and associated histopathology are very significant for ME patient symptoms and potentially create a superficial homology between different subtypes with different initial causes.
My own history does not on the face of it match the idea of neural or immunological hypervigilance as a maintaining factor, as I have mentioned before and don't worry I am used to being ignored, recurring detectable symptomatic virus is a signature symptom of ACAI and CFIDS and my own condition indicating an immune dysfunction in the business of clearing viruses, which is the opposite of hypervigilance as an overreaction to nothing in particular. Mine is an early shut down of vigilance to something substantial and measurable leading to a recurring cycle of viral resurgence. Unless this is a dysregulation overreacting to hypervigilance, causing shut down and subsequent hypovigilance.
Jonathan Edwards
Senior Member (Voting Rights)
I am not quite sure what Lidbury is claiming. He says that 12 weeks are needed to see the appearance of idiopathic, long-term fatigue, PEM, and associated symptoms.
Idiopathic doesn't appear - I am not sure what he means by that.
Long term doesn't appear until the long term, but certainly fatigue can be there from the start and is common with viral infection.
PEM is called malaise because it is a bit like the malaise of infection. My view is that to begin with it is hard to know whether to call it post-exertional because it can come and go unpredictably within the first 3 weeks of a bad viral episode. Moreover, it can certainly seem to be post-exertional during flu or Covid. It takes 12 weeks to be sure it is the PEM of ME/CFS simply because it takes that long to observe the pattern convincingly.
So I don't think 12 weeks are need to see the appearance of these things. 12 weeks are needed to know that they signify ME/CFS or maybe just PVF. It may be that resolving PVF does not have PEM but we have argued this at length and it seems to be an unproductive exercise - maybe in part because PEM is probably not a black and white thing.
I intend to reply asking for clarification. I don't think it is very relevant to the point of the paragraph - which is that the relation of ME/CFS to infective trigger is not stereotyped and clouded by similarity of symptoms with infection.
Utsikt
Senior Member (Voting Rights)
Looking at your article, I think the sentence before their excerpt adds some useful context:
But what do you mean by «stereotyped history of post-infective illness»? Maybe that’s what’s causing the confusion because it might not be clear to all what the stereotype is.