Opinion What are the top replicated ME/CFS findings?

Simon M

Simon M

Senior Member (Voting Rights)
What would you say are the top robust findings about ME/CFS

I'm writing an introduction for a research paper and want to point out how little we know for sure. But as it is an introduction, it has to cover a lot of ground, so I can't go into much detail. I would appreciate references, particularly the best reference that might cover an area.

As a starter, I have:
1. Numerous prospective studies showing ME/CFS after 6, 12, etc, months after certain infections, especially EBV (triggering IM). E.g. Hickie/Dubbo, Katz.
2. A reduced ventilatory threshold on day two of a 2-day CPET. I would appreciate refs for a review/latest significant paper.

What else?

Thanks.
 
@ME/CFS Skeptic

You seem to have a better handle on this subject than most, given your thread on this from 5 years back, your recent blogs on the CPET, and your forensic approach to biomedical studies in general.

Which findings, if any, would you say a robust (and ideally meaningul as well i.e. a clear relevance)
Your thread:
ME/CFS Skeptic said:
I'm hoping to get an overview of biomedical abnormalities found in ME/CFS that were replicated by multiple groups. I realize that, due to the paucity of research, most of the findings are unimportant and non-specific with some inconsistencies in the findings but I still think it would be useful to have an overview.
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Thanks

@Jaybee00 Thanks for pointing out those threads - nothing there seemed to really stand out. What are your views?

I'm just looking for a few of the strongest findings to mention in a study introduction. And it is not proving easy to track them down.
 
Simon M said:
Which findings, if any, would you say a robust (and ideally meaningul as well i.e. a clear relevance)
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I think the main ones are already mentioned so do not have much to add. Perhaps NK cytotoxicity as Baraniuk tried to argue that null results were due to different handling of samples?
Meta-analysis of natural killer cell cytotoxicity in myalgic encephalomyelitis/chronic fatigue syndrome - PubMed

For 2-day CPET perhaps you could use this review as reference:
https://www.tandfonline.com/doi/full/10.1080/21641846.2022.2108628#abstract

Except for infection as a trigger of ME/CFS, I don' think other findings can be viewed as strong even if several groups reported it. There would need to be larger (possibly multi-site) studies with a stronger focus on replication and methodological quality, to have real confidence in the findings.
 
I'm still nervous that the next study will find no difference, but the IGHV3-30 gene segment on BCRs has been high in all three published studies that tested it. [Edit: The oldest study isn't great evidence because they couldn't discriminate between IGHV3-23 and IGHV3-30. And I think they were measuring free antibody, not BCRs, but I'm not sure.]

Latest study, the other two are linked a few posts in:
Deep Sequencing of BCR Heavy Chain Repertoires in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2025, Ryback et al

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Maybe high lactate in the brain measured using brain imaging (not CSF).

Latest study, the others I'm aware of that tested the same thing are linked a few posts in:
Mechanisms of ME/CFS & Long Covid with predominant fatigue: a magnetic resonance spectroscopy study of the brain & muscle at 7 Tesla, 2025, Godlewska
 
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I always thought the very low ESR finding was consistent, but contra this Stanford study https://ashpublications.org/blood/a...rocyte-Deformability-As-a-Potential-Biomarker,
this Nacul study did not find that https://pmc.ncbi.nlm.nih.gov/articles/PMC6627354/

{{Also I think if you are measuring ESR in ME/CFS patients, you should consider stratifying by length of time the patient had the disease—I’d guess that in the initial/smoldering stages you would find consistently low ESR—this my hunch only}}

Also check out the results of this un-official non-peer reviewed poll here.

https://www.healthrising.org/blog/2019/11/06/clumper-slider-esr-chronic-fatigue-fibromyalgia-poll/
 
Jaybee00 said:
{{Also I think if you are measuring ESR in ME/CFS patients, you should consider stratifying by length of time the patient had the disease—I’d guess that in the initial/smoldering stages you would find consistently low ESR—this my hunch only}}
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This is an important factor in general to control for in ME/CFS research, not just for ESR. I suspect we are going to see two different overall profiles: one during the initial stages, then a change to a different profile after that.

I would need to check, but IIRC I had a low ESR early on, including for the initial diagnostic investigations (at 4 years), but not any more. Though that may be due to standard reporting of tests for ESR being inadequate as they don't generally report low values as being significant, only high ones.
 
Yes, I find this real blood flow stuff really interesting, does anyone have any usable links? A review is exactly what we need.

I can’t figure out the relevance of low ESR, given that it’s usually seen as super healthy.

I should point out I’m focused on a few good examples for the introduction for research article, I’m not attempting a review of what’s out there. Though obviously people can use this thread for discussing whatever they want!
 
I am not sure any of the findings (low VitE, low Q10, low Selenium, increased 8ISO-pgf2alpha, low GSH, etc.) pointing towards increased oxidative stress/ROS/redox imbalance have been replicated, but I think these might be significant findings that could be easily replicated.
 
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Simon M said:
Yes, I find this real blood flow stuff really interesting, does anyone have any usable links? A review is exactly what we need.

I can’t figure out the relevance of low ESR, given that it’s usually seen as super healthy.

I should point out I’m focused on a few good examples for the introduction for research article, I’m not attempting a review of what’s out there. Though obviously people can use this thread for discussing whatever they want!
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CBF might be related to OI and not ME/CFS in particular. It was a topic in this study on using Oral Rehydration Solution vs Saline for POTs.
https://pmc.ncbi.nlm.nih.gov/articles/PMC6815702/
 
I don't that there are much in the way of other replicated abnormalities in ME/CFS. We know about age of onset and sex ratio etc. but if you want pathology, no.

I don't think the low ESR is likely to hold up or be helpful, especially with Beentjes finding high CRP. I think these may well involve confounders, especially the ESR. Low ESR can occur with certain pathologies (polycythaemia vera) but I don't think relevant here.
 
Interesting, I had high ESR in the early years when I was less severe, now it's always normal but other inflammatory markers still fluctuate with symptom severity but not enough to be useful diagnostically apparently, so they are usually handwaved away.
 
I think the top replicated findings will have to be all the findings showing absense of abnormalities (both on the biological side and the psychological side as well as treatments for adressing aspects of either side). That is, one should know where not to look!

Though I suspect that wouldn't make for a sexy introduction to a paper.
 
EndME said:
I think the top replicated findings will have to be all the findings showing absense of abnormalities (both on the biological side and the psychological side as well as treatments for adressing aspects of either side). That is, one should know where not to look!

Though I suspect that wouldn't make for a sexy introduction to a paper.
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I had the same thought. The replicated findings to date tell us what we know isn’t going wrong. That might not be sexy, but it is important and would be useful to highlight.
 
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