Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome, 2024, Walitt et al

They've really done an excellent job of leaving the door ajar to a psychogenic interpretation of their findings/conclusions, haven't they? Particularly in the NIH press release.

I actually don't mind the idea that the brain is stuck in some sort of loop / state due to the immune system going rogue. This has long been a hypothesis I have favoured. But the stuff about effort preference etc just seems ludicrous to me. I cannot see how any of this fits with the reality of PEM/PESE.

 

https://twitter.com/user/status/1760381291122274477

 

Submit comments on NIH paper here:
https://www.nature.com/articles/s41467-024-45107-3#article-comments
I'd recommend being polite. Better again if you can reference a scientific paper.

Looks like it could be hard to get formal letters to the editor published for this open access journal
https://www.nature.com/ncomms/submit/matters-arising

 

I've been dreading this paper for 8 years. I'm surprised it's turned out to be worse than my most pessimistic expectations. I just assumed they’d find nothing (which they did) and quietly move on. Instead they wrote a dissertation-length diatribe about us.

 

https://www.scientificamerican.com/...syndrome-may-have-an-exhausted-immune-system/

Better article. Doesn’t quote Walitt and focuses on immune findings.

 

I am concerned that my bias has me misremembering.

What have been the arguments from NIH about the size of this study?

I feel I heard them argue that the small sample size was NOT an issue because they were doing such a deep dive on each person that that would compensate for the small sample. How far off am I?

And is the paper saying now that small sample size makes things problematic?

(Honest questions as I am really in a rotten state)

 

This article puts the study a bit in context with other ME trials and has comments from Mady Hornig who also shared the gift link on Twitter

Bloomberg
Exhaustive Chronic Fatigue Study Points to Infectious Driver

quotes:
“This is a tour de force and an important recognition of ME/CFS as a disease worthy of the best scientific pursuit,” said Mady Hornig, a physician-scientist in New York, who’s been studying the syndrome for more than 30 years. “It is critical to now build on this momentum.”

Clues are beginning to emerge from recently published research. Hornig and colleagues demonstrated similar patterns of immune dysfunction in a December study. Dutch researchers last month detailed muscle and metabolic abnormalities in long Covid patients with post-exertional malaise, which can also trigger crushing exhaustion and worsening symptoms in chronic fatigue patients after mental or physical activity.

...

“Men and women were quite divergent in their data, and that tells you that ME/CFS is not one-size-fits-all,” Nath said. “Considering male and female immune differences in ME/CFS, the results may open up new avenues of research that could provide insight into other infection-associated chronic diseases.”

 

I think this is the politically smart response to the paper - skate over its conclusions and serious flaws, and use it to call for proper funding from the NIH.

The truth is that an $8 million study looking at 17 patients wouldn’t be expected to make serious inroads in any other field. The paper has taken on such intense significance because the NIH provides virtually no funding for ME research. We need to get to a place where it doesn’t hugely matter that an individual study has significant flaws because enough well-funded research is happening that the field builds a momentum of its own.

 

In this study at a UK centre, 13% (24/179) of ME/CFS patients tested positive for POTS (I'm specifically saying tested positive meaning that they had a positive tilt test). https://onlinelibrary.wiley.com/doi/10.1111/joim.12022

This is still considered a significant proportion. It means that in a teensy sample of 17, you would expect about 2 to test positive for POTS, but you could certainly get a bunch of samples of n=17 ME/CFS patients where none would test positive for POTS when tested once. The sample is tiny.

 

But the thing is, long COVID has received over a billion from the NIH and it was completely squandered. So to what extent will money solve our problems, if they just keep wasting it? Wouldn't it be counterproductive if they spent the next 5 years pumping money into useless studies and then concluded "ok there is nothing to study here, no more wasting money"?

If we don't start somehow forcing quality scientists to enter this field, nothing will ever change. We can't keep giving money to doctors, physicians and low quality researchers that have no clue what they are doing.

 

RECOVER is a very different equation to this study. They were essentially, due to the longstanding neglect of ME, trying to understand what they saw as a new disease entity from scratch. They spent the money poorly, but some of that was to be expected. Perhaps the most significant problem with RECOVER, in my opinion, was that they spent the money internally rather than giving it to lots and lots of external investigators.

You can't "force quality scientists to enter this field." Academics need to be enticed to work in a field, and ultimately the only way of doing that is through having long-term, consistent funding. Few top scientists wants to work in a field where there's no research funding so there's no guarantee they'll still be funded in 5-10 years. Also, if you want good science, that emerges out of lots of academics continually working on a question for years, decades. If most Long Covid and ME studies are done by figures who are new to the field, you'll never get particularly good research. And of course, the less studied a disease, the more hit and miss research into it is likely to be.

The only way things can change is through consistent, large-scale research funding. The reason nothing has ever changed is that there has never been any serious funding. $10-15 million a year from the NIH is absolute peanuts. The average funding per disease at the NIH is $200mn - *that's* how you attract top scientists.

 

Helpful.

I'm gonna effort-prefer my way to monotherapy of the former type, should any effective one ever be identified.

 

I think the bolded word is important.

 

https://twitter.com/user/status/1760258927546290204

 

"a mismatch between what someone thinks they can achieve and what their bodies perform" - The only mismatch I know of is the exact opposite of Brian Walitt's, it's when I wrongly think my body can do MORE, not less. Which leads to a crash. He is so dead wrong about ME.

 

sorry, can you explain what this means?

 

"The target endpoint was exertional intolerance defined as the participants’ expressed desire to stop cycling despite strong verbal encouragement from the testing staff"

That is not a pleasant image. I hope that the participants didn't exceed their envelope by too much and cause lasting damage.

"An increase in percentage of naïve and decrease in switched memory B-cells in blood were observed in PI-ME/CFS participants"

Thoughts @Jonathan Edwards ?


I wish there was more detail in the gene expression sections but it's limited to the typical surface level bioinformatic pathway analysis that too often neglects to take into account the actual function of the particular gene products. I really hate this modern trend of "well 5/9 of these genes "involved" in X process are elevated in expression so X process is probably upregulated". Okay and what if one of those 5 inhibits the pathway? What if a rate-limiting enzyme of the pathway is meanwhile downregulated? Well, I guess it is more taxing to read about the function of a few dozen genes of interest that the pathway analysis turned up, rather than only giving the data to a bioinformatician and asking them to press a button and calling it a day. One could call this issue a matter of "effort preference".

 

Imagine that, people lose trust in you when you fuck them over.