2024: NIH National Institutes of Health - ME/CFS Symposium on Intramural study - 2 May

They seem to have cottoned on to the idea that PEM isn't just fatigue. Ratings of fatigue were actually flat during period prior to, during and after PEM.

CPET - lower max VO2, lower anaerobic threshold. Only 8 people with ME/CFS did it.
There was a really dramatic illustration showing the ME/CFS would be at or over the anaerobic threshold just doing activities of daily living. An important slide.
Lower heart rate than expected for the activity - chronotropic incompetence.

No real differences in muscle oxygenation.

 

Diet history - a bit meaningless with 17 ME/CFS participants. Not a lot of difference
Body composition - normal
7 day activity measurement - reduced steps per day - maybe ME/CFC 3500 steps to HC 6500 steps; less moderate activity
but a lot of variability within the group

Metabolic chamber - energy expenditure measurement
Not much that was notable. A few people with ME/CFS seemed to have higher resting energy expenditure.

 

Dr Hwang
(He's been quite engaged - asking questions of speakers)
The first test subject with Li-Fraumeni syndrome but unusually with fatigue - there's a paper on this

Her phosphocreatine recovery after exertion was very slow
Skin cell oxygen consumption was low
Identified that WASF3 was the gene responsible, and it has previously been noted to be associated with ME/CFS
WASF3 inhibits mitochondrial respiration​

The NIH study confirmed this finding, increased expression of WASF3 (and decreased expression of associated proteins, as in the original person)
They were able to fix the mitochondrial dysfunction in cells with salubrinol (removing ER stress)
Number of ME/CFS participants was quite low, maybe 6? with 5 controls?, edit - he later said there were 14 participants

Yaay Dr Hwang, nice presentation

 

In the summary, it was noted that a couple of ME/CFS patients had the highest Vo2max including compared to controls (these patients are not reconditioned)
There is a wide range of bioenergetic capacities.
Things seem fine at resting but there seems to be some mitochondrial dysfunction

Damn, I find myself agreeing with Walitt - the 2-day CPET isn't a measure of PEM.

There was a question to Dr Hwang about doing a WASF3 study in Long Covid - he made positive noises. I think it will be done in the NIH studies.He also said that he hoped that others would investigate it.

Chronotropic incompetence - can do a test with isoprel? to pinpoint the basis of chrontropic incompetence. there was an interesting disagreement between an investigator (must have been David Goldstein) and Walitt. The investigator said that they didn't find a sympathetic noradrenergic problem. Worth another listen - the only indication of disagreements within the NIH team.

Question to Hwang. He said that the ER stress can be a response to viral infection.

 

Walitt on open science:
Walitt bleating about how much it costs to make a publication open access and how good they are that they spent the money to make the paper open access.
Open access to data

They will be doing more work on the data.

 

One of the participants told us about her experience and it sounded really really difficult. It was clearly a huge effort and I am grateful. She said several times that Brian Walitt had been very caring. Of course, someone can be very caring while regarding the people they are caring for as lesser beings. I'm surprised that the patient did not have a problem with the conclusions around the EFFrT study.

Another participant had hypersomnia and extreme difficulty being upright and still chose to participate. She also said that she had felt very cared for.

Very moving presentations from patients and healthy controls. I think it is abundantly clear that these particular patients in no way suffer from an effort preference problem. They were clearly determined to keep choosing to do things that were very difficult.

Some patients made comments from the floor. One noted that PEM is not a subjective experience and another agreed.
One of the patients on zoom expressed their hope that this was just the beginning and said that they felt excited.

 

Panel: Komaroff moderating. Klimas, Lipkin, Vicky Whittemore, Joe Breen

Komaroff says that there have been a lot of papers documenting biological abnormalities. He suggests that this study finds that ME/CFS is a brain disease caused by immune exhaustion. Mentioned the Time 100 in Health - 4 people associated with ME/CFS are included.

Lipkin says the leadership of this study has been extraordinary. He talks about PD-1, that any increase would result in a difficulty in clearing infections. He says that people have been looking for an infection that is causing ME/CFS for a long time and haven't found one. He favours a hit and run hypothesis. He has been doing some work with Komaroff to look for infections when ME/CFS people have a deterioration, and looking for antibodies in the weeks after. He talks about innate immunity going awry and causing sickness behaviour. He mentions butyrate, protecting the gut epithelial integrity and modulating immunity. Pre and probiotics may help - need to start thinking about how to do this. Lipkin stresses sex specific differences. Lipkin continues.

 

Lipkin was surprised about the lack of difference in tilt test findings. (I forgot to say that the healthy control (a sister of a ME/CFS participant) who spoke actually developed Long Covid after attending the NIH first visit.) He found the findings on catecholamines were really interesting.

Vicky Whittemore
She suggests that there are significant differences between people who have been sick for 3 years and people who have been sick for 30 years. Also sex specific differences. Talked about the research webinars and developing the research roadmap. Keen to get clinical trials. The NIH research has helped to move the field forward.

Joe Breen
Commented that the presentations from the patients had been moving, particularly them talking about the hope that there would be answers should grandchildren get the disease. Breen said he hoped it wouldn't take that long. He says we don't have evidence yet that ME/CFS and Long Covid are the same. He thinks the findings of PD-1 and exhausted t-cells; fMRI results interesting.

Nancy Klimas
Some of the findings found in this paper have been known for a long time e.g. immune exhaustion. Low stroke volume is important for clinical care. Bioenergetic problems in the cells - important to know what made them that way. Often people point to bits of the disease and say 'it's an immune disease' 'it's a bioenergetics disease', the good thing about this study is that it looked at the whole elephant, not just bits of it. Nancy and Walitt and Nath doing some work with the VA (it was mentioned earlier). Notes that the people with neurotoxic injury present really similarly. She can not tell someone with GWI from someone with Long Covid from someone with ME/CFS if she did not know the patient's history. She says we have to get to clinical trials.
She says it was a great trial and the small size isn't a problem - you can get value even out of n=1 studies.

Lipkin
He was talking about changes in cytokines with the time of the disease as per his earlier results with Hornig (I'm skeptical).

 

Nath - future directions

There can be missed diagnoses, so it's really important to closely follow them to discover if there is an underlying disease (I assume he means aside from ME/CFS).
They learn that people with ME/CFS can spontaneously recover.
The nervous system does play a critical role, but other parts of the body may be involved.

Therapeutic approaches - shows the diagram that ends with teh person with decreased activity.
Is it possible to intervene early in the immune system?
He suggests that downstream may be self-perpetuating and they see that in pain syndromes.
Will need combination therapies to address that. (sounded suspiciously behavioural)

Treatments should only be done in clinical trials

Also notes some treatments suggested by patients e.g. LDN, aripiprazole

Suggests we hold hands together and move forward and that there is light at the end of the tunnel. (that isn't a paraphrase)

 

NIH director of intramural research - brief comment
All the complexities require a team approach.
A disorder that involves the immune system, microbiome, autonomic nervous system...
Partnership with patients and advocates and universities and industry are critical.
Grateful to everyone who has participated.
Spirit of partnership, hope

Nice comment and all good, but she could have, and I suspect does, make similar speeches about a whole range of diseases, just changing the disease name. She wasn't sure if it is a disease and listed various descriptors such as syndrome and condition. There was no statement made about the disease significance or solving it being a priority.

Edited to clarify title