USA: National Institutes of Health (NIH) intramural ME/CFS study

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Thank you Brian!

A quick summary:
HC = healthy controls
ME = ME/CFS

Figures in brackets are probably SD unless otherwise specified
I've bolded the ones that look statistically interesting (hard to tell in some cases)

Some interesting lack of differences e.g. in CRP, a marker of inflammation, which has sometimes been claimed to be elevated, with little evidence. And no difference in total body energy use, although this may not capture differences during exertion.
It's probably important to bear in mind the small sample sizes.

Don't rely on my report - check the source for any important purpose


1. CPET - volume of oxygen at anaerobic threshold adjusted for participant weight
HC 16.0 (4.3) ::: ME 10.6 (3.8)

2. CPET - RER at AT
Respiratory Exchange Ratio (VCO2/VO2) at the time of anaerobic threshold
HC 1.30 (0.08) ::: ME 1.24 (0.12)

3. Total Body Energy Use - whole room indirect calorimetry - 12 hours
HC 1859 (353) ::: ME 1862 (391)

4. White blood cell count in blood
HC 5907 (1536) ::: ME 6143 (1243)

5. ESR Erythrocyte Sedimentation Rate
HC 7.43 (6.13) ::: ME 10.1 (11.9)
Maybe statistically different, but lots of variability in both groups

6. CRP mg/L
HC 3.29 (6.85) ::: ME 1.4 (2.22)

7. White blood cell count in cerebrospinal fluid
(there are typos with CSF and CFS, if anyone able to edit the entry is reading this)
HC 1.0 (1.12) ::: ME 1.3 (1.66)

8. Mitochondrial respiration
Oxygen consumption rate of peripheral mononuclear cells in unactivated state (median and interquartile range)
HC 46.7 (26.2 to 58.0) ::: ME 52.1 (41.0 to 84.9)

9. Effect of maximal exertion on autonomic function
variability of the time between heart beats over 24 hours (median and interquartile range)
HC 67.8 (58.9 to 77.1) ::: ME 56.3 (46.1 to 64.4)

10. Tilt testing
% of participants with sufficiently severe symptoms to require the tilt test is stopped
HC 36.8%. ::: ME 58.8%

11. Microbiome in stool
Number of specific types of bacteria using Least Known Taxon units
HC 477 (33) ::: ME 427 (44)
Might be statistically different but hard to get excited about this particular measure - there are probably lots of different ways to look at microbiome differences. I think we'd need more detailed information e.g. what is missing

12. Test of variables of attention (cognitive function)
Presumably 0 is the population average
HC 1.1 (3.6) ::: ME 0.9 (4.7)
so, presumably the participants are slightly above average compared to reference populations, but, without a pre-illness measure, I don't think this tells us much about ME/CFS, other than the ME/CFS participants were not grossly cognitively disabled on this parameter when tested

13. Paced Auditory Serial Addition Test (cognitive function)
Auditory information processing speed and calculation ability
HC 52.4 (12.1) ::: ME 52.0 (11)
comments for the previous measure apply

Adverse events
No serious adverse events.
Some differences in not-serious adverse events, although no more than would be expected, and actually less than expected for some e.g. 22.2% of people with ME/CFS reported fatigue as a 'not-serious' adverse event. (A serious event is something like death, so pretty serious, meaning that the fatigue, headaches, back aches in the 'not-serious' category might still have been awful.)
 
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I'd love to hear thoughts from @Jonathan Edwards, @Simon M, @hibiscuswahine, @Snow Leopard, @Tom Kindlon and others on the data being discussed on this thread, ie the data from the NIH Intramural study https://www.clinicaltrials.gov/ct2/show/results/NCT02669212.

Perhaps we need a new thread as these could be really important results that we all want to discuss? @Trish What do you think?

For people like me who are kind of catching up on what happened, here's my summary (please correct me if I've got bits of this wrong!)

The original primary outcomes were:
Effect of exercise on neurocognition, brain connectivity, markers of immune dysfunction and inflammation, metabolic function, autonomic function, and gene expression profiles in blood and CSF https://www.clinicaltrials.gov/ct2/show/record/NCT02669212
Click to expand...

But they explain that the pandemic stopped the exercise part of the trial:
COVID-19 pandemic halted return visit for participation in Exercise Phase of trial.
Click to expand...

So we only have baseline measures for people with ME/CFS and controls, but the researchers think they have found differences between the groups at baseline that are significant enough to publish (paper submitted, not yet published) and render the continuation of the trial unnecessary.

@Hutan summarised the results above. I'm going to just deal with the primary outcomes here.

The first primary outcome is now this:
Cardiopulmonary Exercise Test (CPET) - ATVO2rel
The Relative Volume of Oxygen at the Anaerobic Threshold (ATVO2rel) was determined during a cardiopulmonary exercise test (CPET). ATVO2rel represents the volume of oxygen being consumed when a participant reaches AT, adjusted for their weight during the CPET. Results compared Healthy Volunteer Participants to ME/CFS Participants.
Click to expand...

And the results are (in mL/kg/min):
Healthy controls mean 16.0 (standard deviation 4.3) vs ME/CFS mean 10.6 (standard deviation 3.8)

And the second primary outcome is this:
Cardiopulmonary Exercise Test (CPET) - RER
The Respiratory Exchange Ratio (VCO2/VO2) was determined during a cardiopulmonary exercise test (CPET). VCO2/VO2 is calculated by measuring the volume of carbon dioxide and oxygen the participant breathes during CPET. When the volume of carbon dioxide exceeds that of oxygen, it reflects a change from aerobic metabolism to anaerobic metabolism. When a participant has a Respiratory Exchange Ratio (RER) during CPET that is equal or greater than 1.1 it is considered a sufficient exercise effort. Results compared Healthy Volunteer Participants to ME/CFS Participants.
[my bold]
Click to expand...

Which as I understand it is a check of whether people are putting full effort into the test. If ME/CFS patients were putting less effort into the test than controls, then a difference between groups in the first primary outcome ATVO2rel could be explained by that difference in effort. If the ME/CFS patients were putting the same effort into the test as the controls, then a difference between groups in the first primary outcome means something.

It looks like controls and ME/CFS patients were putting adequate and similar effort into the test (unit is respiratory exchange ratio):

Healthy controls mean 1.3011 (standard deviation 0.0791) vs ME/CFS mean 1.2415 (standard deviation 0.1156)

To my inexpert eye, the Mitochondrial Extracellular Flux Assay results also look interesting, with the inter-quartile ranges for controls and patients in Pmol/min looking quite different:

Healthy controls 26.2 to 58.0 vs ME/CFS: 41.0 to 84.9

A larger proportion of ME/CFS patients needed the 40 minute tilt test stopped

Health controls 37% vs ME/CFS patients 59%

To make a real difference to the field, I think the data would need to find differences that can't be explained by deconditioning. Have we got that here, in the primary outcomes viewed together?

Do some of the other outcomes explain why ME/CFS patients switch into anaerobic respiration quicker than healthy people (have I got that right)?

I'm really looking forward to reading the paper.
 
Hutan said:
2. CPET - RER at AT
Respiratory Exchange Ratio (VCO2/VO2) at the time of anaerobic threshold
HC 1.30 (0.08) ::: ME 1.24 (0.12)
Click to expand...
Evergreen said:
Which as I understand it is a check of whether people are putting full effort into the test. If ME/CFS patients were putting less effort into the test than controls, then a difference between groups in the first primary outcome ATVO2rel could be explained by that difference in effort. If the ME/CFS patients were putting the same effort into the test as the controls, then a difference between groups in the first primary outcome means something.

It looks like controls and ME/CFS patients were putting adequate and similar effort into the test (unit is respiratory exchange ratio):

Healthy controls mean 1.3011 (standard deviation 0.0791) vs ME/CFS mean 1.2415 (standard deviation 0.1156)
Click to expand...

Item 2 made no sense to me, so coming back to this. RER at anaerobic threshold is, by definition, 1.
An RER of 1.0 is the anaerobic threshold, the point at which the body begins to metabolize sugar using the less efficient anaerobic pathway and build up lactic acid.
Click to expand...
So those numbers that are reported cannot be at anaerobic threshold. There's no issue of putting in effort at the anaerobic threshold - it's a metabolic thing. An RER over 1.1 at VO2max indicates something like maximum effort.
 
Evergreen said:
Do some of the other outcomes explain why ME/CFS patients switch into anaerobic respiration quicker than healthy people (have I got that right)?
Click to expand...
To continue the thought process here on whether any of the outcomes explain why we might switch into anaerobic respiration quicker...

They explain that:
Higher levels [of white blood cells in cerebrospinal fluid] than normal suggest inflammation or infection in the central nervous system.
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So is this difference in number WBCs/uL in cerebrospinal fluid meaningful?
Healthy controls mean 1.0 (standard deviation 1.124) vs ME/CFS mean 1.313 (standard deviation 1.662)
 
Hutan said:
Yes, we haven't seen @Snow Leopard for a while. Hope you are doing ok SL, you are much missed, we could use your knowledge here.
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The main problem was this wasn't a 2 day CPET. The fact that the researchers don't seem to be demonstrating an understanding of why this is important is a major concern. In the last 10-15 we've learned a lot about how peripheral fatigue is sensed and how it causes central fatigue from pioneering research by exercise physiologists, but for some reason a majority of ME/CFS researchers seem to have ignored this.

Evergreen said:
Which as I understand it is a check of whether people are putting full effort into the test. If ME/CFS patients were putting less effort into the test than controls, then a difference between groups in the first primary outcome ATVO2rel could be explained by that difference in effort. If the ME/CFS patients were putting the same effort into the test as the controls, then a difference between groups in the first primary outcome means something.
Click to expand...

The RER=1.1 therefore we assume maximal effort is not strictly true, in fact was not true in my the case when I did the 2 day CPET. My RER plateaued but VO2 peaked over 2 minutes later.

The differences at the gas exchange threshold/first ventilatory threshold are the key difference and a key insight into the pathology. (and other submaximal measures such as nonlinearities in effort or EMG results if someone bothers to do that research)

So I simply don't mind if patients don't actually reach their true VO2Max.

Hutan said:
Item 2 made no sense to me, so coming back to this. RER at anaerobic threshold is, by definition, 1.
Click to expand...

It is important not to confuse macro with micro.

VO2Max is ultimately a measure of how much oxygen the heart can deliver to the muscle, rather than a measure of how effectively the muscle cells can take up oxygen.

The the various thresholds that are discussed occur well below maximal motor unit (nerve) recruitment, and given different activation thresholds (and physiological differences between muscle fibres, such as amount of capillarisation) there is a spectrum of the balance of metabolism going on in the muscle.
Some muscle fibres will be driven such that a majority of the energy is coming from anerobic metabolism, while other muscle fibres might not be working very hard if at all!

This is why I don't like to talk about an "anerobic threshold" as it often misleads us as to what is going on at the cellular level.
 
HealthRising covered this study a few weeks ago:
Four Weeks at the Clinical Center: Brian Vastag on the Soon-to-be-Published NIH ME/CFS Intramural Study
https://www.healthrising.org/blog/2023/05/30/vastag-nih-intramural_chronic-fatigue-syndrome-study/

The progress of this study reminds me of the Truck Crash GIF, showing a crash test of a truck. Several shots show the truck hurtling toward a barrier, but the animation restarts before the crash is actually shown, creating an effect of perpetual suspense.
 
RedFox said:
HealthRising covered this study a few weeks ago:
Four Weeks at the Clinical Center: Brian Vastag on the Soon-to-be-Published NIH ME/CFS Intramural Study
https://www.healthrising.org/blog/2023/05/30/vastag-nih-intramural_chronic-fatigue-syndrome-study/

The progress of this study reminds me of the Truck Crash GIF, showing a crash test of a truck. Several shots show the truck hurtling toward a barrier, but the animation restarts before the crash is actually shown, creating an effect of perpetual suspense.
Click to expand...

Honestly between this and P.T. Prusty's Marvelous Biomarker Circus I can't decide which is the most infuriating!
 
V.R.T. said:
Honestly between this and P.T. Prusty's Marvelous Biomarker Circus I can't decide which is the most infuriating!
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I think the NIH carnival is more vexatious. They have the institutional prestige and innumerable resources necessary to muster some progress. Prusty’s pronouncements remind me of the many watershed “breakthroughs” over the decades. A lot of bluster, but not much clinical significance I’m afraid. Do we know when the biomarker will be unveiled? Has it already?
 
Maybe the NIH is taking so long because they think that due to the controversy surrounding ME/CFS they need really solid evidence before making any claims.

That's the wishful thinking on my part, which hopes that delays mean solid evidence.
 
Hoopoe said:
Maybe the NIH is taking so long because they think that due to the controversy surrounding ME/CFS they need really solid evidence before making any claims.

That's the wishful thinking on my part, which hopes that delays mean solid evidence.
Click to expand...

This is thoughtful analysis. I assume they know they’re in for a pummeling from the usual quarters. Ironclad findings in an established journal are necessary, and even then, they’ll have to prepare for the impending onslaught.

I expect the most vehement, and petulant, opposition to come from the FND sector.
 
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