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

janna moen, phd is still masking @jannamoen

I will be posting a comment on @PubPeer
outlining these issues so they are part of the public record, and I would encourage others to do the same. Comments can be submitted anonymously if you don't have an academic publishing record.

 

I probably wasn't clear but I was highlighting it because of her suggestion to post comments on Pubpeer. Here are her other tweets:

 

So far read only the abstract and some of the media coverage. Meh.

I wonder what the 17 pwME are feeling right now. Mixed emotions I guess. Whatever the case, a great big huge enormous thanks for putting your bodies and health on the line for us. Thanks, too, to the healthy controls who chose to take time out of their lives for us.

As for the authors, some will undoubtedly have done a massive amount of good work and thank you unreservedly for that.

But was there really no one among the dozens of authors who stopped and thought that maybe the term "effort preference" was just a teensy weensy tiny bit problematic to use let alone to highlight in the abstract where everybody sees it? What with the well-known history of ME mischaracterisation and all?

From my limited reading I also get a sense that they might be muddling up neurons making "decisions" based on their chemical/electrical environment, and people making conscious decisions. That's certainly what comes across in some of the media coverage. Which is the entirely predictable result of using a term like "effort preference"

And I am sooo tired of reading yet again about effing fatigue fatigue fatigue with nary a mention of PEM. I didn't like it at the time but I now think it's a shame SEID didn't catch on. At least it would have put problems with exertion at the centre of people's thinking, with fatigue relegated where it belongs: just one of the many symptoms arising from the core problems with exertion

Anyway, I admit I'm still clinging to the hope there's something more substantial and substantive hiding out in the raw data, and that the existence of the raw data will attract some funding and some good new brains to the field, some that don't look at ME primarily through the lens of fatigue

 

I pored through this paper all day long to figure out what is new. We already knew MECFS is a centrally mediated disorder. There isn't much in the paper that 2-day CPET test already found: A) MECFS patients are capable of exerting, and B) if they do, they keel over the next day. The only difference is the use of term "effort preference" to denote that the fatigue in non-PEM state is the product of pacing, not peripheral fatigue. That and not tackling PEM at all. They mentioned PEM 3 times: twice in the context of screening the subject, and once to surmise pacing is the cause of effort preference and short time to failure. But they did nothing to figure out the PEM mechanism.

The CSF-NE being proportional to effort preference and CFS-DA to time to failure were the only thing I could get something out of it. (Fig 6-e/f were stunning.) But the fact that HV did not show similar correlations seems to tell me that it is yet another symptom, not the cause or a part of the mechanism. The fact that nicotine, a powerful agent for dopamine and norepinephrine, not working to prevent PEM seems to point to the same thing. (I was hoping it would work since I've been responding to novel stimuli and positive stress).

But I do think this paper further dispels the notion that MECFS fatigue is the product of mitochondrial/metabolic dysfunction. MECFS patients are not incapable of generating energy/power when they are not in PEM state. It's only that they suffer nasty PEM that tanks their QOL and ability to function if they do.

 

In Scientific American: People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome May Have an “Exhausted” Immune System —

And yet there it is headlined in paper and abstract —

I don't know if those are Nath's words, but that wouldn't be my descriptors. I can't for a moment think that moderately to severely affected people would be capable of submitting to the study.

Spoiler: My understanding / rule of thumb classification

Mild = "mostly able to work, unlikely full-time, and with accomodations and recovery eating in to social activities to compensate"; moderate = "Essentially housebound" (which is my situation); severe = "completely or mostly bedbound"; extreme = "unable to tolerate touch, light, sound; gut failure etc" (eg Whitney, Maeve and Merryn).

 

Some other information on recruitment that I found in Supplementary Data 2.

There were 484 people that applied for the study. Of those, 137 were found to have other diagnosis during the initial screening. Not too sure while you'd apply for a ME/CFS study if you knew you had an autoimmune disease or cancer (likely in addition to their ME/CFS diagnosis) but they did. Of those 137, 78 were labeled as having "other diseases". I have no idea if that includes things like POTs or Fibromyalgia, would be nice if they had given more clarity on that.

Of the 484 that applied, 217 went on to a medical records screening. 37 of these 217 applicants then were found to have other diagnosis. These other diagnosis are pretty varied with inflammatory disorder, psychosis, head injury and endocrine disorders being the most common. Again, it looks like most of these people also had a diagnosis of ME/CFS.

Besides other diagnoses, the most common reasons for rejection in the application and medical review stages were greater duration of illness than 5 years and no documented infection.

Of the 27 that the NIH investigated in person, only 4 were found to have other diagnosis that I presume the participants had not previously know about. These four conditions the participants were found to have were cancer, atypical myositis, primary biliary cholangitis and parkinsonism. That means that about 15% of the participants that made it to this stage ultimately had other explanations for their ME/CFS.

My takeaway from this is that there are many people who have a diagnosis of ME/CFS in addition to other diseases. Also, although it was a small sample size by the time they came for the in-person investigation, it doesn't seem like many people had a new condition that wasn't ME.

The numbers also don't add up so I think there must be overlap in the reasons for why people were excluded (ie. I think they included certain people under multiple exclusion categories)

 

In peer review, AK also commented —

Response —

 

A snippet of interest for @Hutan

"Salivary cortisol measurements taken at rest in the morning, at noon, and before sleep showed no group differences but were significantly lower in PI-ME/CFS participants one hour after CPET"

 

Thanks for sharing. First off, this is not my experience at all. There is no lack of willingness to act or exert in my experience of ME. I very simply can't exert energy without getting worse. Wouldn't an experience of lack of willingness be indicative of depression or asked differently what would be different to depression then? If there is a lack of willingness and/or no payback for exertion, is that ME then? I guess the authors of this study conclude it is, and I disagree. Depression is of course a biological disease too, but, it is distinct in my experience.

 

Its not so much that my brain is somehow preventing me from pushing through. I can push through but I understand that comes at a cost. I generally don't push through just because the costs exceed the benefits. When I was a rower I pushed through all the time because the costs weren't very high and mostly immediate. Now I don't push through as the costs are higher and affect me for longer. I guess you could technically say that's an effort preference but in the same way I have a preference not to put my hand on the stove. The question is why is there a larger cost at all.

 

"Differential cardiorespiratory performance in PI-ME/CFS

Cardiopulmonary exercise testing (CPET) was performed on eight PI-ME/CFS and nine HVs (Supplementary Fig. S8A). During testing, all but one PI-ME/CFS participant reached the peak respiratory exchange ratio (RER) of ≥1.1 and there was no difference between the groups. Effort preference did not correlate with peak power in PI-ME/CFS participants (Supplementary Fig. S8B). The ratio of Ventilation/VCO2, oxygen saturation levels in the quadricep muscle as measured by Near Infrared Spectroscopy, and gross mechanical efficiency were not different between groups (Supplementary Fig. S8C–E). These results suggest that PI-ME/CFS participants performed to the best of their abilities.

Peak power (p = 0.08), peak respiratory rate, peak heart rate (p = 0.07), and peak VO2 (p = 0.004) were all lower in the PI-ME/CFS participants (Fig. 5a–d), a difference of approximately 3.3 metabolic equivalent of task units (METs). These peak measures did not correlate with effort preference in PI-ME/CFS."

Can anybody explain how this section fits, or not, with the whole "effort preference" concept. Peak RER was met, so patients exercised to their capacity, and other measures showed that, despite that, what was possible for patients was lower than controls. Surely, if "effort preference" was a thing, then either peak RER wouldn't have been met or peak RER would have been met but there wouldn't have been a difference on the other measures?

 

Is this the same research that is in the following Daily Mail article: Proof chronic fatigue syndrome IS real: Researchers probing poorly-understood illness find subtle differences in brains and immune systems of patients for the first time | Daily Mail Online

 

A barn door is usually a door twelve feet high and twenty feet wide. So a barn door case is a case about which there is no reasonable doubt.

I was just implying that although the CCC is a bit over-imaginative in what it asks for if only 17 people were picked out of 200 and everyone agreed one would expect those cases to be typical enough even to satisfy a slightly quirky CCC.

I am personally not convinced that diagnostic criteria are a major problem with studies. I never took much notice of them for RA. I studied people who obviously had the pathology I was interested in investigating at that time. If all these patients satisfied IOM criteria which needs PEM then I doubt the diagnostic selection process was a major problem. What I do think may be a major problem is that only pretty well people with minimal PEM could volunteer and much of the study is about looking for explanations for significant disability.

 

Nor is it what exertion intolerance is intended to mean, to my mind. The EI in SEID I have assumed implied something like 'food intolerance' in the sense of adverse reaction with PEM. Here they are just using it to mean having had enough. Again it suggests that the authors have no real idea of the concept of ME/CFS. (Which might also be relevant to their claim that the patients satisfied IOM.)

The UCL group found something consistent with this. However, we have seen enough studies to know that lymphocyte subsets in ME are generally fairly normal with maybe a slight shift of this sort and it is hard to give any precise interpretation in terms of mechanisms. Almost any shift in signals could give you a shift in populations either way, depending on trafficking shifts.

Indeed. And whether or not it is annoying it is bad science. The data should be about what was found, not a pre-interpretation of what pathways are implicated. And in discussion implications need spelling out carefully.

 

thanks, never heard that expression. The only barn door expression I can think of is "shutting the barn door after the horses have left."