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

In other words, from the outside world this looks like a non event. I think the coverage actually reflects that, in that it is all 'today's little news item' not some big splash with a specific message.

 

The press coverage has been as dazed and confused as the paper itself which also has no clear message. Normally studies of such low quality would get no press coverage and would struggle to get published in a legitimate journal but thanks to the prestigious institutional affiliation of the authors we’re forced to deal with it. I really hope we’re discussing something else next week as this is rather depressing.

 

Not defending PACE but what do you mean by cheating? Do you mean the lowering of the recovery threshold?

 

I’m guessing that Jo is referring to the decision to drop actigraphy, which the minutes suggest was because a Dutch study had found that it wasn’t useful
(ie it wouldn’t give them the positive result they wanted).

See @Lucibee’s blog “Whatever happened to actigraphy?”
https://lucibee.wordpress.com/2018/05/09/pace-trial-whatever-happened-to-actigraphy/

 

Good strategy!

 

This seemed bizarre to me so I decided to do some digging. They don't include any of the tilt table data in the Supplementary Data and except in file #22 where they list it as a negative finding.

However in a short section on page 49 of the supplementary data they add

They list this paper https://pubmed.ncbi.nlm.nih.gov/21431947/ to define the terms they are using. However, that paper lists orthostatic tachycardia as a BP decreases of ≥ 20 mmHg, but above, the number of patients experiencing orthostatic BP decreases of ≥ 20 mmHg does not match those that have "excessive orthostatic tachycardia". I am not sure what definition they are using for "excessive orthostatic tachycardia" because it seems like it can't be orthostatic BP decreases of ≥ 20 mmHg. They don't mention POTS at all so could "excessive orthostatic tachycardia" be what that is referring to?

It seems perplexing that more than 40% of the controls had symptoms of orthostatic tachycardia by 40 minuets on a tilt table test. This seems entirely inappropriate for a ME/CFS study, if that's actually the case. Roughly 38% of ME/CFS patients had excessive orthostatic tachycardia after 10 minutes on the tilt table test. This is about what I would expect based of the existing literature if this is referring to POTS. Hard to tell without the data, but I find it hard to believe that this would not have achieved statistical significance if such a high proportion of controls did not have orthostatic symptoms. I honestly can't believe that they didn't provide the tilt table test data when they allowed so many healthy controls to have orthostatic symptoms.

The norepinephrine and epinephrine graphs during the tilt table test on page 7 seem interesting but they do not mention this at all in the paper as far as I can tell. Also from this graph I can count at least 5 tilt table tests that were ended early, but I cant find the actually number anywhere.

Finally they add this statement "indicate(s) that not all descriptions of dizziness can be related to dysautonomia" when talking about qualitative experiences of dysautonomia. Seems like a strange thing to claim right after showing that a significant number of patients AND heathy controls had orthostatic symptoms.

 

In my experience, it depends on the personal bias of the rheumatologist. Some will call this UCTD, others will call it "get out of my office and don't come back". I saw a few rheumatologists when I was a young woman with fatigue, sore joints, ulcerations, hair loss etc. and very high ANA titres. Some jumped straight to prednisone and other toxic drugs, arguing that it was pre-lupus/incomplete lupus. Others said it's nothing. There's a huge range of opinions out there and it's quite unsettling to be a patient in this situation. But we're still left with the problem that a quarter of Walitt's thoroughly screened cohort met criteria for UCTD. It's a shaky diagnosis but their fatigue, PEM and crashing may be qualitatively different than ANA-negative ME/CFS. For this reason, I don't volunteer to take part in ME/CFS studies as I don't want to contaminate their study cohorts.

 

Interesting, I assumed that a healthy person couldn't have such an increase in heart rate. It is also possible that these aren't false positives but instead these people really do have orthostatic problems that they aren't particularly aware of or have less severe symptoms. Either way, it seems like if an control had a positive tilt table test they should have been excluded from the study on the basis they may have a medical problem common in ME/CFS. The fact that some of the control group couldn't even complete the tilt table test does seem like an issue.

 

I haven’t been following the discussion comment by comment, so I likely will have missed answers to some of the things I will now be asking, but I was wandering about the following things (I’ve gone through all of the supplementary material but not all of the source data):

• They recorded actigraph data during the trial. I believe this data is what is being recorded in supplementary material 12 (which however is in conflict with what is reported in the paper "This was supported by at-home waist actigraphy measures, demonstrating a lower step count and total activity for PI-ME/CFS participants due to less moderate intensity activity (40.64 ± 37.4 versus 6.4 ± 7.0 min/day; p = 0.007).". Why isn’t the full cohort wearing an actigraph or at least measuring wrist activity (in supplementary data 23 it says that no actigraph data was excluded meaning there were no problems in recording this data)? 2 days post CPET it’s less than half of the cohort and even less females, at only 3 HC’s and ME/CFS patients. What is this data in supplementary material 12 in comparison to the actigraph data they talk about in the study (for which seemingly no data is being provided)?
• This poses an additional question: It appears that the ME/CFS patients, at least those for which there is data, are in fact more active than the controls (going by the Hip-activity and Wrist-activity since energy expenditure in kcal likely means nothing) and only slightly less active when it comes to the duration of their activities (microwave-activity). How can that be, especially after a CPET and strenuous testing? Are the controls all extremely sedentary, is this data from a special subgroup of people, is the data not accurate or meaningful or are there people with ME/CFS not limited in their abilities, or does the post-CPET data include data on things that ME/CFS patients still had to do additionally during the trial? This data makes it seem like the ME/CFS people do more activity in a shorter period of time, which would be the opposite of pacing (unless there are long periods of PEM where they do nothing, but there’s little evidence to suggest that would be the case for this cohort). Going by this data it would seem that patients with ME/CFS would have a higher "effort preference" contradicting everything else.

• Concerning the above discussion. Why didn’t they just send the actigraphs weeks in advance to the peoples addresses to wear them before the trial, to have some data before the people would have to engage in a lot of activities? Seems like that would be far more meaningful than a 1 week measurement in one of the busiest weeks in their life (or is this data indeed different to the actigraph data)?

• In case it wasn’t mentioned. The “analysis/comment” I did earlier in this thread on the criteria used in this study based on Supplementary material 5, can essentially be found in supplementary material 2.

• They did an analysis of the muscles (some of this data is in supplementary data 19). If the WASF3 findings were to be relevant would we expect to see anything in this data for things that would be in some relationship to WASF3?

• There is no data on the autonomic testing in the Supplementary material and I only found in Supplementary material 22: Negative findings “Orthostatic Hypotension- Tilt table test”. Note: POTS is not reported as negative finding here (i.e. apart from the above mention there is no autonomic data in the supplementary material at all). Has anybody looked at the source data closely (is this is where all he autonomic testing data is hidden)?

EDITED via strikethrough: It appears that the data in supplementary material 12 is from the metabolic chamber, so it wouldn't be the actigraph data, so please ignore what I said. The actigraph data is reported in the section "Physical Performance Measures showed Differences between PI-ME/CFS and HV groups" in the Supplementary Information file. I still don't understand why not the full cohort wore the actigraph for an extended duration of time (rather than just a subset for one week). Since the actigraph data is essential in their "effort preference" debate, is the actual data provided anywhere (M/F ratios, BMIs etc)?

 

Yup. They're tremendously interested on initial assessment, and then they get the negative antibody panel and react like I've sullied their office. I got "This nice psychiatrist will help your recovery" (an immunologist), and then from rheumies: "Take paracetamol before your GET sessions", "EXERCISE! EXERCISE! EXERCISE!" and "Do more! Do more! You're deconditioned". Rheumies were, as a class, spectacularly unhelpful. One did try (and failed) to find a pain drug that would help. So that one got points for trying, that were ultimately cancelled out.

 

There's a known false-positive issue with the head-up tilt test, where people without a history of syncope will faint/test positive. It's a really demanding test that takes away people's ability to do all the things they may do naturally and possibly unwittingly that prevent them from fainting eg have their friend queue while they run around the supermarket for the thing they forgot, sit on the train. So you would expect a good few controls to have a positive test and plenty to have symptoms.

 

Btw (related to my post #568 above), I don't believe this has been posted here, but apparently Avindra Nath spoke (by video) on a Finnish BPS long covid symposium alongside Sharpe and Garner (source Twitter Nina Steinkops and ME-media, finnish ME media account - I haven't found a website yet)

 

I wouldn't be suprised if someone above the age of 50 and an increased BMI would have an increase of BPMs on a tilt-test and I wouldn't call that a false positive, but I haven't looked at the source data for this yet.

 

Are the raw data available?

 

Absolutely. I think we can't know what exactly is happening here. My interpretation of what's most likely to be happening is that Walitt, as first author, was in charge of the wording of the paper and wrote the objectionable (and poorly written) presentation of effort preference in it. I think this because it is consistent with how he expresses himself in interviews and with his published work on what he considers somatoform conditions. Then Nath has a different concept of what stops people with ME/CFS being able to continue exerting, and when he's in charge, ie when he's being interviewed, he's keen to clarify what he thinks they found and shape that message.

It's also possible that they're completely on the same page, and Nath is just better at strategy.

My point is just that when the public and medics who are never going to read the paper are hearing about this study on the radio or wherever, I want them to hear what Nath is saying, not what Walitt is writing and saying, regardless of whether Nath is being genuine, or just trying to not attract ire.

What's difficult is that most ME/CFS and long COVID patients won't read the paper, and so if Nath is being disingenuous, you could end up with people signing up for studies that they wouldn't sign up for if they knew.

It's the same old story as having to learn that just because someone reassures you that your symptoms are "real" and "biological" doesn't mean they don't think you have a psychosomatic condition.

 

If someone naturally has to do things to prevent themselves from fainting in everyday life, I would argue they should not be a control in a ME/CFS or POTS study. Perhaps it is a function of my youth, but I have met very few people in the general population (far less than the 40% here) who have significant orthostatic symptoms. I think we need some clarification on what criteria they are using for "excessive orthostatic tachycardia" but there is no way that 40% of the population has POTS.