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

[Midnattsol]

The study has been picked up by Norwegian media, and focus is of course on ME being a "disease" where patients believe they can't do what they are actually capable of.. I must admit I've skipped the part where Vegard Wyller (strong proponent of the "chronic stress activation" hypothesis) was interviewed. Glad the article ended with a Karl Tronstad (biomedical scientist) who talked about the limitations of the study.

ME can be caused by an imbalance in the brain

 

[Midnattsol]

To zoom out conceptually, you could even question if the rash of quantitative metabolomic deepdives recently might partially explain the lack of progress. It's easy to imagine that 40 subjects * 1500 datapoints MUST be useful because its such rich data. But ... what if it isn't?! Perhaps it is still just dominated by noise?

Just thinking out loud. I love to look at big data and I remain hopeful. But I'm open to the idea metabolomics needs to improve to actually reveal the mechanisms of disease.

We need more basic science on the metabolome to know what is normal. It's so frustrating it's not being done!

A dataset I worked with had multiple blood samples drawn 2-4-10 weeks apart for 20 weeks (+ some additional bloodwork in a 20 week follow-up period), but most studies only have a snapshot like you said. The number of datapoints in "my" dataset enabled us to make a timeline and find metabolites that reacted similarly over time and our hypothesis were/is that those metabolites were the most likely to be changed by the intervention in the study. But over such a a long time period, stretching through multiple seasons, there would be variations in the environment and behavioral patterns (more sun exposure and activity in hot, warm weather for example, and maybe more sleep in winter) that could also be behind at least some of the changes we saw. This was a diet intervention, and it took ~10 weeks for the metabolome to stabilize after a change in diet, if a metabolomic study today "control for" diet they at most ask participants to eat a standardised diet for three days, if that.

 

[Karen Kirke]

Van Campen et al. (2020) found that most people in the 0-29 range of SF36PF scores had severe ME/CFS according to International Consensus Criteria. Most in the 30-59 range had moderate ME/CFS, and most in the 60-100 range had mild ME/CFS. (See table 3 in this paper: https://pubmed.ncbi.nlm.nih.gov/32823979/)

Using van Campen's ranges, in the Walitt 2024 study, 10 patients were in the severe category, 4 were in the moderate category, and 3 were in the mild category.

I mentioned these van Campen severity ranges in an email to Dr Walitt - I wonder if this influenced this part of the Q&A the NIH subsequently posted https://www.nih.gov/mecfs/nih-intramural-mecfs-study-qa

Why did you not include more severe or chronically ill ME/CFS patients?

• The researchers wanted to make sure that their observations would not be confounded by comorbidities and by deconditioning which are most often present in individuals with prolonged illness. Although they did not include bedridden patients, most of the participants would be classified as severe as described in this paper (van Campen et al., 2020). [My bold. There are 3 more bullet points, see link above for more.]

I see the availability of data and willingness of the authors to email with patients as a positive feature of this study.

 

[Kalliope]

Scientific American's podcast Science, Quickly 's latest episode was about the study. Interview with Vastag and Nath. One of the interviewers has known Vastag from before he got sick.

"Large Study of ME/CFS Patients Reveals Measurable Physical Changes"

https://www.scientificamerican.com/...patients-reveals-measurable-physical-changes/

There's a transcript.

 

[Hoopoe]

This was a diet intervention, and it took ~10 weeks for the metabolome to stabilize after a change in diet

Interesting because it took me 2-3 months to recover from previous Christmas and I suspect it was all the unhealthy food.

 

[SNT Gatchaman]

Commentary in JAMA: NIH Study Provides Long-Awaited Insight Into Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Generally OK, but points off at the start for the artistic form of "woman-reclining-with-hand-on-forehead". Good that they interviewed Nath not Walitt.

In the eyes of the medical community, myalgic encephalomyelitis/chronic fatigue syndrome, or ME/CFS, has had a legitimacy deficit for decades.

“Overall, what we show is that ME/CFS is unambiguously biological, with multiple organ systems affected,” Nath said in an interview with JAMA. “It’s a systemic disease, and the people living with it deserve to have their experiences taken seriously.”

According to Nath, the study has several instructive messages for clinicians seeing people who report symptoms consistent with ME/CFS. The first is that these patients should not be dismissed or told that their symptoms have a psychological basis.

He noted that even if the origin and pathophysiology for ME/CFS remain unclear, people with ME/CFS can be treated for their symptoms.

For patients, a point of frustration is the word fatigue, which is a temporary experience for most people but is chronic in ME/CFS. This often leads physicians, as well as friends and family, to discount the severity of the symptoms. Individuals’ complaints are often interpreted as having a psychological basis, the IOM report acknowledged.

“The word fatigue warped mainstream medicine’s understanding of ME/CFS for decades,” Liz Burlingame, leader of the Georgia chapter of ME Action, a patient advocacy group, said in an interview. “These are people who can’t function.”

Hector Bonilla, MD, director of Stanford’s ME/CFS clinic, who was not involved with the new study, said that more investigation should focus on central nervous system inflammation and microglial activation, as well as muscle physiology, in ME/CFS. The NIH study did not find significant differences in muscle composition, in contrast with other reports, but the authors did report sex-based differences in muscle gene expression, which could help guide future investigations.

“The most important message arising from this paper is that people with ME/CFS show significant objective changes across multiple systems,” Bonilla said. “It shows to nonbelievers that people with ME/CFS have a real problem—but we still have a lot to learn.”

Less good sections include —

The authors attributed ME-CFS participants’ fatigue “to dysfunction of integrative brain regions that drive the motor cortex,” such as the temporal-parietal junction. They noted that “psychiatric disorders were not a major feature in this cohort and did not account for the severity of their symptoms.” The group with ME/CFS also performed normally on neurocognitive tests, despite reporting greater cognitive symptoms.

As in this thread, that's not supportable on the data. Also neurocognitive tests are deficient if they can't correlate the symptoms that are so commonly reported (and easily observable to anyone interacting with a patient).

Depending on their symptoms, people with ME/CFS may need to see a neurologist, a psychiatrist, a cardiologist (for autonomic nervous system symptoms such as orthostatic hypotension), or a pain management specialist, [Nath] said.

Not clear why people would need to see a psychiatrist if you've just said it's not a psychiatric problem.

This also was an important point, but clumsy use of the word "severe" which might be read to suggest ME/CFS itself is not also a severe disease. "Other serious" would have worked well there.

[Nath] added that several of the participants with ME/CFS who passed initial review, and then were excluded after an in-person evaluation, were diagnosed with serious conditions. Examples of diagnoses leading to exclusion at this stage included cancer, myositis, and the autoimmune liver disease primary biliary cholangitis. The physicians these individuals previously consulted had not identified these problems. Nath concluded that even if people who display ME/CFS-like symptoms don’t have ME/CFS, they may have another condition for which medical attention would be beneficial.

 

[SNT Gatchaman]

(We can add "legitimacy deficit" to "effort preference" in terminology we would prefer not to be associated with this condition.)

 

[cfsandmore]

Not clear why people would need to see a psychiatrist if you've just said it's not a psychiatric problem.

Dr. Nath has faulty logic. He also seems to enjoy talking out of both sides of his mouth.

 

[Hutan]

Scientific American's podcast Science, Quickly 's latest episode was about the study. Interview with Vastag and Nath. One of the interviewers has known Vastag from before he got sick.

"Large Study of ME/CFS Patients Reveals Measurable Physical Changes"

https://www.scientificamerican.com/...patients-reveals-measurable-physical-changes/

There's a transcript.

A helpful, sympathetic interview, it's not long, the transcript doesn't take long to read. Here's a key bit of the transcript:

Fischman: Brian wasn’t too thrilled about the study results Nath was talking about before.

Vastag: The findings were pretty meager, I'm just so conflicted about how the study turned out.

Lewis: Yeah, I mean, he’s glad they did the study, but he didn’t really think it found a whole lot that was new.

He also took issue with the fMRI findings, which he thought was not an appropriate test and was only based on a handful of participants. Overall, though, the study may have been too small to draw strong conclusions.

That said, he did think the study helps validate that ME/CFS is a real illness, with real biological causes. And that’s important, given that many doctors still dismiss people with the disease, and we don’t really have that many treatments.

Fischman: Ok, that’s Brian. What about Avi? Does Avi think the study will help lead to potential treatments?

Lewis: Avi, really hopes this will lead to treatments. Even though the study didn’t find so-called “autoantibodies,” a sign that the body is attacking itself, like some studies have found. It did find signs of B and T cell wonkiness, if you will. And the treatments could depend on your sex. So, in women, you could try checkpoint inhibitors, which are used as a type of immunotherapy for cancer. And for men, perhaps you could try various T cell therapies,

Vastag: They need to do treatment trials, like, that needs to be the next step. Patients are desperate and patients need treatment. And we can't just wait to figure out the entire pathophysiology, like we need to start.

Lewis: So researchers are already testing some of these therapies.

Fischman: Well, I’m glad to hear they’re starting. But what about long Covid—could this research benefit people with that?

Lewis: Yeah, it might. There’s certainly a lot more interest in these conditions now, given how many people have long Covid.

Fischman: That’s really important because ME/CFS and long COVID both take a real toll. They ruin lives.

Vastag: I want people to know that this is a matter of life or death. You know, you try 100 different medicines, and nothing ever helps you. It's really hard to keep going.

 

[Medfeb]

Less good sections include —

Quoted from JAMA
The authors attributed ME-CFS participants’ fatigue “to dysfunction of integrative brain regions that drive the motor cortex,” such as the temporal-parietal junction. They noted that “psychiatric disorders were not a major feature in this cohort and did not account for the severity of their symptoms.” The group with ME/CFS also performed normally on neurocognitive tests, despite reporting greater cognitive symptoms.
​

As in this thread, that's not supportable on the data. Also neurocognitive tests are deficient if they can't correlate the symptoms that are so commonly reported (and easily observable to anyone interacting with a patient). [emphasis added]

I think this is an important point. Reviewer #4, (appears to be Tony Komaroff, see p 6), questioned how they could have found no cognitive issues when it's been so widely reported. And Gudrun Lange is a neuropsychiatrist with extensive experience evaluating pwME. She's recommended specific test methods (as discussed in this article) to identify the subtle differences and that these are often not use

Edited to clarify - I don't know if NIH used the methods Dr. Lange recommends

 

[Andy]

Trial By Error: Professor Chris Ponting on the NIH’s Findings and the Latest on the Genome-Wide Association Study Update

https://virology.ws/2024/03/17/tria...-on-the-genome-wide-association-study-update/

 

[Hutan]

Chris Ponting's response to the NIH study, as set out there in the discussion with David, is spot on.
The study is too small to produce useful results; and there are unwarranted interpretations of the meagre data that is there. It's a disappointment.
Chris hints that the mediocre nature of the study may in fact prompt the pendulum to swing in our favour.

 

[Jonathan Edwards]

Patients are desperate and patients need treatment. And we can't just wait to figure out the entire pathophysiology, like we need to start.

I understand where Brian Vastag is coming from but it isn't so much that we haven't figured out the entire pathophysiology. It is that we still have no data at all that you can base a reasonable justification of using powerful drugs on. Fluge and Bella were right to follow what seemed like a serendipitous lead. But using checkpoint inhibitors on the basis of a few slight shifts in cell patterns in a tiny group of people isn't enough.

The physician has to ask the question. Would I give this drug to my sister? Or my neighbour over the road? I actually did that (the second) and although it was worth it, the story was long and complex. Immunotherapeutic drugs that have the power to make big differences tend also have the power to do great harm. And if nobody really has a cogent theory they might do harm not just from side effects but by turning out to be the opposite of what is needed and making the ME five times worse.

 

[dave30th]

Chris hints that the mediocre nature of the study may in fact prompt the pendulum to swing in our favour.

Yes, he was looking for a way not to view it as a complete loss, I think.

 

[SNT Gatchaman]

Vastag: The findings were pretty meager, I'm just so conflicted about how the study turned out.

[ChrisP] looking for a way not to view it as a complete loss

The WASF3 paper that resulted circuitously seems to be the best part of this research work, albeit orthogonal, and needing larger replication. Along with that paper, Brian's description in the WaPo of how it all transpired was one of the brighter aspects of last year - a joy to read.

Around the same time, in 2017, Hwang received another serendipitous correspondence. NIH researcher Brian Walitt had heard Hwang was studying energy production inside mitochondria.

Walitt was interested because he was orchestrating an intensive study on a small number of inpatients at NIH’s research hospital who were diagnosed with chronic fatigue syndrome, also known as myalgic encephalomyelitis or ME/CFS.

But was this Walitt himself interested in the mitochondria at that early stage or was this a group prompting? If it was then he can reclaim a bit of ground in my view. But in 2017 he seems to have had fixed and quite opposite views on "somatic and interoceptive disorders".

A final serendipity broadened Hwang’s research from a single patient to an entire population of sick people: He obtained muscle tissue from Walitt’s ME/CFS patients.

“There’s this difference between cancer and chronic fatigue syndrome,” a diagnosis her rheumatologist has finally added to her file, [Amanda Twinam] says. “Everybody believes you when you have cancer. You joke about having a ‘cancer card’ to get off from doing things. No one is handing out CFS cards. I can finally say, ‘It’s not psychological. I’m not a malingerer.’ We now have a scientific explanation.”

I still struggle to see how this paper could end up being framed the way it was, given the lead-in findings in Paul Hwang's paper. It's just weird to have had the above in August 2023 and then this paper six months later with little to connect the two and a reversion to lightly encoded FND/psychosomaticism. There's no reference to either WASF3 or Wang, Hwang et al. in this paper. See also @EndME's post up-thread.

 

[Kitty]

There's no reference to either WASF3 or Wang, Hwang et al. in this paper.

That struck me too—I was expecting to see it being put in context with the other findings. When it wasn't, I assumed it must be due to publishing conventions, or the work being done by separate labs/in separate studies, or some other technical reason.

Or perhaps Walitt thought it might undermine his argument, or Hwang didn't want his work associated with it?

 

[EndME]

That struck me too—I was expecting to see it being put in context with the other findings. When it wasn't, I assumed it must be due to publishing conventions, or the work being done by separate labs/in separate studies, or some other technical reason.

Or perhaps Walitt thought it might undermine his argument, or Hwang didn't want his work associated with it?

I think the most reasonable explanation might be your first explanation, i.e. that the intramural study predates the Hwang study by multiple months/years, even though it was published later. (The Hwang study was submitted in Feb. 2023, I have no idea when they had their first results, but it's possible that by that time the intramural study was basically already written apart from some authors possibly being in disagreement about certain spins they wanted to still put on the data).

The intramural study isn't too coherent. My guess is the whole thing was written before the WASF3 findings came to light and technically they could and maybe should have made a small amendment once they knew about the WASF3 results, but I guess that would have made the whole thing even less coherent and then all the different authors might have even come up with even stranger stories that aren't really supported by the data.

Now we're left with 2 papers where the one is story telling without any "abnormal measurement results" and the other has supposedly "abnormal measurement results" but without any connection or detailed information on anything at all.

 

[Braganca]

Errors, omissions, potential bias: Why some ME experts are calling for a retraction of the NIH intramural study

https://thesicktimes.org/2024/03/19...for-a-retraction-of-the-nih-intramural-study/

 

[Trish]

Errors, omissions, potential bias: Why some ME experts are calling for a retraction of the NIH intramural study

https://thesicktimes.org/2024/03/19...for-a-retraction-of-the-nih-intramural-study/

That's a very good well researched article with lots of familiar names quoted.

 

[Laurie P]

Here are two articles in the the Washington Post by Leana Wen about the NIH ME/CFS study. I'm posting them because the first one is about a patient in the study and the second one has some quotes from Nath. I didn't encounter a paywall for either article.

Opinion
Chronic fatigue patients are bravely offering their illnesses to science
By Leana S. Wen
March 19, 2024 at 7:30 a.m. EDT

https://www.washingtonpost.com/opinions/2024/03/19/chronic-fatigue-long-covid-nih-study/

Michelle tried several experimental treatments, which involved traveling from her home in Wyoming to Utah for weeks at a time. As hard as it was, she was told she had to get herself up and moving. One of her daughters put up a chalkboard where she wrote down everything she had to do that day, from brushing her teeth to putting on clothes to trying to walk at least 1,000 steps.

About a year and half after her illness started, she realized she could hear the birds outside her window. “I know that sounds so silly, but I had been so compromised I couldn’t even hear the birds sing,” she explained. She was able to start speaking with her family on the phone again. On some days, she could run basic errands such as going to the grocery store.

Participating in the NIH study was a daunting challenge. It required travel across the country and days of tests that carried significant risks. Specifically, there were numerous tests in which she had to exert herself to the point of exhaustion.

Researchers told her that, on any given task, she might stress her body in a way that could undo all her progress. “They would remind me each day that this could be the last exercise you’re able to do,” she said. They’d regularly ask her if she was sure she wanted to continue. They also explained that, unlike many clinical trials, this one didn’t offer treatment. Participation was not going to make her better.

Opinion
New landmark study offers hope to people with long covid
By Leana S. Wen
March 11, 2024 at 7:30 a.m. EDT

https://www.washingtonpost.com/opinions/2024/03/11/long-covid-treatment-research-hope/

The senior author of the study, Avindra Nath, told me in an interview that “we can pretty emphatically say that deconditioning and psychological factors cannot explain their symptoms.” This is huge for many ME/CFS sufferers who have been repeatedly dismissed by medical professionals and told there was nothing physically wrong with them.

Second, researchers found functional and not structural abnormalities. For instance, there were no masses or lesions in the brain, but there was a region called the temporoparietal junction that had lower activity compared with healthy controls. It’s possible that the decreased activity disrupts how the brain tells the body to exert effort, worsening fatigue.

This finding, too, is good news, because functional abnormalities are potentially treatable and might even be reversible. Indeed, there were a few participants in the study who spontaneously recovered.

Overall, the results support the hypothesis that ME/CFS is due to persistent immune activation. Normally, when someone comes down with an infection, their immune system works overtime to get rid of the foreign agent and then calms down when the infection is gone. But in ME/CFS patients, pieces of the virus or bacteria may linger in the body and continue to stimulate the immune system long after the infection should have resolved.

“These patients are very desperate, and we should give them hope,” Nath said. He wants to assure people with post-infectious syndromes that there are researchers dedicated to studying their illness and that everyone is extremely motivated. “The answers may take some time, but we will find them,” he said.