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

Well, sure, I get that but I don't get the argument that because that happens there shouldn't be an attempt to formalize PEM with a diagnostic code.

 

Is the wording of the quotes absolutely accurate? Given the source, it's hard for me to parse this without knowing how accurately wording was captured.

Also, does Nath not remember that Walitt did this 2020 study which Nath's name is on?
Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
https://www.frontiersin.org/article...Rk9H8AmY65TIZS6mzzJZdc-XATnakNxsayiPF6JftCm8k

If PEM hasn't yet been accurately characterized, he should accept blame for that.

 

Sad state of affairs in 2023, that we are still here, trying on one hand to explain personal experience of PEM and on the other hand for the professionals to understand.

PEM is highly different from patient to patient, such as delay until crash, symptoms, intensity and duration, type, duration and intensity of trigger. And then to make it more complicated, the added influence and effect of stress on PEM, positively and negatively.

I look forward to reading the paper. Did they say when it would publish?

 

I asked my friend who attended the conference about what Dr. Kaplan was referring to when he said that only 40% of patients noted worsening after cardiovascular exercise. She said that "Kaplan said that in the Q&A summarizing what was reported in the Stussman / Walitt qualitative paper on PEM."

I don't believe the participants in the focus groups for the qualitative paper overlapped with the participants in the in-patient study at all, and they didnt go through the same selection process. The percentage is of course still surprisingly low.

 

I'm gonna wait for the study to come out. I appreciate people going to these things and giving us their accounts but this seems so muddled that it's really hard to tell what is what. I rarely get my hopes up for any specific paper so this won't be any different, can only be positively surprised if something good comes out of it. Not a slight on Nath btw.

 

Yes it is, but that's true of many (most?) symptoms of many (most?) diseases. People experience things differently for all sorts of reasons.

That doesn't mean it's difficult to characterise the symptoms. Very few diseases have a single defining symptom or sign, it's more that they form a pattern. PEM ought be easy to profile in this way—partly due to the common elements, partly the bizarreness of some of the symptoms, and partly the clear cause-and-effect relationship.

 

That's definitely not what the paper says though.

Seems like Dr. Kaplan misread the paper, to start with. In it, they report 21 patients reported PEM after a CPET or 18 in the abstract (not clear why these are different). But not all of the 43 patients had a CPET and it isn't clear how many did, so it's impossible to calculate a percentage here. I think 18 of 43 is the source of the 40%, but that's just a misreading.

Of course, reporting PEM after a particular CPET versus in general is quite different. They do report 30 of 43 patients reported PEM in their daily life, which is 70% and still very low, but very different from 40%.

But since these were focus groups, I would assume that people who experience PEM but didn't speak up in response to that particular question about specific PEM symptoms would not have been counted as experiencing PEM. So I think it's incorrect to even try to make any kind of claim about PEM prevalence from this study.

 

I looked at the two papers on PEM from Stussman et. al, and also found that the reported data doesn't line up with that quote.

In the results section of the qualitative paper based on the focus groups, the authors said, "Of 18 participants who responded to questions centered around symptoms following a cardiopulmonary exercise test, 17 reported that symptoms started within 24 h and peaked in severity within 72 h following the cardiopulmonary exercise test."

In the mixed methods paper based on 10 participants in the in-patient study, "every ME/CFS volunteer experienced PEM within the 72-hour study period with only one returning to their pre-CPET level by the final 72-hour timepoint."

I was curious about the second paper in particular because I share a lot of common concerns about the study (especially the lack of urgency and low number of patients included in the final paper), but feel that the selection process was rigorous.

Edit: I'm also not certain about why the chart says 21 people reported having had CPET PEM in the first paper but the text talks about 18, although my guess is that only 18 of the 21 answered the follow-up questions in the focus groups. But I agree that it doesn't seem clear how many of the 43 reported having had a CPET.

 

I think I know where the stats that Dr Kaplan mentioned likely come from.

In the second paper the authors say, "QI data analysis revealed four symptoms as most bothersome for ME/CFS volunteers: physical fatigue (40%), mental fatigue (20%), headache (30%), and muscle ache (10%)."

So for 4/10 patients their worst PEM symptom was physical fatigue and for 2/10 it was mental fatigue. The paper goes into detail on how the most bothersome symptom was determined ("team consensus after an analysis of the patient’s textual descriptions of symptoms") and also makes clear that patients have multiple symptoms at once and that the severity of each symptom varies over time after the CPET. The graphs of the Visual Analog Scale Data (Figure 5) show that every patient reported both mental and physical fatigue.

 

With respect to patients having to have an infectious onset as well there being a time-limit for illness duration, I'm going to break a lance for the researchers conducting the study. I can see why one could do this.

I haven't followed ME/CFS research half as long as most other people on this forum, but the most commonly and rightfully criticised problem in Long Covid research are the cohorts. In that case most researchers are either looking too close, at the soon to be resolving, acute phase (or are just studying the acute phase without even realising a difference), are only looking at hospitalized patients (sometimes even studying PICS unintentionally), are recruiting patients that simply have a cough or something similar, that is most likely to be self-resolvent, are mixing too different phenotypes together or are possibly studying some phenomena not directly related to Long Covid to begin with. The main point of criticism is usually that these researchers are quite far from studying Long Covid and are much closer to studying some noise or some other random pertubations of being healthy, being arbitrarily ill (see the whole cortisol discussion) or having an acute illness.

Any illness duration limit in the intramural study will always be arbitrary and can't be justified at a case-by-case basis (as seen in the examples above), but I can see why one could want such a limit. Simply to rule out some possible bodily functions that naturally alter after someone has been housebound to 10+ years (since bed-bound patients are anyways excluded from the Intramural study, something that could also be criticised). The problem of being "too close" to illness onset probably doesn't exist in the Intramural study, as the diagnostic marathon in itself would usually take at least a year. In either case a longitudinal follow-up seems necessary or at least warranted.

I can also understand how an infectious onset is similar in that regard. It could reduce some noise if someone was perfectly healthy (and is documented as such) and develops ME/CFS overnight, rather than having had a slow or non-apparent onset (apart from that it of course aligns with their hypothesis).

Neither of these things mean that those that don't meet these criteria don't have the same disease, but simply from reducing some noise or background phenomena I can understand it. It also doesn't mean that the deconditioning reasoning makes any sense to begin with. Some BPS researchers pretend to be believe that Long Covid patients would be able to fully decondition overnight, whilst their BPS colleagues argue that the cause for being sick over a long duration is a slow deconditioning, of course naturally these arguments always completely fail when scrutinised.

I also have no idea why you'd only end up with 17 patients, what Walitt's role in this process was and why you can apply the CCC without allegedly understanding PEM or having to recruit patients with PEM (when allegedly fatigue might be sufficient to be part of the trial). I was inititally hoping that if there were to be findings that these would at least be somewhat robust (and of course given the small sample size would always require replication in other cohorts), but I don't think that having an infectious onset or a given illness duration have anything to do with the above problems.

I'm not sure how much I can read into some things that might get lost in translation in Twitter threads, but my hopes for the intramural study are anyways relatively low (and I haven't seen completely groundbreaking results on this front in LC research either, which would have been the natural next step to expand ones work, especially since members of the intramural group have done studies on LC). At least some of the new and younger researchers like Iwasaki, Peluso and Henrichs seem to be somewhat more willing to share their data and publish preprints.

 

I’ll wait for the paper, but this sounds disappointing:

"Our conclusion--we think the infection leads to a persistent antigen--though we have no evidence of the antigen-we don't know what antigen to look for, so we never detected one. But we think all our findings suggest this."

But Nath did say earlier that they think they have a druggable target to justify running clinical trials, not sure what gives.

 

Gee, with only 17 patients, and all those years, I'd have thought they could look for pretty much any pathogen. Detecting them, that's different. But saying "we don't know what antigen to look for, so we never detected one" suggests to me that somehow not detecting pathogens was in part tied into their not knowing which ones to look for, as opposed to the diagnostics?? I may be trying to infer too much. Are they implying they have evidence of "a" persistent antigen, but not enough to establish which one(s)?

These snippets are intriguing but too little to go on. Some are encouraging, some foreboding. Some seemingly contradictory.

I am eager for - and simultaneously dreading - the study in Nature Communications. I think @Milo had asked when it's coming out? Does anyone know the publication date?

 

The study did extensive pathogen screening, including in spinal fluid.

But an antigen can be any piece of a pathogen or even a non-pathogen.

 

Bloodwork and CSF, correct? Pretty good for acute infections. Even then, though, the metrics or diagnostics may be problematic depending on the infection. As for persistent infections, those lasting months or years, I'm not sure how strong we are at identifying them; that hasn't been our medical culture's focus as far as I can tell. Any tissue testing?

The key for me was the qualifier "persistent." Remnants or debris will likely have a half life.

But I have no interest in rehashing the study protocol. Any idea when the Nature Communications article will be published?

 

If my memory is correct some had muscle biopsies.

 

That's the part I don't understand. If Nath is saying he thinks it is persistent antigen, but not active infection, then it pretty much has to be autoimmune, because otherwise it makes no sense for people to stay ill for decades. I guess you can imagine some kind of repeated infection or maybe even something environmental that is totally pervasive, but those both seem farfetched — some kind of viral reservoir seems more likely than those options.

 

Indeed! Antigens are expressed during latency for a lot of viruses, seems more common than the average GP would like to admit.

 

The paper will be published in Nature Communications Feb. 21. It's getting some attention from reporters thanks to some work from @Dakota15.

 

From @B_V

(Mastodon)

“I've read a draft. It reconfirms previous findings, pushes back on pervasive medical misinformation & reports a few things that, to my eye, look new. But I don't think there's anything really earth-shattering in there. The researchers have come up with an overarching hypothesis for the illness, but they're doing so based on 17 patients...so that's a little dicey.

Now NIH has to follow through with clinical trials. The paper has some ideas for drugs to try. They need to do so.”