What research do you want to see? (study ideas)

I don't think putting anyone through a 2-day CPET to investigate diagnostic questionnaires is ethical. I'm beginning to doubt there's ever a strong enough case for it, to be honest.

 

I see that point.
But I think there’s a counterpoint in that society and medicine does not take PEM seriously at all, or even really believe it exists. And pwME are constantly forced into PEM through interacting with these two systems.

If we’re gonna have people in PEM we may aswell advance the research on it, in order for society to eventually take it seriously. Valudating/invalidating diagnostic criteria will have an enormous long term benefit until there is a reliable (non-CPET) biomarker.

Obviously though informed consent is an absolute **must**. And I like Trish’s version of the study too.

 

But CPET is neither validated nor a biomarker. That's part of the problem.

People giving detailed accounts of the symptoms they experience in PEM is as reliable as anything we have, and we don't need to expose them to the risks of CPET to provoke those symptoms.

 

I agree.

The question to me however is whether more 2-day CPET studies will really lead us to understanding anything about more pathology. Because several 2-day CPET studies have been published, thousands of patients have gone through the procedure and Workwell has data on several hundreds of patients (that for whatever reason they don't publish). So I sceptical whether there'll ever be an "aha moment" from these studies. Society/medicine doesn't take ME/CFS any more serious after those studies have been published. An argument can be made that one needs more "response to exertion" studies, for example the one by Rob Wüst.

 

I think Todd Davenport said they were planning on publishing them in the next year or two.

 

In which case it's clearly not a priority since they've been sitting on this data for years. I wonder whether they will match controls and patients, since he somehow had a problem with that and I wasn't able to understand his argument.

 

Yes I was similarly confused reading that exchange with Todd

 

RCT of Low Dose Apiprazole. Small cohort of severe people.

Follow patient made protocol. Titrate from 0.1mg - a couple mg as tolerated. Don’t increase activity levels for first 6 months.

Long trial, 1.5+ years, to measure “poop out” effect some describe.

Primary outcome measure = Fitbit activity data + FUNCAP

 

Wouldn't it make more sense for all 2-day CPET research to be done 48 hours apart instead of 24?

Correct me if I'm wrong, but most people's PEM lasts at least a few days. And while some will already be experiencing PEM after 24 hours, for many others, it's closer to 48. Doing the second test at 48 hours would ensure that most people's PEM is high without being so long that many are recovered.

 

I seem to remember that Dr Lynette Hodges from NZ was looking at repeat CPETs with different time intervals.

 

I would like to see this study on GDF15 replicated.
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-019-02153-6


Forum thread on the study here:
Circulating levels of GDF15 in patients with myalgic encephalomyelitis/chronic fatigue syndrome, 2019, Melvin, Lacerda, Nacul et al

 

A combined lower dose Aripiprazole and lower dose Naltrexone trial.

Gradual titration up but to patient tolerated maximum to allow for sensitivity especially in severe patients. Eg I only tolerate 1.7mg of ldn and 0.65mg of lda way below the prevailing wisdom. I think alot of people don't succeed because they are started on or forced up to too high a dose for their phenotype .

Also a big, focussed biomarker program that collates all the possible candidates from studies (I've seen so many studies mentioning things), triages them and takes the most viable ones through to validation into a diagnostic or diagnostic set to take to the NHS. This would sooo take the wind out from under the BPS argument's sails.

 

I'd like to see a study on energy expenditure in ME/CFS or long COVID vs healthy controls, larger than the NIH deep phenotyping study, possibly before and after exercise.

The differences weren't statistically significant, but it was a bit higher in ME/CFS, at least after the CPET. All days when normalized for body weight, and it seems there might be a trend of the difference increasing in the days following a CPET.

Could it be that people with ME/CFS are so tired because the body is burning as much fuel as possible on some internal body process, like fighting pathogens, and there's none left over for normal life?

I tried searching for other metabolic chamber or energy expenditure studies on ME/CFS or long COVID, or even any disorder involving chronic fatigue, but couldn't find anything relevant other than the NIH study, which only had 21 people on the first day and 17 on the following days.

Edit: Oh, I found one:
Increased Resting Energy Expenditure in the Chronic Fatigue Syndrome, Watson, 2011

 

This sounds like an interesting approach. Would it mean that rather than just PEM it’s possible to see if there are differences when someone is on the way down / it feels like a deterioration is ‘active’

I don’t know enough about what epigenetics can cover to imagine what it could pick up and how careful the method can be to this but I think the more longitudinal the better, and of course it needs to be within patients rather than just between in order to see pattern of what is going on.

it’s not like we aren’t forced over threshold all the time anyway in daily life so as useful as / an important approach to add rather than the focus on an arbitrary objective ‘amount’ to trigger a ‘reaction’ eg from cpet when I think most of us can feel there is also a cumulative element

 

For the proposed study by @Hutan above I would also find it sensible to have one group of ME/CFS patients that has reported a variable status of ill health, i.e. better periods followed by worse periods etc, vs one group of ME/CFS patients who has reported no change in health, i.e. a rather constant period of ill health. I think that could be helpful in understanding whether one is actually measuring what one thinks one is measuring.

I wonder if that isn't sort of a contradiction itself?

I think it may be very hard or even impossible to recruit healthy controls that reduce their activity levels to that of a severe or very severe person. I know Rob Wüst has done studies on bedbound healthy controls but that was for a couple of weeks, rather than several months.

I wonder if maybe there isn't even larger problem here, which makes means that controlling for activity between pwME/CFS and HCs in previous studies could have been skewed with the reason simply being we have no metric to control for such activity.

Some studies use average step count, but even when 2 people have the same average step count the one person might have paced whilst the other one wouldn't have which could impact muscle composition etc. For someone who struggles with OI, step count might not be an adequate metric in the first place, with hours of being upright being potentially more crucial and so on.

I wonder if it is sensible to first study, how should one control for activity in different ME/CFS study setups (arguably a microbiome study will have to control for different factors than a skeletal muscle study or a metobolimics study) to be able to set some minimally required standard in the field.