Preprint Hypothesis: Myalgic Encephalomyelitis (ME) as a Mast Cell Activation Disorder (MCAD), 2026, Carroll

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TiredMathematician

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Hypothesis: Myalgic Encephalomyelitis (ME) as a Mast Cell Activation Disorder (MCAD)

Harriet A. Carroll

Abstract
Background: Myalgic encephalomyelitis (ME) is a severely debilitating neuroimmune disease with the characteristic feature of post-exertional malaise (PEM). Whilst multiple studies have found various abnormalities, there is significant heterogeneity in findings; as such there is no consensus regarding the underlying aetiology.

Mast cells are immune cells most commonly recognised for their role in allergy. The scope of biological effects mast cells have is growing in recognition, with inappropriate mast cell degranulation increasingly recognised to cause a range of symptoms and downstream effects.

Hypothesis: ME may be a mast cell activation disorder variant, with exertion being the primary trigger to inappropriate mast cell degranulation, possibly due to mast cell hypersensitivity to metabolically produced reactive oxygen species.

Mast cell activation releases mitochondrial components which further act as an “autopathogen”, whilst each degranulation cycle reduces mast cell metabolic flexibility. This cycle is perpetuated in those with genetic susceptibility towards Th2-dominance, which acts to both impede pathogen clearance and drive autoinflammation. The resultant chronic immune activation triggers immune and host metabolic changes resembling sickness metabolism. This causes a range of multisystemic symptoms, worsened by exertion, akin to a chronic sickness behaviour.

Due to the close and bidirectional interactions between mast cells, the nervous system, and mitochondria, such a hypothesis can potentially explain various aspects of ME, such as: Why ME can be caused by a range of exposures; the core symptoms of ME; individual variances in clinical presentations; why pacing can prevent worsening; and time trends and symptoms of PEM. Several potential counterarguments are also discussed, along with methods to try and test the hypothesis.

Conclusion: Several lines of evidence suggest it is at least plausible that (a subgroup of) ME could be a unique and distinct variant of a mast cell activation disorder. As the immune system and metabolism are intrinsically linked, it could be argued this is an immunometabolic mast cell disorder phenotype.

However, this is one of many plausible hypotheses, requires testing and validation, and does not change the current recommendations for managing ME, nor should it be used as evidence that the aetiology of ME is established.

 
I recently watched a presentation by Dr. Stingl from Vienna, and it would be interesting to hear his opinion on this. As far as I know, he prescribes quite a few medications commonly used for MCAS, such as famotidine, desloratadine and ketotifen, and treats a very large number of patients. Some patients seem to report improvements, although, as always, we lack proper clinical studies to support this.

And yes, a patient subgroup is probably quite relevant here.
 
Sadly, there is nothing in the abstract that would not have been presented at some lecture 40 years ago. And none of it makes any real sense in terms of what we know clinically and biologically. I cannot see the point in writing a hypothesis paper if it is the same old stuff as before.

I note that Harriet sells appointments to patients, carers and health professionals wanting help with cases. It is not clear what expertise she is selling. It all looks very worrying to me.
 
Dude said:
As far as I know, he prescribes quite a few medications commonly used for MCAS, such as famotidine, desloratadine and ketotifen, and treats a very large number of patients. Some patients seem to report improvements, although, as always, we lack proper clinical studies to support this.
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So why would we want the opinion of someone who does that? Making money out of sick people without an evidence base.
 
Jonathan Edwards said:
So why would we want the opinion of someone who does that? Making money out of sick people without an evidence base.
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I understand the criticism, but if there is a chance of improvement, and given his clinical experience, he may be in a good position to assess that. In my opinion, there is nothing wrong with trying these medications, particularly since they are generally considered low-risk.

People are desperate for some relief and naturally tend to cling to any possible hope. Just because there are no controlled studies doesn't automatically mean these medications don't work.

Just my two cents. I also tried those medications, but unfortunately didn't notice any benefit. I should add, though, that I didn't have any MCAS symptoms either. I was basically just trying them on the off chance they might help.
 
Dude said:
I understand the criticism, but if there is a chance of improvement, and given his clinical experience, he may be in a good position to assess that.
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I used to believe in 'clinical experience' when I was a senior registrar let loose on patients in my 30s. I grew out of that. There is no such thing in this context.
Dude said:
there is nothing wrong with trying these medications, particularly since they are generally considered low-risk.
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Unless you consider conning people wrong, which I do.
Dude said:
People are desperate for some relief and naturally tend to cling to any possible hope.
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All the more reason not to con them if they are vulnerable.

Dude said:
Just because there are no controlled studies doesn't automatically mean these medications don't work.
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There is an a priori 98% chance that they don't.

Te longer patients go on supporting this sort of practice the longer it will be before we get any answers. The money could pay salaries for the researchers now desperate to get grants on ME/CFS - the 45 WE%ME applications they could not fund maybe.
 
Okay, i found at least one study:
14 Long COVID patients were treated with fexofenadine (H1 blocker) and famotidine (H2 blocker). All reported improvements in at least some symptoms, including fatigue, brain fog, gastrointestinal issues and increased heart rate. 29% experienced complete symptom resolution.

Unfortunately, the study was neither placebo-controlled nor blinded, but it's still an interesting finding.

Study on PubMed
 
I've tried them and they did nothing. Loads of other LC patients have tried them, and some got better and some didn't. It's as "interesting" as saying that Long Covid patients drank water and some got better.

Sorry for the blunt tone but I'm really over reading that things "might be worth trying" on the basis of no evidence!
 
Jonathan Edwards said:
Te longer patients go on supporting this sort of practice the longer it will be before we get any answers. The money could pay salaries for the researchers now desperate to get grants on ME/CFS - the 45 WE%ME applications they could not fund maybe.
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Yes, I completely agree. When you read in the support groups how much people spend on consultations and all these useless supplements and treatments they end up buying, that money would probably be much better invested in donations to ME/CFS research.
 
Famotidine with loratidine (H1 + H2 blocker) was trialed for long Covid in STIMULATE-ICP. It did not reach the benchmark for clinically meaningful improvement. They reported one tiny statistically significant outcome on their fatigue scale, which was less than 2 point improvement on a 50 point scale beyond control arm (where the average improvement across all groups was 4 points)

If even an open label design reports null results that’s pretty damning
 
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Dude said:
Okay, i found at least one study:
14 Long COVID patients were treated with fexofenadine (H1 blocker) and famotidine (H2 blocker). All reported improvements in at least some symptoms, including fatigue, brain fog, gastrointestinal issues and increased heart rate. 29% experienced complete symptom resolution.

Unfortunately, the study was neither placebo-controlled nor blinded, but it's still an interesting finding.

Study on PubMed
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I’ll also note that this study measured improvement just by asking if a list of symptoms were better/worse/unchanged compared to the beginning of the study, and the comparator group was people who refused any further treatment (presumably after trying a bunch of things and nothing working). So I think at most this study tells us that people who are hopeful about something working may report it working
 
Dude said:
Observational studies can be useful for identifying potential treatment leads that can then be investigated in controlled clinical trials.
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Yes, but in this case the lead was already there and looking pretty tired and unpromising. There was no justification for an observational study.

I wouldn't even have bothered with a trial but as jnmacicuh points out, the NIHR, in their great wisdom, did a trial that should have been properly blinded but even on an open basis failed to show useful benefit.
 
jnmaciuch said:
Famotidine with loratidine (H1 + H2 blocker) was trialed for long Covid in STIMULATE-ICP. It did not reach the benchmark for clinically meaningful improvement. They reported one tiny statistically significant outcome on their fatigue scale, which was less than 2 point improvement on a 50 point scale beyond control arm (where the average improvement across all groups was 4 points)

If even an open label design reports null results that’s pretty damning
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I'd also be cautious about generalising these findings to every patient subgroup. The trial investigated a broad Long COVID population rather than specifically targeting patients with suspected mast cell involvement or an MCAS-like phenotype.

I've come across the MCAS topic quite frequently on this forum, and my impression is that it is generally viewed rather sceptically. I'm not trying to defend these medications, but Dr Stingl doesn't strike me as someone trying to make money off desperate patients. He seems genuinely interested in helping them. That's why I'd be interested to hear about his clinical experience with these medications and the patients he has treated.

That said, I agree that a properly designed, placebo-controlled trial specifically targeting patients with an MCAS-like phenotype would be extremely valuable and probably necessary to answer this question more conclusively.
 
Dude said:
I'd also be cautious about generalising these findings to every patient subgroup. The trial investigated a broad Long COVID population rather than specifically targeting patients with suspected mast cell involvement or an MCAS-like phenotype.
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There is no reason to suspect anyone with Long Covid of 'mast cell involvement' or having an 'MCAS phenotype" which is whatever complaints the patient brings along to Dr Afrin. This is all folklore @Dude. It is not biology. We aren't particularly sceptical here in comparison to the rest of the biomedical clinical and research community who are totally sceptical of this stuff. It belongs to a sort of religious sect supported by the failing wallets of vulnerable people. We need to dig everyone out of this cloud-cuckoo land.
 
Dude said:
I'd also be cautious about generalising these findings to every patient subgroup. The trial investigated a broad Long COVID population rather than specifically targeting patients with suspected mast cell involvement or an MCAS-like phenotype
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Sure, failure to pick out a correct subgroup can be invoked any time there’s a null trial result. I’m not sure it’s a particularly novel insight that people with distinct allergy-like symptoms may have a problem that involves allergy-related pathways.

But you can’t really explain ME/CFS-specific (or non-allergic LC specific) symptoms by these mechanisms when we know that millions of people have horrible allergies and most don’t have ME/CFS. Even if we could be certain that someone’s ME/CFS all started with some histamine-driven problem, it would have to be something else on top of that which drives ME/CFS. And we already knew that ME/CFS can happen after a grab bag of different triggers.
 
Dude said:
I've come across the MCAS topic quite frequently on this forum, and my impression is that it is generally viewed rather sceptically
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Only because people say it with no evidence. If they have evidence show us.

It’s usually though instances like this, where someone is making money out of, as you say, people who are desperate. That is IMHO very very wrong.
Dude said:
Just because there are no controlled studies doesn't automatically mean these medications don't work.
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But we won’t know they work until there is a trial. And the people peddling these never seem to want to do that. They want to make money out of us, boost their own egos and pretend they are being kind rather than put in the hard work.

Dude said:
That said, I agree that a properly designed, placebo-controlled trial specifically targeting patients with an MCAS-like phenotype would be extremely valuable and probably necessary to answer this question more conclusively.
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Great! Until then maybe let’s not pretend it has any more value than any other theories that have been tried and failed to show results.

I am fully supportive of exploring ideas and theories. We need to encourage that. And sometimes it does feel as if things are shot down too quickly. Ideas need space to grow and be explored. And I understand ultimately someone is going to have to make some money out of making us well. That’s the way the world works.

But this is not a new theory. And it’s not being presented as just an idea to explore. So I don’t think this is the right way to go about it. Mixing hypothesis generation with a consultancy service targeted at patients (or one prescribing unproven medications) is sketchy.

From the author themselves. This after they’ve spent a while touting their PhD and credentials of course. The disclaimer is always the tell.
My service is not medical advice (I'm not a medical doctor), it is as best as possible an impartial take on the evidence so far, to help you make an informed decision
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My service is not medical advice (I'm not a medical doctor), it is as best as possible an impartial take on the evidence so far, to help you make an informed decision

I don't know if this is the sort of thing the advertising standards people get interested in but personally I think it should be illegal. The author appears to have no grasp of the evidence.
 
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