Long-COVID and CFS/ME are not MCAS

[nerd]

The inducement for this post is the growing publicity of the theory that Long-COVID is just a simple disease in disguise, such as MCAS, and that there is a quick solution around the corner. For MCAS, a low histamine diet would be a simple fix to all the problems. This is the subtext of the message of Dr. Tina Peers. For an understanding of what her work is about, check the video below. And I'm afraid that many patients will fall for it, because they feel better, unknowing that their lack of pacing thereafter can eventually cause CFS/ME relapses.

First, let me describe my personal experience. I had MCAS before I developed CFS/ME, for many years actually. A low histamine diet helped. It was my lifestyle. At some point, the symptoms were so mild that I believed it was gone, so I relaxed the diet. But MCAS isn't a differential diagnosis of CFS/ME. It's just a ticking time bomb of the same pathophysiology. One viral reactivation or infection was all that was necessary to blow it off.

When you look at the vast explosion of case numbers in histamine intolerance and MCAS forums, it's doubtful that these are just underreported cases and risen awareness. For some reason, many virally-induced/immunological conditions have spiked over the recent years. This includes ADHD, autism, food intolerances, and CFS/ME. But most of these patients believe that their illness is primarily related to food, when it's not.

I have to be honest. I'm not aware of the whole MCAS literature. But I did a short literature research on my theory without any matching findings. And it's surprising. But I've already mentioned it in the context of CFS/ME in this forum. It's about histone deacetylation.

Here is the CFS/ME literature on the topic:

• Post-exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation, and Purine Metabolism Deregulation in ME/CFS Cases (10.3390/diagnostics9030070)
• Epigenetic Components of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Uncover Potential Transposable Element Activation (10.1016/j.clinthera.2019.02.012)
• Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop? (10.1007/s11011-019-0388-6)

Consistent findings have been made on viral infections (10.1007/s13148-010-0003-5).

Though I couldn't find a direct match for MCAS, I found one match for "Mast-Cell-Mediated Food Allergic Responses". This 2018 article doesn't mention MCAS directly. But from my understanding, this CFS/ME subpathology that they explore is clearly the root functional pathophysiology of MCAS.

Epigenetic Regulation via Altered Histone Acetylation Results in Suppression of Mast Cell Function and Mast Cell-Mediated Food Allergic Responses

Krajewski D, Kaczenski E, Rovatti J, Polukort S, Thompson C, Dollard C, Ser-Dolansky J, Schneider SS, Kinney SRM and Mathias CB (2018) Epigenetic Regulation via Altered Histone Acetylation Results in Suppression of Mast Cell Function and Mast Cell-Mediated Food Allergic Responses. Front. Immunol. 9:2414. doi: 10.3389/fimmu.2018.02414

Spoiler: Abstract

Mast cells are highly versatile cells that perform a variety of functions depending on the immune trigger, context of activation, and cytokine stimulus. Antigen-mediated mast cell responses are regulated by transcriptional processes that result in the induction of numerous genes contributing to mast cell function. Recently, we also showed that exposure to dietary agents with known epigenetic actions such as curcumin can suppress mast cell-mediated food allergy, suggesting that mast cell responses in vivo may be epigenetically regulated. To further assess the effects of epigenetic modifications on mast cell function, we examined the behavior of bone marrow-derived mast cells (BMMCs) in response to trichostatin A (TSA) treatment, a well-studied histone deacetylase inhibitor. IgE-mediated BMMC activation resulted in enhanced expression and secretion of IL-4, IL-6, TNF-α, and IL-13. In contrast, pretreatment with TSA resulted in altered cytokine secretion. This was accompanied by decreased expression of FcεRI and mast cell degranulation. Interestingly, exposure to non-IgE stimuli such as IL-33, was also affected by TSA treatment. Furthermore, continuous TSA exposure contributed to mast cell apoptosis and a decrease in survival. Further examination revealed an increase in I-κBα and a decrease in phospho-relA levels in TSA-treated BMMCs, suggesting that TSA alters transcriptional processes, resulting in enhancement of I-κBα transcription and decreased NF-κB activation. Lastly, treatment of wild-type mice with TSA in a model of ovalbumin-induced food allergy resulted in a significant attenuation in the development of food allergy symptoms including decreases in allergic diarrhea and mast cell activation. These data therefore suggest that the epigenetic regulation of mast cell activation during immune responses may occur via altered histone acetylation, and that exposure to dietary substances may induce epigenetic modifications that modulate mast cell function.

I will discuss treatment options in another post.

 

[nerd]

Here is the post on the (not-)treatment option:

Histone Deacetylase (HDAC) Inhibitors and the Ketogenic Diet

Other than clearing out these latent and dysfunctional cell reservoirs, there is only Ketotifen that has the potential to inhibit mast cell activation systemically. This just inhibits one functional subpathology of CFS/ME though.

 

[MCASMike]

"Growing publicity?" I don't know anyone who has heard of MCAS, let alone the possible relation of MCAS to something else, other than the people I have talked to about MCAS. I have done a pretty good job of dealing with most of my MCAS symptoms since late October, 2020 (I have to wait on the DEXA scan until next year to see where my osteoporosis is at), and I have only used Ketotifen in the eye drop form. Over the last few weeks, I've found that wearing a mask all day and sleeping under a sheet has helped some other symptoms (most likely due to raising the humidity level), and nicotinic acid has really helped with some other lingering symptoms. Could you state your hypothesis more concisely, because I can't say I know what it is? Thanks.

 

[Wishful]

I expect there are a lot of PWME who don't have a histamine problem, and who didn't have one before developing ME. I agree that it's just one possible trigger for ME.

As MCASMike said, I never heard of MCAS before reading about it here in this forum.

 

[nerd]

"Growing publicity?" I don't know anyone who has heard of MCAS, let alone the possible relation of MCAS to something else, other than the people I have talked to about MCAS. I have done a pretty good job of dealing with most of my MCAS symptoms since late October, 2020 (I have to wait on the DEXA scan until next year to see where my osteoporosis is at), and I have only used Ketotifen in the eye drop form. Over the last few weeks, I've found that wearing a mask all day and sleeping under a sheet has helped some other symptoms (most likely due to raising the humidity level), and nicotinic acid has really helped with some other lingering symptoms. Could you state your hypothesis more concisely, because I can't say I know what it is? Thanks.

You are right. I overstated this. Because it's more like an abstract movement. The movement to classify long haulers the same way CFS/ME patients were labeled for years.

"It's just a vitamin deficiency. Take this vitamin."
"It's just pain. Take this pain killer."
"It's just a viral infection. It will go away."
"It's just a food intolerance. Just leave it out from your diet."
"You're just exhausted. Try to get some fresh air and do some sports."
"Don't worry. You'll be fine. Just take this. It's all you need. You'll see."

 

[MCASMike]

Okay, that seems like a likely development.

 

[Judee]

Just take this. It's all you need. You'll see.

With the "just take this" usually being an antidepressant that the drug industry seems to want everyone to be taking.

 

[hapl808]

And enough people will get used to their newfound level of (dis)ability with Long Covid. Symptom management and CBT will again rule the day. The 'stubborn' cases will be told gently to see a psychiatrist or take some antidepressants because they seem 'upset' about their situation. Eventually people will move on to a cooler disease when funding disappears. (Obviously hard to be super optimistic when you've followed the CFS world for decades and the main improvement is the existence of online searches so we can attempt to treat ourselves.)

 

[nerd]

Could you state your hypothesis more concisely, because I can't say I know what it is?

I think it's best described in the paper on a potential endotoxin tolerance pathogenesis (10.1007/s11011-019-0388-6). This paper is really worth reading for people who want a thorough understanding of the disease. Their theory would be consistent with chronic exposure to black mold and GI toxins as causality.

A short summary of the relevant pieces on histone deacetylase (HDAC): The HDACs are all mediated by SIRT1, SIRT3, and SIRT6 upregulation. This way, the whole metabolism ends up hypo-inflammatory. So normally, there wouldn't be any mast cell activity because the mast cells are inhibited by SIRT1-AMPK. But AMPK is dysregulated by activated GSK-3 and PI3K/Akt signaling. This makes the mast cells susceptible again. As Krajewski et al. elaborate, the following triggers can cause an abrupt activation then.

As cells that can be rapidly activated during immune responses, they respond to diverse stimuli including alarmins such as IL-33, pathogen components such as TLR ligands, and antigen engagement via antibodies such as IgE and IgG.

Under this circumstance, you'd be extremely susceptible to any food with the slightest allergic potential, e.g. any mixed genes from mild pollen allergies, causing untypical localized cross-allergic reactions in the GIT. "Untypical" because the whole body is still hypo-inflammatory, presumably.

As far as I can tell at the moment, the same pathogenesis could be mediated by viral proteins as well. Many pathogens utilize the TLR4-MyD88-NF-kB pathway and the innate immune system adapts to it, e.g. as triggered by the COVID-19 vaccines (the S-protein vaccine excluded), to a certain amount. But chronic exposure to any pathogen that interacts with the innate immune system and its cell cycle responses can disrupt the homeostasis permanently unless appropriate therapy finds a suitable way for pushing it back.

Latent EBV, for example, uses the PI3K/Akt/TSC2/mTOR/Ras signaling, which is responsible for the GSK3 activation mentioned before. In fact, most herpes viruses use this pathway to inhibit apoptosis.

It's utmost unlikely to find a medication that only interacts with a single mechanism that can do this job. In fact, it might only cause severe adverse effects. We either need a multi-purpose drug or multiple drugs that correct the most important contributors of the disease at the same time.

However, it's important to consider that mast cell activation should be avoided under normal CFS/ME circumstances because it only contributes to the existing pathology. Strong HDAC inhibitory medications might be too strong without antiviral or antibacterial co-medication, as mentioned in the treatment post. But Krajewski et al. also suggest curcumin as a milder HDAC inhibitor to suppress food allergies and intolerances. Quercetin is another option with wide HDAC inhibitory potential.

 

[Wishful]

Under this circumstance, you'd be extremely susceptible to any food with the slightest allergic potential, e.g. any mixed genes from mild pollen allergies, causing untypical localized cross-allergic reactions in the GIT.

I do have two type I allergies; one developed a couple of years before my ME, and one a couple of years ago. Aside from those, I haven't noticed any problems with that part of my immune systems. If I do get exposed to these allergens, I get a normal type I reaction, but it doesn't affect my ME symptoms noticeably.

Some PWME might suffer additional ME symptoms or severity due to mast cell problems, but I think that would be just a subset of ME. I think it's likely that if you could treat the problem that makes mast cell activation worsen ME symptoms, the patient would still have ME symptoms; they'd just avoid extra severity or triggering.

 

[nerd]

I do have two type I allergies; one developed a couple of years before my ME, and one a couple of years ago.

The allergy diagnosis is oriented at a threshold of allergen-specific IgE. This is translatable for someone with normal mast cell function. This is translatable for CFS/ME patients without MCAS and whose mast cells aren't susceptible for the moment. But once they are susceptible, any minor trigger would be sufficient. When you look at your allergy test, lower all threshold by a factor of x, and the positive ones would be the additional allergens for susceptible mast cells.

I get a normal type I reaction, but it doesn't affect my ME symptoms noticeably.

This is not to be expected. The mast cell pathology would be localized. It would be an "untypical" allergic manifestation due to the SIRT1 activation. This involves GI issues predominantly, such as IBS. And GI issues have a great influence on endotoxin intake, the microbiome, bacterial overgrowth, leaky gut, etc.

Some PWME might suffer additional ME symptoms or severity due to mast cell problems, but I think that would be just a subset of ME.

Indeed. Not all patients might exhibit sufficient GSK3 activity to make any noticeable difference. The histone deacetylation still happens then, but without MCAS.

 

[frozenborderline]

I have made posts about how I don't think "MCAS" is the answer, but along different lines than you. MCAS as a disorder sort of suggests a specific type of cell behaving abberantly in response to environmental triggers. I think tis more likely that mast cell activation is a normal part of a broader innate immune system hyperreaction to various toxins. I have no doubt that "MCAS" is a meaningful comorbidity to ME/CFS, but the classic understanding of mast cell disease certainly doesnt explain every symptom of me/cfs, although I have to admit i think environmental toxins and sensitivities are pretty primary (BUT NOT ALWAYS MEDIATED BY MAST CELLS).

 

[lenora]

I probably suffer from Mast Cell problems (used to be called plain old allergies). I noticed a number of years back that putting out Xmas decs lead to a winter full of suffering...and this was inside a very clean home, with even the air conditioning vents cleaned out. I just think certain things are with us all of the time and, as we get older, they attack our systems more and more.

I'm now taking quercetin with bromelain once again. I also take boswellia....the latter two are from the pineapple and are good for inflammation as it quercentin itself. Since I now have rather severe allergies year-round something had to be done. I hope this combo will work. Don't take if you're allergic to pineapple.

I think it's almost impossible to eradicate things like mold and fungus in the environment around us. At least I haven't had much luck.... a new home is even worse because then we confront the problem of gasses being sent off by flooring, paint, carpet....the usual. So that's my latest trial, and If something works, stick with it. Talk to your Dr. and make certain it's safe (good luck, as not a lot know about the interactions between vitamins, supplements and drugs). You may have better luck with your pharmacist. A visit with a list of all things you take would be helpful. I've received plenty of good advice from them over the years. (Always speak to a pharmacist not a pharmacy team member), Lenora.