Note: Exceptionnellement, cette entrée sur mon blog est en anglais, puisque je voulais également recueillir l'avis de patients diagnostiqués EM/SFC de la communauté anglophone. Par contre, le contenu de cette théorie se retrouve également en français sur mon blog.
So, I recently saw this entry on Health Rising, and it got me thinking...
We already know that physical activity can act as a pseudo-allergen for people who, like me, are diagnosed with Mast Cell Activation Syndrome (MCAS), as well as those who suffer from other types of Mast Cell Activation Disorders (MCAD).
We also know that there is another health condition, still largely unexplained, called “Exercise Induced Anaphylaxis” (EIA), where someone doing physical activity will suddenly present the same symptoms as someone going through anaphylaxis, to the point where the reaction can be life threatening.
And we also know that not every allergic reaction (or pseudo-allergic reaction, as the case may be) involves anaphylaxis. Some of the milder symptoms may include vertigo, dizziness, nausea, gastrointestinal issues, itching, fatigue, brain fog, flushing, sweating, and so forth.
Before being diagnosed with MCAS (i.e. during the 7 years I’ve lived with a CFS/ME diagnosis), I used to describe my “post-exertional malaise” (PEM) as being the rough equivalent of feeling drunk or drugged. I had a lot of brain fog, dizziness, nausea, sometimes palpitations. At times, I could get a bit of paresthesia in the hands and feet; but basically, I just felt generally “unwell” and weakened.
Sometimes, the only immediate PEM I felt was a slight sense of general weakness and tiredness. Instead, it was the day after, and/or the day after that, that most of the symptoms would occur. But once they did, it could take me days, weeks, or even months to recover.
So, the reaction itself could be either immediate, delayed, or both. However, once the pseudo-allergic reaction to physical activity was triggered, it almost always took me a very long period to be able to recover from it.
Most of the time, it depended on my level of exposure to the pseudo-allergen. i.e. Physical activity in more intense doses (ex: going to a medical appointment) would typically take me a longer time to recover from than in smaller doses (ex: taking a bath at the end of a “better day”).
Therefore, this study is really making me wonder if the PEM that is found in patients with a CFS/ME diagnosis, MCAS, and perhaps even a certain number of other patients suffering from other types immunological disorders couldn’t be, in fact, a variant of EIA. At the very least, in a certain subgroup of these patients.
Whereas EIA might involve the more immediate and sometimes life-threatening symptoms of anaphylaxis, post-exertional malaise might involve a milder, pseudo-allergic reaction to physical exertion (of virtually any kind and/or intensity), accompanied by a delayed systemic immune reaction.
Because, while physical exercise has been shown to decrease systemic inflammation, fatigue, and increase physical endurance in patients with fibromyalgia, systemic lupus, Crohn’s disease, and so forth; there have been exceptions within those groups.
And those exceptions are often dismissed as suffering from anxiety, and/or having developed some type of phobia towards physical activity causing them to entertain catastrophic thoughts regarding the potential negative impact that said physical activity could have on their ability to properly function, the intensity of their pain, and all of their other symptoms.
We tend to believe that they just have a harder time tolerating certain levels of discomfort compared to other patients suffering from the same illnesses, and/of finding the motivation to put in the required efforts to fight the deconditioning they acquired during the more acute stages of their illness.
Sometimes, however, the burden of the overall disease is still recognized, and those patients are encouraged to implement certain techniques to avoid depleting their energy reserves within the day. Since one of the most popular models uses spoons as energy units to illustrate how pacing works, patients suffering from many chronic illnesses will often nickname themselves “spoonies”.
And when you read entries from blogs belonging to spoonies that are homebound or bedbound, what you may find are patients describing a reality that is very close to what is experienced by patients with a CFS/ME diagnosis.
Should they meet a doctor familiar with CFS/ME fatigue, they will tend to be given both diagnosis. Ex: a patient suffering from both CFS/ME as well as systemic lupus.
So, with time, it seems that the concept of what Myalgic Encephalomyelitis is has moved away from the epidemic infectious illness that was initially described following the Royal Free Hospital outbreak, to instead include all the cases where such a disabling fatigue, accompanied by an aberrant response to physical activity, has been found.
That type of CFS/ME fatigue, combined with PEM, is often believed to be what differentiates CFS/ME from all other chronic illnesses where chronic fatigue is involved. And I’ve seen people go as far as suggesting that the 2 days CPET (cardio-pulmonary exercise testing) protocol developed by Staci Stevens should be used to diagnose patients as having CFS/ME.
Except I did the 2 days CPET protocol back in 2012.
On the very first day of the test, I was already a little more exhausted than usual from all the traveling I did to get from the area of Montreal (Qc) to Ithaca (NY); so my anaerobic threshold was already abnormally low at 2.1 METS (which is about the effort required for washing hands, or leisurely typing on a computer).
Thus, we didn’t see a huge difference between day 1 and day 2 in terms of the anaerobic threshold itself (7.46 ml/kg/min vs 7.27 ml/kg/min).
Except, my VO2 Max values decreased from:
Day 1: 6.2 METS, to
Day 2: 5.7 METS.
Those results are highly typical of patients diagnosed with CFS/ME.
I did the same test again in 2014 in Ottawa (as part of a research project to see if the technicians of the hospital the test was being done in were sufficiently comfortable applying Steven’s protocol), and while there were a few issues with some of the data collected (they somehow failed to identify the anaerobic threshold on the very first day), the reviewing doctor still concluded that the results of:
Day 1, were compatible with mild to moderate deconditioning, and
Day 2, were compatible with a pulmonary vascular disease which is mild to moderate.
So, we could still see that “something” was going on there between day 1 and day 2.
And the interesting thing is that, no matter where the “mast cell degranulation threshold” in response to physical activity would be in a MCAS patient like myself (assuming that’s indeed what is happening), having the patient reach maximal effort would technically ensure that they would reach it, and mast cell degranulation in response to physical activity would inevitably occur.
Of course, this would likely happen only in patients for whom physical activity might be a trigger for mast cell degranulation. Some patients with MCAS - just like some patients with lupus, fibromyalgia, Crohn’s disease and so forth – can be slightly more tired than the general population, yet they seem to be able to tolerate physical activity, and/or even get some relief from their symptoms with a gentle exercise routine or program.
But I couldn’t. Physical activity above a certain level of intensity almost never failed to trigger PEM and worsen my symptoms, like all patients that are being diagnosed with CFS/ME.
And since January 2016, I’ve been receiving Xolair (Omalizumab) treatments, 300mg s/c injections q. 4 weeks.
Few months later, in October 2016, I was spending the whole day in New York, visiting the city and being able to walk 20 km in a single day (with some rest periods to eat or sit down a bit), without suffering from post-exertional malaise on the day itself, or the next!
Before those treatments, I could not even walk the distance between my partner’s car and the doctor’s office if I had a medical appointment in a hospital. Thus, he had to push me in a wheelchair. At home, I needed someone to cook and prepare all my meals for me, because all I was able to do was re-heat them in the microwave, and even that required rest afterwards. I was virtually homebound, and if I hadn’t been living with a partner, I never would have been able to care for myself.
So, I believe that this is a pretty dramatic improvement achieved in barely 10 months of treatments.
Today, I can do 1 hour of fast paced walking + 45 minutes of light weight lifting as part as my rehabilitation program routine twice a week, and 1 hour of dance practice every day of the week without having to “pay for it” afterwards.
I can’t say for sure if physical activity still triggers some level of mast cell degranulation. Basically, all I know is that PEM is no longer a phenomenon that I can consciously detect following physical exercise (or nowhere near the level I used to). And other triggers, such as exposure to sunlight, car vibrations, environmental and food sensitivities and intolerances, and so forth aren’t triggering any of my other symptoms anymore.
So, I am sharing all of this right now, because I believe that the link between exercise induced anaphylaxis (EIA) and post-exertional malaise (PEM) in CFS/ME patients, and perhaps other “spoonies” suffering from a vast array of chronic infectious and non-infectious diseases, might genuinely be worth exploring.
Basically, what I’m wondering is, could it be possible that there are many other diseases out there that could trigger secondary mast cell activation syndrome in some (genetically predisposed, perhaps?) patients? And/or many other diseases out there where mast cell activation might play a pivotal role in the overall pathogenesis and/or the chronicity of the disease?
Among those mast cell activated patients, could some of them also suffer from a pseudo-allergic response to physical activity?
Essentially, what if, for the vast majority of systemic lupus patients, for example, physical activity DID reduce inflammation, and thus brought them some relief from their symptoms, including the fatigue?
What if, because of those patients with a normal and positive response to physical activity, we’ve always assumed that physical activity was perfectly safe for all systemic lupus patients?
What if we’ve unwittingly been missing that, in some systemic lupus patients, a pseudo-allergic response to physical exertion occurred. And that pseudo-allergic reaction instead contributed to the systemic and chronic inflammation found in their illness, thus worsening their symptoms and the fatigue itself?
What if the fatigue, that many seem to believe is exclusive to ME/CFS, was a form of disease process common to many different chronic health issues involving the immune system, and we’ve made the mistake of assuming it was unique to a single group, turning a common disease process into a single clinical entity/disease instead?
And if my theory, based on my own extremely limited understanding of those pathologies, made any sense, could it be possible that this is exactly what is shown to happen here, in this very particular study?
Because recently, another study by Dr. Theoharides’ team showed that, when mast cells (that are neither damaged nor dying) are activated, their mitochondria will move closer to the cell’s surface, where they will released their mitochondrial ATP and DNA extracellularly.
Some of these components – the mitochondrial DNA at the very least – can travel through the blood circulation, and then even reach and go through the blood-brain-barrier (BBB).
Once released into the extracellular space, that study has shown that these mitochondrial components are mistaken by the immune system for pathogens. Their presence triggers, once again, mast cell degranulation, thus causing them to send signals to the other cells of the immune system to go fight and destroy those pathogens.
And here, if I understand correctly, Dr. Wang hypothesized that those peripheral blood mononuclear cells (PBMCs) are in a state of activation caused by “something” – an “innate pathogen” released during mast cell degranulation, perhaps? – that causes them to switch from catabolism to anabolism, where they become more reliant on glycolysis for their ATP needs.
In patients affected by EIA and MCAD, we know that physical exertion of any kind can be a potent trigger for mast cell degranulation.
And mast cells just so happen to be the little sentinels of the immune system, responsible for signaling those PBMCs (lymphocytes T, B, NK, monocytes…) through the release of cytokines, chemokines, and other mediators.
Interestingly enough, I believe that CFS/ME patients have also been associated with very high concentrations of cytokines in their blood, too.
So, if we go with the theory that a pseudo-allergic reaction to physical activity is what could be happening in CFS/ME patients (just like it is what we assume is happening in a subgroup of MCAD patients), perhaps a patient diagnosed CFS/ME’s response to physical activity could look a little like this:
1. physical activity triggers mast cell degranulation;
2. during mast cell degranulation, the mitochondria move to the cell’s surface, where they release their mitochondrial ATP and DNA extracellularly;
3. the mitochondrial ATP and DNA enter the tissues and blood circulation, where they are mistaken for pathogens, thus triggering mast cell degranulation (autocrine inflammatory response);
4. during mast cell degranulation, mast cells signal PBMCs to go attack and destroy those innate pathogens (paracrine inflammatory response);
5. to destroy the mitochondrial ATP and DNA, the PBMCs switch from catabolism to anabolism;
6. thus, PBMCs become more and more reliant on glycolysis and non-mitochondrial sources of ATP production.
During that whole process, the body of a person with a CFS/ME diagnosis (and or MCAD), would therefore be consuming massive amounts of ATP to satisfy its energy requirements, including:
- providing the energy needed to maintain its vital functions,
- providing the energy needed to perform the physical activity itself,
- providing the energy needed for mast cell degranulation, triggered by the physical activity,
- providing the energy needed for mast cell degranulation, caused by the presence of extracellular mitochondrial ATP and DNA in the tissues and plasma,
- providing the energy needed for the other cells of the immune system involved in the body’s defense against pathogens to go attack and destroy the extracellular ATP and DNA released by the mitochondria, and
- providing the energy needed for the other cells and organs of the body to deal with the overall organic stress caused by systemic inflammation.
So, assuming we would ask that particular patient to perform two CPET within 24 hours of each other, we just might get the following results:
Day 1 : Physical activity triggers a pseudo-allergic reaction leading to systemic inflammation.
Assuming the patient is well rested on day 1, it is highly possible that the results obtained during the first day of testing would be compatible with physical deconditioning, given that CFS/ME patients tend to greatly avoid or limit their exposure to whatever triggers their symptoms on a day to day basis.
Day 2 : Since the body usually needs from 24 to 48 hours to recover from an allergic reaction, either the person would be barely recovered, and still need some rest to replenish their energy reserves. Or, their PBMCs might still be fighting an “ongoing infection”, thanks to the mast cells having confused their own extracellular mitochondrial ATP and DNA for pathogens.
With those ATP levels already partially depleted at the very beginning of the exercise, and/or the PBMCs still activated and attacking the extracellular mitochondrial ATP and DNA; if you ask the patient to do another CPET, it makes a lot of sense that both the anaerobic threshold and the VO2 Max would be reached that much faster.
It’s not that the patient would have a hard time producing the ATP required to sustain the physical effort during the exercise, but rather that a huge amount of ATP – both mitochondrial and non-mitochondrial – has already been produced and used up before the patient even had a chance to begin the exercise!
And to make matters worse, you are also exposing that patient to the same pseudo-allergen that triggered the whole inflammatory response on the first day.
You can therefore assume that if you were to ask the same patient to perform yet another CPET on a third day, they’d once again be getting a worse result than they did on day 2. Albeit, the difference between the two might be less spectacular (perhaps similar to my own test results, since I was already in a state of mast cell activation on day 1).
And it would be getting worse, and worse… Until at some point, such prolonged exposure to a pseudo-allergen might lead to alterations in the number, structure, and function of the cells of the organs and systems affected by the chronic pseudo-allergic reaction.
Using graded exercise therapy in CFS/ME patients would therefore make just about as much sense as using graded gluten exposure therapy to treat coeliac disease patients, and then wonder how come they’re not doing any better.
Come on now, we’ve been increasing the gluten you must eat each day SLOWLY… Surely you must feel better each time you’re eating gluten now!
So, there is a very good reason why MCAD doctors encourage their patients to exercise only within their own safe personal limits. Prolonged or constant exposure to something triggering mast cell degranulation does not make someone feel better!
And should this theory be making any sense, it might also mean that the immune system of CFS/ME diagnosed patients would produce and invest huge quantities of mitochondrial energy (ATP) and non-mitochondrial energy (ATP) into attacking and destroying their own mitochondrial energy (ATP).
Good job! That’s ATP well spent!
And, of course, we haven’t even begun to consider all the multi-systemic symptoms and malaise that can be triggered through mast cell mediators release following exposure to the pseudo-allergen (physical activity) into the equation.
Nor have we spoken about the risk of the patient being exposed to other triggers for mast cell degranulation while at rest. If we take example on MCAD patients: heat or cold, certain smells, sunlight, positive and negative stress, certain chemicals (even completely non-toxic and 100% natural ones), the vibrations from a car, noises, etc. Thus, maintaining those high energy (ATP) production and consumption levels, even while the person is at rest.
So, the density of those folds in the cristae of the mitochondria being increased in those exhausted patients suffering from PEM being observed here? Yeah. I would think so.
If, for a MCAS patient like myself, getting dressed is enough to trigger a pseudo-allergic reaction, I have no trouble imagining it happening in CFS/ME-diagnosed patient as well.
Therefore, the more it goes, the more I am getting highly confused and intrigued regarding what the difference between Chronic Fatigue Syndrome and Mast Cell Activation Syndrome might be.
First, the chronic fatigue and PEM found in MCAS patients have a very good chance to be a mast cell mediated inflammatory response.
Either that, or I was, indeed, suffering from both CFS/ME and MCAS.
If that is the case, however, this would mean we might have found a monoclonal antibody, Omalizumab, with mast cell stabilizing effects, that just happens to be effective against both CFS/ME fatigue and PEM in a patient with a 2.1 MET anaerobic threshold, and a VO2 Max that decreased 8,8% in response to physical activity.
Otherwise, the most common symptoms consistently reported here by patients with a MCAD greatly resemble many of the symptoms found in the Canadian and International Consensuses (yes, I did fit those criteria, too).
MCAS also happens to be linked to POTS and EDS, in such a way that they may be sharing a common genetic mutation. It’s also often found in patients with fibromyalgia and/or IBS. Lyme disease might be a potential trigger for mast cell activation… And all these conditions are also highly linked with CFS/ME diagnosed patients.
And the thing is, unless monoclonal, MCAS is no more a disease than CFS is. It is a syndrome. All it really means is “mast cells are abnormally degranulating in an exaggerated manner spontaneously, randomly, or in response to triggers that should not be causing an allergic response”.
But, as a patient with the idiopathic form of MCAS, I have absolutely no clue why my mast cells are (mis)behaving that way. Innate or acquired genetic mutation? Another underlying disease we have missed that’s causing the aberrant mast cell activation? Who knows?
So, I’m thinking mast cell activation might just be something that could be found in a hundred of different chronic diseases involving the immune system! Including possibly subgroups of people with Lyme Disease, ME (according to Dr. Hyde’s definition), systemic lupus, Crohn’s disease, and so forth.
And among those patients, perhaps some of them have developed a severe chronic “allergy” to physical activity, and were never those lazy, unmotivated individuals that are refusing to activate themselves (Ha! Good one! Turns out they’re likely more activated and most people will ever get to be! ; ) ).
Thanks for such a detailed article.It def. is an interesting connection.I have suffered from ME and PEM for long time and is much worse these last 5 years.I have said for years it feels like an allergy when I crash
Are you better today?
Hello je cherche un specialiste des SAMA a Bruxelles. As tu qq’un a me conseiller ?
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