Mast cell activation syndrome: Importance of consensus criteria and call for research (J Allerg Clin Immunol), Valent et al 2018

[MSEsperanza]

Mast cell activation syndrome: Importance of consensus criteria and call for research, Valent, Peter et al. 2018, Journal of Allergy and Clinical Immunology, Volume 142, Issue 3, 1008 - 101, https://www.jacionline.org/article/S0091-6749(18)30854-6/fulltext (letter to the editor)

I found this letter in my drafts folder. Only have skimmed it. ME not mentioned. Thought it could be interesting nevertheless, but am not capable of assessing its quality. So just leave it here and for now only want to highlight this minor point:

Table I: Estimated percentage of patients with a specific disorder (underlying condition) who experience events that meet the diagnostic criteria of MCAS

Disorder/underlying condition - Estimated percentage of those with events meeting the definition of MCAS
Ehlers-Danlos syndrome ------- <1

 

[Jonathan Edwards]

Thanks for posting this. I don't have a drafts folder with interesting stuff like this in it. Where do I buy one - can I get an app ?!!

It is an interesting committee-generated paper that seems to try to balance two rather different desires. The first is to try and dissuade hordes of people from getting referrals for MCAS when they have nothing to suggest it. The second is to say, because they are all mast cell experts, that there might be other unknown fascinating mast cell problems out there and it would be good to find out about them.

It sounds a bit like a private clinic saying please do not come along with all your boring headaches and sore throats but do come along with all sorts of fascinating illnesses we can make money out of.

Maybe I am being unfair. At least the main message seems to be don't go around telling everyone they have MCAS because mostly they don't.

The figure for EDS is significant. It is probably right. But it does rather look as if it has been slipped in specifically to warn off all those people who think they have EDS and MCAS that are becoming a bore.

 

[MSEsperanza]

Thanks for your opinion on this.

The second is to say, because they are all mast cell experts, that there might be other unknown fascinating mast cell problems out there and it would be good to find out about them.

I thought maybe they wanted to show that they attempt to (or give the impression to attempt to) appreciate some patients' experiences as well as some of their colleagues' research endeavors despite they judge both as unsound.

The figure for EDS is significant. It is probably right. But it does rather look as if it has been slipped in specifically to warn off all those people who think they have EDS and MCAS that are becoming a bore.

They neither explain how they got to their estimation nor give a reference though.

What I actually wanted to do is to check whether or how the research that links MCAS to EDS, POTS, ME or cervical issues references the diagnostic criteria proposed by this group, but since I'm having only some short breaks from my forum break, I abstain and just add the link to these criteria:

Valent, Peter et al. “Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal.” International archives of allergy and immunology vol. 157,3 (2012): 215-25. doi:10.1159/000328760
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3224511/

I don't have a drafts folder with interesting stuff like this in it. Where do I buy one - can I get an app ?!!

A short answer will be put together in my drafts folder over the next couple of weeks or so and most probably will stay there unfinished, as most of this folder's content does. So for now: This typeof folder is ME-brain-crafted and the full package is delivered as a surprise bag -- inconsistent and often disappointing. But it comes with a search function. Anyhow, thanks for the laugh.

 

[Hutan]

The consensus group set forth criteria for the diagnosis of MCAS as follows.

The first criterion is the episodic occurrence of typical MC-related clinical symptoms, such as urticaria, angioedema, flushing, pruritus, nausea, hoarseness, vomiting, diarrhea, abdominal cramping, hypotensive syncope, tachycardia, wheezing, conjunctival injection, nasal congestion, and headache. To meet this first diagnostic criterion, the episodic occurrence of such symptoms affecting 2 or more organ systems should be observed.1, 2

The second criterion is an increase in serum tryptase level by 20% over the individual baseline plus 2 ng/mL total (eg, from 10 ng/mL to ≥14 ng/mL or from 30 ng/mL to ≥38 ng/mL) within a 4-hour window after the reaction.

The third criterion is a clear response (improvement) of the symptoms to drugs targeting MC-derived mediators, MC-stabilizing agents, or both.2

When these criteria are met in patients with systemic mastocytosis, by consensus, MCAS is referred to as primary or clonal MCAS. MCAS is also observed in patients with evidence of clonal MCs not fulfilling the criteria of mastocytosis.3, 4 When fulfilled in patients with IgE-dependent allergic reactions or other reactive processes, the term applied is secondary MCAS

MCAS isn't something I have thought about much. But reading that list of symptoms, it makes me wonder if I should think about it some more.

A couple of days ago after a three hour exam my son (who has ME) came out looking extremely pale and with a swollen face. It was so swollen that he looked quite different, in the way that someone who has been stung by a bee on the face might look. (He knew he'd done well in the exam and was happy, just exhausted from study and a previous three hour exam.) I thought of the MCAS criteria.

I've seen this facial swelling in my son before. I also get noticeable facial swelling during a crash, especially around my eyes. I've seen this appearance in pictures of people with ME, and the mother of a young woman with ME agreed that swelling is associated with a crash. And, as I've mentioned before, there is a feeling that my skin is too tight all over. I don't wear rings because periodic swelling in my fingers is a problem. There are times when I even take my watch off because it has become too tight. And both my son and I often have swelling in our lower legs, with socks causing imprints and shoes that are usually ok becoming too tight.

Those other symptoms that I've bolded occur too. There's often a headache where it feels as though my brain is squeezing out my nose. Diarrhea seems to always be associated with a crash. Heart rate goes up and small levels of exertion make it spike. Symptoms also seem a lot like shock, with chills, pallor and a high shock index.

Wikipedia on hives is amazing for the bizarre types of things listed that can cause a reaction. There's even a delayed reaction type.

This type of hives [pressure hives] can occur right away, precisely after a pressure stimulus or as a deferred response to sustained pressure being enforced to the skin. In the deferred form, the hives only appear after about six hours from the initial application of pressure to the skin. ... The hives may last from eight hours to three days.

And it seems that what you eat can influence whether symptoms result from an exposure to a stressor:

[Exercise urticaria] sometimes occurs only when someone exercises within 30 minutes of eating particular foods, such as wheat or shellfish.

I'd be really interested to know why people think ME can't be a form of MCAS (or why it could be).

 

[Jonathan Edwards]

I think it is very unlikely that mast cell activation relates to ME in general.

The reason is that although many of the features of mast cell activation sound a bit like features of ME true mast cell based phenomena have characteristic patterns that are not like ME, at least in my experience.

The mast cell response, at least in terms of histamine, was described in detail by Sir Thomas Lewis, who founded the Medical Research Council and worked for many years on the second floor of the UCL Medical School Building. I know that because my father took over the space in around 1948 and passed on to me a small cabinet in which Lewis kept his lab equipment. There are drawers marked 'histamine', 'cannulae' 'needles', 'clips' etc.

A mast cell response includes swelling and blood vessel constriction and dilatation that contrasts with surrounding tissue. The blood vessel changes reverse with time - so Lewis called it a triple response. One phase is pale and another red. At least part of the response is due to histamine. Nettle stings mimic the natural histamine response.

There are a variety of reasons for facial swelling. Mast cell activation can cause facial swelling but usually as part of a typical anaphylactic reaction which is fairly easy to recognise and produces significant distress.

The trouble with the sort of list that appears in the consensus document is that on its own it is pretty meaningless. These sorts of features are only significant if they form part of typical mast cell activation patterns. I am inherently distrustful of lists of features that seem to be designed to over diagnose syndromes of interest.

The other thing is that MCAS requires a rise in tryptase and I think if that had been found repeatably in people with ME it would now be documented. There are enough people interested in making connections of this sort to be sure someone has looked.

In addition there are features of ME like PEM and sensitivity to light and sound that do not fit mast cells as far as I can see.

I realise that individuals or families may be atypical - and of course 'ME' sometimes turns out to be something identifiable. Familal complement-related conditions might also produce facial swelling.

 

[wigglethemouse]

The other thing is that MCAS requires a rise in tryptase and I think if that had been found repeatably in people with ME it would now be documented.

I think you are confusing MCAS with Mastocytosis. Mastocytosis requires elevated tryptase but MCAS usually does not have elevated tryptase according to two of the experts Dr Lawrence Afrin and Prof Theoharis Theoharides.

Here are some links for those interested on learning more about MCAS. What I want to stress is that blood borne markers along with symptoms and response to medications are used to make a solid diagnosis. It is not a symptom only diagnosis.

"Never Bet Against Occam" is a good read if you want to update yourself on the clinical presentation of mast cell disease/MCAS. It presents in so many different ways due to the variety of mediators that mast cells secrete.
Amazon product ASIN 0997319615
This paper, by Dr. Afrin, details the testing and MCAD vs MCAS
https://www.wjgnet.com/2218-6204/full/v3/i1/1.htm

These are some tests available in the US.
Lab Corp Order
004280 - Tryptase
081315 - Histamine
140848 - Chromogranin A
Link: https://www.labcorp.com/test-menu/22496/chromogranin-a

Quest Order For Interscience
94402 - Prostaglandin D2, Serum, (frozen) @InterScience
94533 - Prostaglandin F2a, Serum, (frozen) @InterScience
10180 - Prostaglandin D2 PG-D2, 24 hour Urine frozen @InterScience
Link : http://www.interscienceinstitute.com/index.php?book/p#17

Quest Order For Mayo
N Methylhistamine , 24 hour urine - Wild to mayo
2,3 -DInor 11 Beta Prostaglandin F2alpha, 24 hour urine - WILD to mayo
Chilled plasma Heparin anti Xa - Wild to Mayo

Mayo leukotriene E4 Test
https://www.mayocliniclabs.com/test-catalog/Overview/62530

[24 hour urine needs to be kept refrigerated. Blood needs to be frozen immediately for some tests and the lab needs to be told this. Half life of Prostaglandin D2 is short]

Mastocytosis and sometimes MCAS results in elevated mast cell counts in tissue. Tissue from a colonoscopy or endoscopy can be stained. Biopsies are stained for Tryptase, CD117, & CD25 as shown on page 3 of this presentation
http://handouts.uscap.org/2016_cm16_lamhi_1.pdf

Last years IMEC13 talk was interesting as well for those wanting to learn more


Note : This post is not related to the opinions of the paper in the originating post (which seems to be a political statement). It is based on what I have read and watched from Dr Lawrence Afrin and Prof Theoharis Theoharides who are highly regarded both as doctors and researchers. Unfortunately like ME, research into MCAS/mast cells is lacking NIH support.

 

[Jonathan Edwards]

I think you are confusing MCAS with Mastocytosis.

No, I have looked at this in detail. You can see above from the quote above mine that MCAS requires a temporal rise in tryptase.

 

[Jonathan Edwards]

"Never Bet Against Occam" is a good read if you want to update yourself on the clinical presentation of mast cell disease/MCAS.

I think it is a major red flag if a physician who is an enthusiast for a condition that has yet to be generally recognised as real writes popular book like this. Much like the zeal for EDS it is supposed to explain everything. It looks very much to me that it explains very little.

What makes things even stranger is that so many people get diagnosed with both of these explanations for everything - which is exactly 'betting against Occam'.

 

[ME/CFS Skeptic]

It sounds a bit like a private clinic saying please do not come along with all your boring headaches and sore throats but do come along with all sorts of fascinating illnesses we can make money out of.

Maybe I am being unfair.

I think if they wanted to make money they would say that all those people coming in with boing headaches have some form of MCAS and only they as experts know how to treat it... I think this is the responsible thing to do for them: to speak out that the term MCAS is currently being applied to patients who do not have MCAS.

The diagnosis of MCAS is being applied currently to patients with unresolved complex medical problems after extensive medical evaluations, and a substantial number of these patients do not meet the diagnostic criteria for MCAS.[...] MCAS should not be applied on the basis of a persistently elevated basal serum tryptase level and not based on the fact that the condition has resisted previous attempts to establish a medical diagnosis.

I think you are confusing MCAS with Mastocytosis. Mastocytosis requires elevated tryptase but MCAS usually does not have elevated tryptase

Tryptase does not have to be elevated but as Jonathan explained there has to be a temporal rise. The consensus proposal is that "a minimal increase in the acute serum tryptase level to greater than plus 20% of baseline þ 2 ng/mL absolute tryptase strongly supports the diagnosis of MCAS." See: https://www.ncbi.nlm.nih.gov/pubmed/30737190

 

[Jonathan Edwards]

I think if they wanted to make money they would say that all those people coming in with boing headaches have some form of MCAS and only they as experts know how to treat it.

Maybe, but credibility would depend on some degree of apparent quality control - hence having diagnostic criteria despite the fact that nobody actually knows quite what these criteria are supposed to recognise.

 

[wigglethemouse]

Tryptase does not have to be elevated but as Jonathan explained there has to be a temporal rise. The consensus proposal is that "a minimal increase in the acute serum tryptase level to greater than plus 20% of baseline þ 2 ng/mL absolute tryptase strongly supports the diagnosis of MCAS." See: https://www.ncbi.nlm.nih.gov/pubmed/30737190

Don't want to get in an argument, but for balance I wanted to quote the following from the paper you linked. It's not always black or white re:Tryptase with Idiopathic Mast Cell Activation

It is suggested that an event-related increase in 2 or more of the plasma or urinary histamine metabolites or PGD2 metabolites, or LTE4 of at least 50% from baseline (eg, from 50 to at least 75), could function as an indication of MCA. Another possibility is a determination of a level 2-fold above the upper limit of normal. Measurement of such additional mediators may indeed be helpful in the evaluation of patients with suspected MCA/MCAS, and should therefore be considered, especially when the serum tryptase test is not available or did not produce a convincing result or when no blood (but only urine) could be collected during the event. This is important because other MC mediators are sometimes also relevant clinically, because they can provoke MCA and may lead to adjustments of (individualized) therapeutic approaches.32 It is also worth noting that PGD2 is primarily synthesized in MCs but not in blood basophils.

In other patients, severe symptoms may be recorded, but tryptase levels increase only slightly. In these patients, it isreasonable to determine the levels of additional relevant media-tors such as PGD2, if the test is available.

 

[Jonathan Edwards]

Don't want to get in an argument, but for balance I wanted to quote the following from the paper you linked. It's not always black or white re:Tryptase with Idiopathic Mast Cell Activation

I think those quotes show rather clearly that 'MCAS' is still not a meaningful clinical category. They don't say anything about other tests being allowed into the diagnostic criteria, just that they 'may be helpful' or 'it is reasonable to determine' - which leaves us none the wiser.

There is a basic confusion between trying to find evidence of mast cell activation (MCA) and the presence of a 'mast cell activation syndrome' based on clustered criteria. The clinical criteria for MCAS look to me useless because they are so diverse and such common complaints. A temporal rise in tryptase might be a good guide to mast cell involvement but if you allow clinicians to scrabble around for all sorts of other evidence until they find some I suspect you end up with just as useless a list of tests.

I can only go on my experience over the years as to which disease concepts hold up as useful and which do not. This looks like a phoney category to me, or a least a category that is likely to be grossly over diagnosed.

 

[rvallee]

Maybe, but credibility would depend on some degree of apparent quality control - hence having diagnostic criteria despite the fact that nobody actually knows quite what these criteria are supposed to recognise.

I think it can be safely acknowledged that this far from true. It's the idea, certainly, in practice it's clearly not the case or we wouldn't even be here as a result of a complete breakdown in quality control. In our domain, those with the highest credibility have entirely bypassed all quality control and successfully promoted an elaborate belief system. And if it can happen once, it's a short step from systemic creep into all areas.

 

[Jonathan Edwards]

I think it can be safely acknowledged that this far from true. It's the idea, certainly, in practice it's clearly not the case or we wouldn't even be here as a result of a complete breakdown in quality control.

I think you have missed my point @rvallee? I saw 'apparent quality control'. The whole point of my remark was that to sell an idea you have to appear to have things in place like 'quality control' even if in fact the control is enable in any direction you like. I absolutely agree that people with high credibility have bypassed any real quality control.

 

[Art Vandelay]

A couple of days ago after a three hour exam my son (who has ME) came out looking extremely pale and with a swollen face. It was so swollen that he looked quite different, in the way that someone who has been stung by a bee on the face might look. (He knew he'd done well in the exam and was happy, just exhausted from study and a previous three hour exam.) I thought of the MCAS criteria.

I've seen this facial swelling in my son before. I also get noticeable facial swelling during a crash, especially around my eyes. I've seen this appearance in pictures of people with ME, and the mother of a young woman with ME agreed that swelling is associated with a crash.

I've also noticed this facial swelling/puffiness when I'm very unwell (relatively speaking) and have noticed it in other ME sufferers. I liken it to looking like I've been beaten up (without the bruising).

 

[Milo]

I've also noticed this facial swelling/puffiness when I'm very unwell (relatively speaking) and have noticed it in other ME sufferers. I liken it to looking like I've been beaten up (without the bruising).

Wait a minute, in a past life i was a registered nurse. I have seen patients puffing up like pillsbury dough men from one day to the next. To claim that it’s the MCAS doing that is a big claim. We are still in the beginning of trying to understand the disease. Some still think it’s the enterovirus, stupid, while others think it’s CCI, while other believe-still- it’s a retrovirus. A little science, please.

 

[Hutan]

Neither @Art Vandelay nor I have claimed that the facial swelling means we must have MCAS. Just that we have experienced and seen some facial swelling in people with ME. It's an observation.

And I asked about the MCAS theory to understand it more.

 

[Jonathan Edwards]

One or two more thoughts about facial puffiness.

I looked in to this years ago because I was interested in why people with kidney disease get facial puffiness. In heart failure the legs swell up, but in certain type of kidney disease - specifically glomerulonephritis - the face swells up first, despite being at the top of the body.

The reasoning is too complicated to give in one post in full but is roughly this:

Any condition that makes tiny blood vessels a bit more leaky all over the body (that includes most causes of glomerulonephritis) tends to produce swelling more in the face, at least at first. The most likely reason for this seems to be that the small vessels in other parts, especially legs, are surrounded by connective tissue that resists leakage and swelling because they have to cope with gravitational pressures most of the time. Basically your foot tissues are toughened up, otherwise they would fill up with water during the day. The face does not need to have tough tissues because we do not go around upside down.

So if there is general leakiness the face swells up first.

I find it interesting that our faces swell up when we cry - which presumably means that even having water under the eyelids is enough to seep into the face. Faces also swell up if we do hang upside down and of certainly my face always looks different in the morning just from lying flat at night.

If you are ill for any reason then you tend to lie flat for more than just one night. In addition there may be some circulating inflammatory mediators that increase vessel leakiness. Complement components are likely ones.

 

[Jonathan Edwards]

There is then the question as to whether face swelling from mast cell activation looks different from the sort of swelling you get from lying down, crying or just being ill. I am not sure about that but from what I have seen I think there is an explainable difference. With mast cell activation the skin may be pinker, but not necessarily. I think it is also tighter. Mast cells are rich within the skin itself - in the dermis. With allergic reactions the blood vessels in the skin specifically get leaky because they are being stimulated within the skin by mast cells. That is different from the facial tissues as a whole soaking up water, as in crying or lying in bed, where the face looks doughy rather than tight.

As I say, I am not sure that one can distinguish just on this alone. Mast cell activation tends to give other tell tale signs that are probably more helpful. But I think may be the main point is that the great majority of swollen faces are not due to mast cell activation. That is why the list of symptoms in the diagnostic criteria for 'MCAS' may well be unhelpful.

 

[Art Vandelay]

Neither @Art Vandelay nor I have claimed that the facial swelling means we must have MCAS. Just that we have experienced and seen some facial swelling in people with ME. It's an observation.

Exactly this. Thank you @Hutan.