Diagnosis of mast cell activation syndrome: a global “consensus-2”, 2020, Afrin et al

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Free full text: https://www.degruyter.com/view/jour...dx-2020-0005/article-10.1515-dx-2020-0005.xml
Diagnosis 2020;
Review
Lawrence B. Afrin*, Mary B. Ackerley, Linda S. Bluestein, Joseph H. Brewer, Jill B. Brook,
Ariana D. Buchanan, Jill R. Cuni, William P. Davey, Tania T. Dempsey, Shanda R. Dorff,
Martin S. Dubravec, Alena G. Guggenheim, Kimberly J. Hindman, Bruce Hoffman, David L.
Kaufman, Stephanie J. Kratzer, Theodore M. Lee, Mindy S. Marantz, Andrew J. Maxwell,
Kelly K. McCann, Dwight L. McKee, Laurie Menk Otto, Laura A. Pace, Dahra D. Perkins,
Laurie Radovsky, Mary S. Raleigh, Sonia A. Rapaport, Emma J. Reinhold, Mark L. Renneker,
William A. Robinson, Aaron M. Roland, E. Scott Rosenbloom, Peter C. Rowe, Ilene S. Ruhoy,
David S. Saperstein, David A. Schlosser, Jill R. Schofield, Janet E. Settle, Leonard B. Weinstock, Martina Wengenroth, Mark Westaway, Shijun Cindy Xi and Gerhard J. Molderings
Diagnosis of mast cell activation syndrome:
a global “consensus-2”
https://doi.org/10.1515/dx-2020-0005
Received January 5, 2020; accepted February 15, 2020
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Abstract:

The concept that disease rooted principally in chronic aberrant constitutive and reactive activation of mast cells (MCs), without the gross MC neoplasia in mastocytosis, first emerged in the 1980s, but only in the last decade has recognition of “mast cell activation syndrome” (MCAS) grown significantly.

Two principal proposals for diagnostic criteria have emerged. One, originally published in 2012, is labeled by its authors as a “consensus” (re-termed here as “consensus-1”).

Another sizable contingent of investigators and practitioners favor a different approach (originally published in 2011, newly termed here as “consensus-2”), resembling “consensus-1” in some respects but differing in others, leading to substantial differences between these proposals in the numbers of patients qualifying for diagnosis (and thus treatment).

Overdiagnosis by “consensus-2” criteria has potential to be problematic, but underdiagnosis by “consensus-1” criteria seems the far larger problem given (1) increasing appreciation that MCAS is prevalent (up to 17% of the general population), and (2) most MCAS patients, regardless of illness duration prior to diagnosis, can eventually identify treatment yielding sustained improvement.

We analyze these proposals (and others) and suggest that, until careful research provides more definitive answers, diagnosis by either proposal is valid, reasonable, and helpful.
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This sentence seems to sum up the paper and the whole MCAS situation:
There are many reasons to expect it will take a long time before our profession learns how to design and conduct MCAS studies well and to make truly reliable conclusions from such research. We may know very little thus far about MCAS, but even just the little we do know is turning out to be enough to significantly help most MCAS patients. Thus, it would be a shame for our profession if many such patients were to continue suffering for decades, years, or even a month longer than necessary just because a perfect, unified set of diagnostic criteria or clearly reliable therapeutic guidance is not yet available
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Michiel Tack said:
This sentence seems to sum up the paper and the whole MCAS situation:
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Yes, but what does it mean?
Superficially the situation might be similar to ME, where arguing about criteria gets in the way of helping a group of people with a clinical syndrome we know exists. But we do not know that a syndrome due to one or more (unspecified) problems with mast cell activation exists. If the prevalence is estimated to be somewhere between less than 1% - people with disorders of tryptase levels maybe - to 17% then we can be pretty sure nobody actually nows if this exists or not. And why is one of the authors someone who is an advocate for Ehlers-Danlos syndrome, which has nothing to do with MCAS?
 
According to Wikipedia Afrin suggests that MCAS could cause spontaneous human combustion, presumably there is no such thing and that cannot be a valid theory? I recall reading a very long article by him years ago on MCAS dymptoms and thinking it sounded like me until I got to the end and he brought in spontaneous human combustion and then I discounted the whole thing.
 
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Don't know if this paper warrants an own thread --the first author is also a co-author of the 'golbal consensus':

Code: 
https://twitter.com/awgaffney/status/1358474398706106370/CODE]

Code: 
https://twitter.com/awgaffney/status/1358474406859862020

Edit: clarity and fixed links.

Edit 2: No idea how the tweeter's stance on other evidence in LC is, I just thought the info about Afrin's and Weinstock's and also Theoharides' COI, if true, is interesting.
 
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In essence, this consensus statement (which mostly included clinicians and few researchers) is a rebuttal of the restrictive “consensus-1” diagnostic criteria that were established by mastocytosis experts (Valent et al 2010), which are as follows per their 2019 update:
Criteria for mast cell activation syndrome (MCAS):

1. Typical clinical signs of severe, recurrent (episodic) systemic MCA are present (often in form of anaphylaxis) (definition of systemic: involving at least 2 organ systems) (symptoms typically associated with local or systemic MCA include urticaria, flushing, pruritus, angioedema, nasal congestion, nasal pruritus, wheezing, throat swelling, hoarseness, headache, hypotensive syncope, tachycardia, abdominal cramping, and diarrhea)

2. Involvement of MCs is documented by biochemical studies; preferred marker: increase in serum tryptase level from the individual’s baseline to plus 20% + 2 ng/mL; other MC-derived markers of MCA (histamine and histamine metabolites, PGD2 metabolites, and heparin) have also been proposed, but are less specific compared with tryptase

3. Response of symptoms to therapy with MC-stabilizing agents, drugs directed against MC mediator production, or drugs blocking mediator release or effects of MC-derived mediators

Diagnosis made by demonstrating all three of the above-noted criteria; the diagnosed individual should then be assessed for primary, secondary, or idiopathic MCAS as outlined previously.
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The authors mainly critique:
  • that it requires a response to therapy (antihistamines, leukotriene antagonists or cromolyn) rather than permits it
  • the absence of evidence for the “20% + 2” tryptase level criterion
  • an over-reliance on tryptase at the detriment of other mast cell mediators
  • the small panel of experts that devised the criteria at an invitation-only conference in 2010
Instead, the authors propose that the more permissive “consensus-2” diagnostic criteria elaborated by the senior author (Molderings et al 2017) be broadly adopted:
Major Criterion:
  1. Constellation of clinical complaints attributable to pathologically increased MC activity (MC mediator release syndrome)
Minor Criteria:
  1. Multifocal or disseminated infiltrates of MCs in marrow and/or extracutaneous organ(s) (e.g., gastrointestinal or genitourinary tract; >19 MCs/high power field)

  2. Abnormal spindle-shaped morphology in >25% of MCs in marrow or other extracutaneous organ(s)

  3. Abnormal MC expression of CD2 and/or CD25 (i.e., co-expression of CD117/CD25 or CD117/CD2)

  4. MC genetic changes (e.g., activating KIT codon 419, 509 or 560 mutations) shown to increase MC activity

  5. Evidence (typically from body fluids such as whole blood, serum, plasma, or urine) of above-normal levels of MC mediators including:
• tryptase​

• histamine or its metabolites (e.g., N-methylhistamine)​

• heparin​

• chromogranin A (note potential confounders of cardiac or renal failure, neuroendocrine tumors, recent proton pump inhibitor use, or chronic atrophic gastritis)

• other relatively MC-specific mediators (e.g., eicosanoids including prostaglandin (PG) D2, its metabolite 11-β-PGF2α, or leukotriene E4)
​
6. Symptomatic response to inhibitors of MC activation or MC mediator production or action​

Diagnosis established upon demonstration of the major criterion combined with at least one minor criterion (and in the unstated but inferred absence of any other disease better accounting for the patient’s problems).
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They are also very critical of the American Academy of Allergy, Asthma and Immunology’s diagnostic criteria (2019), which are based on the consensus-1 but contain episodes of anaphylaxis as an added required criterion. Indeed, they argue that most MCAS patients do not have such episodes and that this requirement deprives many of them from a diagnosis and subsequent treatment.

The AAAAI recommends the following diagnostic tests, probably based on this 2017 review (see Table 3):
Increases in serum mast cell tryptase and in urine levels of N-methylhistamine, 11B -Prostaglandin F2α (11B-PGF2α) and/or Leukotriene E4 (LTE4) are the only useful tests in diagnosis of MCAS.
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Unlike both consensus statements, they do not mention heparin.

Finally, the figure of the 17% prevalence rate comes from a single 2013 paper by Molderings, where 266 healthy controls were recruited in a German city (out of 1000 persons randomly contacted) and where 45 of them (17%) fulfilled the original “consensus-2” criteria published in 2011.
 
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I talked briefly with a clinical lead consultant in allergology and expert for the French Health and Food Security Agency.

He mentioned that he has seen about 10 cases of MCAS in almost 3 decades (as diagnosed by serum tryptase and urinary metabolites of histamine, i.e. as per the AAAAI / consensus-1 diagnostic tests) and that it seems to be as rare as actual mastocytosis.

He believes that in the US, there may be sampling bias stemming from the diagnostic tests for food allergies, which are based on commercial extracts rather than problematic foods directly.
 
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