Consensus 1 & 2 // Comparison
Navigating a diagnosis for Mast Cell Activation Syndrome (MCAS) can be pretty complicated, largely because two distinct sets of 'Consensus Criteria' exist within the medical community. Developed by two different groups of international experts, these guidelines — often called Consensus 1 and Consensus 2 — take different approaches to identifying the disease. Both sets of criteria are scientifically valid. Both bring unique strengths and limitations to the table. Ultimately, which framework is used to evaluate your symptoms will depend on your healthcare provider's specific training and clinical focus.
Number of criteria you need to meet for an MCAS diagnosis:
Consensus 1
(Valent / Akin)
3
Consensus 2
(Molderings / Afrin)
2
Criteria in a nutshell:
C1
Severe, acute and recurrent symptoms
Evidence of abnormal mast cell activation in lab tests
Symptom improvement once mast cell medicines are prescribed
All 3 criteria must be met for an MCAS diagnosis.
C2
Acute and/or chronic symptoms
AND at least 1 of:Evidence of abnormal mast cell activation in lab tests, tissue samples, genetic tests and/or symptom improvement once mast cell medicines are prescribed
Symptoms considered as part of the diagnosis:
C1
A narrow range of acute symptoms typically associated with anaphylaxis including:
Flushing, swelling, itching, wheezing, throat swelling, headache, low blood pressure, diarrhoea, fainting
C2
A broad range of acute and chronic symptoms including:
Flushing, swelling, rashes, wheezing, headache, migraine, vomiting, diarrhoea, nausea, reflux, blood pressure issues, fainting/near-fainting, fatigue, shortness of breath, palpitations, brain fog, cognitive issues
Lab tests considered as part of the diagnosis:
C1
Serum Tryptase (preferred)
Histamine metabolites
Prostaglandins
Heparin
+ others where warranted
C2
Histamine metabolites
Prostaglandins
Heparin
Tryptase
Chromogranin A
Leukotrienes
—
Tissue samples
Genetic testing
+ others where warranted
Medicines prescribed to confirm diagnosis?
C1
Yes
C2
Yes
Known sticking points:
C1
Serum tryptase is the preferred lab test but may not be accurate in cases of MCAS.
The limited number of accepted lab tests are often difficult to access and perform.
Only the most severe cases of mast cell activation are considered.
There’s a possibility of UNDER-diagnosis.
C2
Many of the accepted lab tests are difficult to access and perform.
A very broad range of symptoms are considered which may not be related to mast cells.
There’s a possibility of OVER-diagnosis.
View the criteria:
C1
-
Criterion A
Clinical signs of severe, recurrent (episodic) mast cell activation involving at least 2 organ systems (systemic). This often presents as anaphylaxis.
Criterion B
Biochemical evidence (laboratory tests) of mast cell involvement. The preferred marker is an increase in serum tryptase of plus 20% + 2ng/ml from a baseline level.
Other mast cell-derived markers such as histamine and histamine metabolites, PGD2 metabolites and heparin are also acceptable but are less specific than serum tryptase.
Criterion C
Symptom improvement when drugs and therapies directed at stabilising mast cells, reducing mediator production or blocking mediator release or effects are used.
———
All three of the criteria must be met in order to be diagnosed with Mast Cell Activation Syndrome (and in the absence of any other disease better accounting for the symptoms).
-
Consensus criteria for MCAS*
Criterion A: 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)
Criterion B: Involvement of MC is documented by biochemical studies: preferred marker: increase in serum tryptase level from the individual’s baseline to plus 20% + 2 ng/ml†
Criterion C: 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‡
___
*The consensus criteria for MCAS were first published in Valen et al.27. All 3 MCAS criteria (A + B + C) must be fulfilled to call a condition MCAS.
†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.
‡Example: histamine receptor blockers.
C2
-
Major criterion
A constellation of symptoms that can be attributed to abnormally (pathologically) increased mast cell activity.
Minor Criteria
Evidence of clusters or scattered groups of mast cells in bone barrow and/or organs, excluding the skin, such as the gastrointestinal or genitourinary tract; greater than 19 mast cells per high power field when viewed under a microscope.
More than 25% of mast cells obtained from marrow and/or non-skin organs show an abnormal, spindle-shape when viewed under a microscope.
An abnormal expression of proteins on the mast cell (CD117/CD2 or CD117/CD25)
Evidence of mast cell genetic changes known to increase mast cell activity (e.g. activating KIT codon 419, 509 or 560 mutations).
Evidence of above-normal levels of mast cell mediators (typically via blood and urinary tests) including:
Tryptase
Histamine or its metabolites (e.g. N-methylhistamine)
Heparin
Chromogranin A
Other relatively mast cell-specific mediators such as prostaglandin (PG) D2, its metabolite 11-β-PGF2α or leukotriene E4
Symptom improvement when drugs or therapies that inhibit mast cell activation or mast cell mediator production/action are used.
___
Both the major criterion and at least one minor criterion must be met in order to be diagnosed with Mast Cell Activation Syndrome (and in the absence of any other disease better accounting for the symptoms).
-
Major Criterion:
Constellation of clinical complaints attributable to pathologically increased MC activity (MC mediator release syndrome)
Minor Criteria:
Multifocal or disseminated infiltrates of MCs in marrow and/or extracutaneous organ(s) (e.g., gastrointestinal or genitourinary tract; >19 MCs/high power field)
Abnormal spindle-shaped morphology in >25% of MCs in marrow or other extracutaneous organ(s)
Abnormal MC expression of CD2 and/or CD25 (i.e., co-expression of CD117/CD25 or CD117/CD2)
MC genetic changes (e.g., activating KIT codon 419, 509 or 560 mutations) shown to increase MC activity
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)
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).
Sources:
Consensus 1
Vienna Consensus (1) (Valent / Akin)
From: Proposed Diagnostic Algorithm for Patients with Suspected Mast Cell Activation Syndrome (MCAS), 2019, J Allergy Clin Immunol Pract. 2019 Apr; 7(4): 1125–1133.e1.
Consensus 2
Global Consensus 2 (Afrin / Molderings)
Afrin LB, Ackerley MB, Bluestein LS, Brewer JH, Brook JB, Buchanan AD, et al. Diagnosis of mast cell activation syndrome: a global "consensus-2". Diagnosis (Berl). 2021 May 26;8(2):137-152. doi: 10.1515/dx-2020-0005. PMID: 32324159.