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Cited by 220Mast cells and histamineUrticaria and Related ConditionsAsthma and respiratory diseases

Proposed Diagnostic Algorithm for Patients with Suspected Mast Cell Activation Syndrome

Open access
Valent, Peter, Akin, Cem, Bonadonna, Patrizia, Hartmann, Karin, Brockow, Knut, Niedoszytko, Marek, Nedoszytko, Boguslaw, Siebenhaar, Frank +16 more·2019·The Journal of Allergy and Clinical Immunology: In Practice
DOI 10.1016/j.jaip.2019.01.006PMC PMC6643056
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Abstract

Mast cell activation (MCA) accompanies diverse physiologic and pathologic processes and is one of the more frequently encountered conditions in medicine. MCA-related symptoms are usually mild and often transient. In such cases, histamine receptor blockers and other mediator-targeting drugs can usually control MCA. In severe cases, a MCA syndrome (MCAS) may be diagnosed. However, overt MCAS is an unusual condition, and many patients referred because of suspected MCAS are diagnosed with other diseases (autoimmune, neoplastic, infectious) unrelated to MCA or suffer from MCA-related (e.g., allergic) disorders and/or co-morbidities without fulfilling criteria of an overt MCAS. These considerations are important as more and more patients are informed they may have MCA or even MCAS without completing a thorough medical evaluation. In fact, in several instances, symptoms are misinterpreted as MCA/MCAS, and other, clinically relevant conditions are not thoroughly pursued. The number of such referrals is increasing. In order to avoid such unnecessary referrals and to prevent misdiagnoses, we here propose a diagnostic algorithm through which a clinically relevant (systemic) MCA can be suspected and MCAS can subsequently be documented or excluded. In addition, the algorithm proposed should help guide the investigating care providers to consider the two principle diagnoses that may underlie MCAS, namely severe allergy and systemic mastocytosis accompanied by severe MCA. Although validatio…

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Written from the paper’s full text.

TL;DR

This article proposes a stepwise diagnostic algorithm for suspected mast cell activation syndrome (MCAS), centered on severe recurrent systemic symptoms, event-related tryptase elevation, and response to mediator-targeted therapy. It aims to separate true MCAS from other mast cell activation–related or unrelated conditions and to classify cases as primary, secondary, or idiopathic.

Key findings

  • MCAS diagnosis requires all three consensus criteria: typical severe recurrent systemic mast cell activation signs, biochemical evidence of mast cell involvement—preferably a tryptase rise using the 20% plus 2 ng/mL formula—and symptom improvement with mast cell–stabilizing or mediator-targeting drugs. The paper gives an example where a baseline tryptase of 5 ng/mL with a rise above 8 ng/mL suggests mast cell activation.
  • The algorithm recommends measuring acute serum tryptase 1–4 hours after the event and comparing it with a baseline obtained at least 24–48 hours after symptoms resolve. A persistently elevated baseline tryptase above 20 ng/mL should prompt consideration of hereditary alpha-tryptasemia, systemic mastocytosis, or non–mast cell myeloid neoplasms.
  • Other mediators, including histamine, histamine metabolites, the PGD2 metabolite 11β-prostaglandin F2α, and LTE4, are less specific than tryptase. The paper suggests an event-related rise of at least 50% from baseline or a level twofold above the upper limit of normal may indicate mast cell activation, but notes that no validated minimal threshold exists for these mediators.
  • MCAS is classified as primary when KIT-mutated, CD25+ clonal mast cells are found with or without mastocytosis; secondary when an IgE-dependent allergy or other reactive hypersensitivity disorder is present without clonal mast cells; and idiopathic when neither is identified. Severe allergy and systemic mastocytosis with severe mast cell activation are described as the two principal underlying diagnoses.

Methods

  • This is a narrative proposal of a diagnostic algorithm, not an empirical study; no patient cohort, sample size, or data collection procedure is reported.
  • The authors synthesize existing consensus criteria, mediator assays, and clinical scenarios into a stepwise evaluation pathway, referencing tables and figures that are not reproduced in the provided text.
  • The main analysis is conceptual: it moves from clinical stabilization and symptom classification to tryptase and other mediator testing, treatment response, final MCAS classification, and differential diagnosis.

Limitations

  • The paper states that validation of the proposed algorithm is required and that the authors anticipate it will facilitate management.
  • The paper states that no data establish reliable minimal increase thresholds for histamine metabolites, PGD2 metabolites, or LTE4 as MCAS criteria, and that tryptase sensitivity decreases with less severe reactions and delayed blood draws.
  • Evident from the text: no prospective testing, diagnostic accuracy data, or patient outcomes are presented; pediatric MCAS prevalence is described as unknown, and the algorithm relies on expert consensus rather than empirical validation.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.jaip.2019.01.006

Cites

86 of 86 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

66 of 133 cited sources checked · 28 supported · 2 flagged · accuracy not yet measured

  • Premisecitation

    In patients with systemic mastocytosis and MCAS, IgE-dependent allergy such as insect venom allergy is frequently documented.

    “in patients with systemic mastocytosis (SM) and MCAS, an IgE-dependent allergy (e.g., against insect venom) is frequently documented.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [21] Akin, 2007, Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis, Blood source

      The Results and discussion report anaphylactic attacks following yellowjacket stings in one patient with clonal mast-cell markers. They do not establish that this patient had systemic mastocytosis, document IgE-dependent venom allergy, or show that such allergy is frequent in patients with systemic mastocytosis or MCAS. No page number is provided in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [22] Sonneck, 2007, Diagnostic and subdiagnostic accumulation of mast cells in the bone marrow of patients with anaphylaxis: monoclonal mast cell activation syndrome, Int Arch Allergy Immunol source
    • cites [23] Bonadonna, 2009, Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels, J Allergy Clin Immunol source

      The Final diagnosis section reports Hymenoptera venom allergy in patients diagnosed with indolent systemic mastocytosis or monoclonal mast cell activation syndrome; allergy tests were negative in 4 of the 34 evaluated subjects. But the Methods (Subjects) section shows that participants were selected because they had already had systemic sting reactions and elevated tryptase, so these findings do not establish that IgE-dependent allergy is frequent among patients with SM or MCAS generally. The paper does not assess the frequency of other IgE-dependent allergies in those populations. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    CD63 and CD203c increase on the surface of FcεR cross-linked MC and basophils.

    “Both proteins (antigens) increase on the surface of FcεR cross-linked MC and basophils (51-55).”
    Quote in the paperSubstantial claim1 of 5 sources checked
    • cites [51] Knol, 1991, Monitoring human basophil activation via CD63 monoclonal antibody 435, J Allergy Clin Immunol source
    • cites [52] Hauswirth, 2002, Recombinant allergens promote expression of CD203c on basophils in sensitized individuals, J Allergy Clin Immunol source

      The section on CD203c and CD63 upregulation reports that allergen stimulation increased both markers on basophils, and the Discussion (p. 107) describes rapid CD203c upregulation after FcεRI cross-linking. The paper does not establish the claimed increase on mast cells (MC), so it supports the basophil portion only. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [53] Bühring, 2004, The basophil-specific ectoenzyme E-NPP3 (CD203c) as a marker for cell activation and allergy diagnosis, Int Arch Allergy Immunol source
    • cites [54] Valent, 2004, Assays for measuring in vitro basophil activation induced by recombinant allergens, Methods source
    • cites [55] Hauswirth, 2008, CD203c is overexpressed on neoplastic mast cells in systemic mastocytosis and is upregulated upon IgE receptor cross-linking, Int J Immunopathol Pharmacol source
  • Premisecitation

    Patients with combined primary and secondary MCAS are at high risk of recurrent life-threatening anaphylaxis.

    “These patients suffer from a combination of primary and secondary MCAS, and, as a result, they are at high risk to develop recurrent life-threatening anaphylaxis (21-23).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [21] Akin, 2007, Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis, Blood source

      The Results and discussion (page unavailable) identify clonal mast-cell markers in some patients with recurrent anaphylaxis; one patient's attacks followed yellowjacket stings. The paper does not establish that these patients had combined primary and secondary MCAS or that the combination caused a high risk of future life-threatening attacks. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [22] Sonneck, 2007, Diagnostic and subdiagnostic accumulation of mast cells in the bone marrow of patients with anaphylaxis: monoclonal mast cell activation syndrome, Int Arch Allergy Immunol source
    • cites [23] Bonadonna, 2009, Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels, J Allergy Clin Immunol source

      The introductory discussion (page not available) says that patients with Hymenoptera venom allergy and systemic mastocytosis have an increased risk of severe systemic reactions. The “Systemic reactions to” section also says early diagnosis could help prevent further severe reactions. The paper does not establish that patients with combined primary and secondary MCAS generally face a high risk of recurrent life-threatening anaphylaxis; its findings concern patients with sting reactions and increased baseline tryptase. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Premisecitation

    A minimal increase of acute serum tryptase to greater than 20% of baseline plus 2 ng/mL absolute strongly supports the diagnosis of MCAS.

    “a minimal increase of the acute serum tryptase level to greater than plus 20% of baseline plus 2 ng/mL absolute tryptase strongly supports the diagnosis of MCAS (27).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [27] Valent, 2012, Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal, Int Arch Allergy Immunol source
  • Premisecitation

    Response to mediator-blocking drugs is a criterion of MCAS.

    “Indeed, the response to such drugs is helpful in practice and is therefore a criterion of MCAS (26-28).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [26] Akin, 2010, Mast cell activation syndrome: proposed diagnostic criteria, J Allergy Clin Immunol source
    • cites [27] Valent, 2012, Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal, Int Arch Allergy Immunol source
    • cites [28] Valent, 2013, Mast cell activation syndromes: definition and classification, Allergy source
  • Classified as probably not a substantial claim. 12
  • May combine two claims. 18

  • Classified as probably not a substantial claim.

    Premisecitation

    If an IgE-dependent allergy or other underlying reactive disease is present without clonal MC, the diagnosis is secondary MCAS.

    “If an IgE-dependent allergy or other underlying reactive disease (e.g., IgE-dependent or other hypersensitivity disorder) is present in the absence of clonal MC, the diagnosis is secondary MCAS (Table 2, Figure 2).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [26] Akin, 2010, Mast cell activation syndrome: proposed diagnostic criteria, J Allergy Clin Immunol source

      In “Proposed Criteria for the diagnosis of idiopathic mast cell activation syndrome,” the paper calls this a secondary mast cell activation disorder when clonal markers are absent and an allergic or other concurrent disease is established. It proposes an MCAS diagnosis only after secondary diseases associated with mast cell activation have been eliminated, contrary to the cited sentence’s diagnosis of “secondary MCAS.” (LLM, conf=0.84)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [27] Valent, 2012, Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal, Int Arch Allergy Immunol source

      The Classification of MCAS (pp. 5–6) identifies allergy or another underlying disease causing mast-cell activation as secondary MCAS, rather than primary clonal MCAS. But Table 4 also requires the criteria for mast-cell activation to be fulfilled; the presence of an allergy or reactive disease without clonal mast cells does not, by itself, establish secondary MCAS. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [28] Valent, 2013, Mast cell activation syndromes: definition and classification, Allergy source

  • May combine two claims.

    Premisecitation

    Patients with clonal KIT-mutated CD25+ MC but only one or two minor SM criteria and no major SM criterion, as well as those with cutaneous mastocytosis or SM, are classified as primary clonal MCAS.

    “These patients as well as those with cutaneous mastocytosis (CM) or SM are both classified as primary (clonal) MCAS (Table 2).”
    Quote in the paperSubstantial claim4 of 5 sources checked
    • cites [21] Akin, 2007, Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis, Blood source

      The Results and discussion and Table 2 identify patients with clonal mast-cell markers but no major systemic-mastocytosis criterion, and separately describe patients with cutaneous or systemic mastocytosis. The paper does not classify these groups as primary (clonal) MCAS. It also reports KIT mutations in only three of the five patients in the first group, rather than establishing that all were KIT-mutated. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [22] Sonneck, 2007, Diagnostic and subdiagnostic accumulation of mast cells in the bone marrow of patients with anaphylaxis: monoclonal mast cell activation syndrome, Int Arch Allergy Immunol source
    • cites [26] Akin, 2010, Mast cell activation syndrome: proposed diagnostic criteria, J Allergy Clin Immunol source

      The section on primary mast cell activation identifies patients with one or two minor mastocytosis criteria as having MMAS. But the proposed diagnostic criteria section explicitly says patients with urticaria pigmentosa, a form of cutaneous mastocytosis, are excluded from an MCAS diagnosis; it assigns patients with clonal markers to systemic mastocytosis or MMAS according to WHO criteria. The copy does not classify all these patients together as primary (clonal) MCAS. Page numbers are unavailable in the indexed passages. (LLM, conf=0.86)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [27] Valent, 2012, Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal, Int Arch Allergy Immunol source
    • cites [28] Valent, 2013, Mast cell activation syndromes: definition and classification, Allergy source

      The ‘Underlying disorders and classification of MCAS’ section classifies MCAS with KIT-mutated, usually CD25-positive clonal mast cells as primary, including cases with CM or SM and cases with neither. Our copy does not specify the claimed threshold of one or two minor SM criteria and no major criterion. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    MCAS is classified into primary MCAS with clonal KIT-mutated CD25+ MC, secondary MCAS with an underlying non-neoplastic disease usually IgE-dependent allergy or hypersensitivity, and idiopathic MCAS with no KIT-mutated MC, no overt inflammatory disorder, and no hypersensitivity trigger.

    “Based on the underlying condition, patients with MCAS should then be further classified into i) primary MCAS where KIT-mutated, clonal (CD25+) MC are detected (with or without an underlying diagnosis of mastocytosis), ii) secondary MCAS where an underlying non-neoplastic disease, usually an IgE-dependent allergy or other hypersensitivity reaction is detected, and iii) idiopathic MCAS, where no KIT”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [27] Valent, 2012, Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal, Int Arch Allergy Immunol source

      Split into 3 atoms — 2 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [28] Valent, 2013, Mast cell activation syndromes: definition and classification, Allergy source

  • May combine two claims.

    Premisecitation

    The likelihood of MCA increases when two or more recognized symptoms are documented, and increases further when symptoms respond to agents blocking mediator effects, production, or secretion.

    “The likelihood of MCA increases when two or more of such symptoms are documented, and the likelihood is even higher when the symptoms respond to agents blocking mediator effects, mediator production or mediator secretion.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [26] Akin, 2010, Mast cell activation syndrome: proposed diagnostic criteria, J Allergy Clin Immunol source
    • cites [27] Valent, 2012, Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal, Int Arch Allergy Immunol source

      The Clinical Symptoms section (p. 3) says the likelihood of systemic MCA increases when signs or symptoms occur in two or more organ systems in parallel, require therapy, and are recurrent or permanent—not merely when two symptoms are documented. The Response to Therapy section (p. 4) supports the second part: a major response to antimediator agents is highly suggestive of MCA, although responses to some agents are nonspecific. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [28] Valent, 2013, Mast cell activation syndromes: definition and classification, Allergy source

  • May combine two claims.

    Premisecitation

    Tryptase is more specific for MC than other mediators and is considered the most precise parameter for demonstrating and documenting MCA.

    “Some mediators, like tryptase, are more specific than others for MC and thereby considered as the most precise parameters for the demonstration and documentation of MCA (27,28,37-40).”
    Quote in the paperSubstantial claim2 of 6 sources checked
    • cites [27] Valent, 2012, Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal, Int Arch Allergy Immunol source
    • cites [28] Valent, 2013, Mast cell activation syndromes: definition and classification, Allergy source
    • cites [37] Schwartz, 1987, Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis, N Engl J Med source
    • cites [38] Shanmugam, 2006, Prolonged elevation of serum tryptase in idiopathic anaphylaxis, J Allergy Clin Immunol source
    • cites [39] Schwartz, 2006, Diagnostic value of tryptase in anaphylaxis and mastocytosis, Immunol Allergy Clin North Am source
    • cites [40] Ferrer, 2010, Serum total tryptase levels are increased in patients with active chronic urticaria, Clin Exp Allergy source

  • May combine two claims.

    Interpretationreasoning

    A rapid substantial increase in serum tryptase above the individual baseline is considered specific for MC involvement and MCA and can be used as an MCAS criterion.

    “Therefore, in a routine evaluation, a rapid substantial increase in serum tryptase levels above the individual’s baseline is considered specific for MC involvement and MCA, and thus can be employed as a MCAS criterion.”
    Quote in the paperSubstantial claim2 of 6 sources checked
    • cites [27] Valent, 2012, Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal, Int Arch Allergy Immunol source
    • cites [28] Valent, 2013, Mast cell activation syndromes: definition and classification, Allergy source
    • cites [37] Schwartz, 1987, Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis, N Engl J Med source
    • cites [38] Shanmugam, 2006, Prolonged elevation of serum tryptase in idiopathic anaphylaxis, J Allergy Clin Immunol source
    • cites [39] Schwartz, 2006, Diagnostic value of tryptase in anaphylaxis and mastocytosis, Immunol Allergy Clin North Am source
    • cites [40] Ferrer, 2010, Serum total tryptase levels are increased in patients with active chronic urticaria, Clin Exp Allergy source

  • May combine two claims.

    Premisecitation

    The sensitivity of the tryptase algorithm decreases with decreasing clinical severity and with delayed blood draws after symptom resolution.

    “However, the sensitivity of the tryptase algorithm decreases with decreasing clinical severity and with delayed blood draws after resolution of clinical symptoms.”
    Quote in the paperSubstantial claim2 of 6 sources checked
    • cites [27] Valent, 2012, Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal, Int Arch Allergy Immunol source
    • cites [28] Valent, 2013, Mast cell activation syndromes: definition and classification, Allergy source

      The Laboratory assessment of systemic MCA section says mast-cell mediators are measurable in most severe systemic reactions and describes a rapid rise in tryptase from baseline as a diagnostic parameter. It recommends measuring the baseline after symptoms resolve, but does not state that the algorithm’s sensitivity decreases progressively with milder symptoms or quantify the effect of delayed acute blood draws. The Differential diagnoses section likewise calls for a post-resolution sample to establish baseline, not as a substitute for an acute sample. (LLM, conf=0.77)

      Experimental — accuracy not yet measured
    • cites [37] Schwartz, 1987, Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis, N Engl J Med source
    • cites [38] Shanmugam, 2006, Prolonged elevation of serum tryptase in idiopathic anaphylaxis, J Allergy Clin Immunol source
    • cites [39] Schwartz, 2006, Diagnostic value of tryptase in anaphylaxis and mastocytosis, Immunol Allergy Clin North Am source
    • cites [40] Ferrer, 2010, Serum total tryptase levels are increased in patients with active chronic urticaria, Clin Exp Allergy source

  • May combine two claims.

    Interpretationcitation

    If a major increase in PGD2 metabolite is found and symptoms respond to cyclooxygenase inhibitors, MCAS may be considered, although the cell source may be ambiguous if tryptase and histamine or histamine metabolite levels are normal.

    “Whenever a major increase in the PGD2 metabolite level is found and the symptoms respond to cyclooxygenase inhibitors, the diagnosis of MCAS may also be considered (27) although the cell source may be ambiguous, particularly if both tryptase and histamine or histamine metabolite levels are normal.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [27] Valent, 2012, Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal, Int Arch Allergy Immunol source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hereditary alpha-tryptasemia is an autosomal dominant condition defined by germline replications, usually duplications or triplications, of the TPSAB1 gene encoding alpha-tryptase.

    “hereditary alpha-tryptasemia, an autosomal dominant condition defined by germline replications (usually duplications or triplications) of the TPSAB1 gene encoding alpha-tryptase (64-67).”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [64] Lyons, 2014, Mendelian inheritance of elevated serum tryptase associated with atopy and connective tissue abnormalities, J Allergy Clin Immunol source

      The “To the Editor” section reports an autosomal dominant inheritance pattern of elevated basal serum tryptase in nine families. It does not identify TPSAB1 duplications or triplications as the cause; the authors say additional genetic study is ongoing. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [65] Lyons, 2016, Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number, Nat Genet source
    • cites [66] Lyons, 2018, A common haplotype containing functional CACNA1H variants is frequently coinherited with increased TPSAB1 copy number, Genet Med source

      The Introduction (page unavailable) identifies hereditary α-tryptasemia with extra germline copies of α-tryptase-encoding TPSAB1, and the Results (page unavailable) refer to TPSAB1 duplications or triplications. The Results also describe affected families with increased copy number on one allele, but our copy does not explicitly establish autosomal-dominant inheritance or show that duplications and triplications are the usual forms. (LLM, conf=0.81)

      Experimental — accuracy not yet measured
    • cites [67] Sabato, 2018, First identification of an inherited TPSAB1 quintuplication in a patient with clonal mast cell disease, J Clin Immunol source

  • May combine two claims.

    Premisecitation

    An elevated basal serum tryptase level by itself is neither an indication for MCA or MCAS nor an a priori risk factor for MCA or MCAS.

    “an elevated basal serum tryptase level per se is neither an indication for MCA or MCAS nor is it an ‘a priori’ risk factor for the occurrence of MCA or MCAS.”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [68] Sperr, 2001, Expression of mast cell tryptase by myeloblasts in a group of patients with acute myeloid leukemia, Blood source

      The Discussion (p. 7) reports that elevated serum tryptase can come from AML blasts rather than mast cells, supporting the point that an elevated level alone does not establish mast-cell activation. The paper does not assess whether basal tryptase is a risk factor for MCA or MCAS. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [69] Sperr, 2002, Serum tryptase measurements in patients with myelodysplastic syndromes, Leuk Lymphoma source
    • cites [70] Sperr, 2009, Elevated tryptase levels selectively cluster in myeloid neoplasms: a novel diagnostic approach and screen marker in clinical haematology, Eur J Clin Invest source
    • cites [71] Valent, 2014, The serum tryptase test: an emerging robust biomarker in clinical hematology, Expert Rev Hematol source

      The section on the test’s development (page not supplied) identifies a rise above baseline during anaphylaxis—not an elevated basal level—as a diagnostic parameter of mast-cell activation. The screening section also describes elevated basal levels in other conditions. These passages support the distinction between basal elevation and evidence of activation, but do not address whether basal elevation is an a priori risk factor for MCA or MCAS. (LLM, conf=0.79)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    If no evidence for primary or secondary MCAS is found, the patient is classified as having idiopathic MCAS.

    “If no evidence for primary or secondary MCAS is found, the patient is classified as having idiopathic MCAS (Table 2, Figure 1) (26-28).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [26] Akin, 2010, Mast cell activation syndrome: proposed diagnostic criteria, J Allergy Clin Immunol source

      The section on proposed criteria for idiopathic MCAS supports ruling out primary and secondary causes before making the diagnosis. It also requires three additional diagnostic criteria; the cited sentence makes exclusion alone sound sufficient for classification. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [27] Valent, 2012, Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal, Int Arch Allergy Immunol source
      Experimental — accuracy not yet measured
    • cites [28] Valent, 2013, Mast cell activation syndromes: definition and classification, Allergy source
      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Elevated basal tryptase is found in mastocytosis, hereditary alpha-tryptasemia where anaphylaxis risk may be increased, and myeloid non-MC-lineage neoplasms.

    “an elevated basal tryptase level is not only found in patients with mastocytosis or hereditary alpha-tryptasemia (where the risk for anaphylaxis may be increased) but also in patients with myeloid non-MC-lineage neoplasms (Supplemental Table S1) (68-71).”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [68] Sperr, 2001, Expression of mast cell tryptase by myeloblasts in a group of patients with acute myeloid leukemia, Blood source

      The Discussion (p. 7) identifies tryptase as a marker of mastocytosis, and the Results (p. 3) report elevated serum tryptase in subsets of patients with acute myeloid leukemia, a non-mast-cell-lineage neoplasm. The paper does not address hereditary alpha-tryptasemia or its possible association with anaphylaxis risk. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [69] Sperr, 2002, Serum tryptase measurements in patients with myelodysplastic syndromes, Leuk Lymphoma source
    • cites [70] Sperr, 2009, Elevated tryptase levels selectively cluster in myeloid neoplasms: a novel diagnostic approach and screen marker in clinical haematology, Eur J Clin Invest source
    • cites [71] Valent, 2014, The serum tryptase test: an emerging robust biomarker in clinical hematology, Expert Rev Hematol source

      The sections on elevated basal serum tryptase and cellular origin report elevated levels in systemic mastocytosis and several other myeloid neoplasms, including AML and CML (page not provided). The paper also mentions familial mast-cell activation syndromes, but the passages do not identify hereditary alpha-tryptasemia or link that condition to increased anaphylaxis risk. Its discussion of anaphylaxis concerns a rise in tryptase during a reaction, not that risk claim. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Induction of long-term tolerance to insect venom allergen is reduced in primary MCAS, and severe or fatal reactions after discontinuation of immunotherapy have been described.

    “The induction of long-term tolerance to an insect venom allergen is reduced in primary MCAS and severe or even fatal reactions after discontinuation of immunotherapy have been described (71,72).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [71] Valent, 2014, The serum tryptase test: an emerging robust biomarker in clinical hematology, Expert Rev Hematol source

      The 'Value of tryptase testing in patients with mastocytosis' section (page unavailable) discusses hymenoptera venom allergy as a context for screening for systemic mastocytosis, not as an immunotherapy outcome. Searches for long-term venom tolerance and reactions after discontinuing immunotherapy found no passage in our copy addressing either claim. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
    • cites [72] Oude Elberink, 1997, Fatal anaphylaxis after a yellow jacket sting, despite venom immunotherapy, in two patients with mastocytosis, J Allergy Clin Immunol source

  • Classified as probably not a substantial claim.

    Premisecitation

    In cases with mastocytosis and MCA not fulfilling MCAS criteria, the consensus group recommends the diagnostic label SY for any MCA requiring continuous mediator-targeted therapy.

    “The consensus group has recommended that in cases with mastocytosis (irrespective of the variant) any form of MCA requiring continuous mediator-targeted therapy should be marked by the diagnostic label ‘SY’”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [27] Valent, 2012, Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal, Int Arch Allergy Immunol source

      The Mastocytosis section (p. 7) says MCA can occur in any variant of mastocytosis and that its presence may be recorded with the subscript ‘SY’. The Response to Therapy section (p. 4) describes SM SY as mediator-related symptoms requiring therapy, but does not specify continuous therapy or explicitly recommend SY for cases that do not fulfill MCAS criteria. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [63] Valent, 2007, Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria, Eur J Clin Invest source

  • May combine two claims.

    Premisecitation

    Diagnostic MCAS criteria include typical clinical symptoms often with hypotension, an event-related substantial increase in serum tryptase, and symptom response to MC-stabilizing drugs or drugs counteracting MC mediators.

    “Diagnostic MCAS criteria include typical clinical symptoms, often with hypotension, an event-related, substantial increase in serum tryptase levels and response of clinical symptoms to MC-stabilizing drugs or drugs counteracting the effects of MC-derived mediators.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [27] Valent, 2012, Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal, Int Arch Allergy Immunol source
    • cites [28] Valent, 2013, Mast cell activation syndromes: definition and classification, Allergy source

  • May combine two claims.

    Premisecitation

    In affected family members, MCA symptoms if present may be chronic or acute, and other findings such as dysautonomia, chronic pain, and connective tissue abnormalities including joint hypermobility may be observed.

    “In affected family members, symptoms of MCA, if present, may be chronic and/or acute, and other symptoms and findings, including dysautonomia, chronic pain, and connective tissue abnormalities such as joint hypermobility, may also be observed (64-67).”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [64] Lyons, 2014, Mendelian inheritance of elevated serum tryptase associated with atopy and connective tissue abnormalities, J Allergy Clin Immunol source
    • cites [65] Lyons, 2016, Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number, Nat Genet source
    • cites [66] Lyons, 2018, A common haplotype containing functional CACNA1H variants is frequently coinherited with increased TPSAB1 copy number, Genet Med source
    • cites [67] Sabato, 2018, First identification of an inherited TPSAB1 quintuplication in a patient with clonal mast cell disease, J Clin Immunol source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingcitation

    The prevalence of MCAS in pediatric patients is unknown, but cutaneous and systemic reactions have been reported.

    “The prevalence of MCAS in pediatric patients is unknown, but both cutaneous and systemic reactions have been reported (82).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Matito, 2015, Cutaneous and systemic mastocytosis in children: a risk factor for anaphylaxis?, Curr Allergy Asthma Rep source

  • May combine two claims.

    Study design and conductcitation

    The 20%+2 tryptase approach has been validated in mastocytosis and in non-mastocytosis conditions.

    “This approach has recently been validated in the context of mastocytosis (PV, KB and LBS, unpublished data) and non-mastocytosis conditions (44).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Baretto, 2017, Validation of international consensus equation for acute serum total tryptase in mast cell activation: a perioperative perspective, Allergy source

  • May combine two claims.

    Premisecitation

    Indirect signs of occult systemic mastocytosis include elevated baseline serum tryptase after symptom resolution, D816V KIT mutation in circulating blood leukocytes, blood count abnormalities such as eosinophilia, symptoms suggestive of SM such as unexplained osteoporosis or gastrointestinal symptoms, or an elevated REMA or NIHCAS score.

    “Indirect signs for the presence of an underlying (occult) SM include an elevated baseline serum tryptase level detected well after complete resolution of all symptoms or a D816V KIT mutation in circulating blood leukocytes, blood count abnormalities (e.g., eosinophilia), symptoms suggestive of SM such as unexplained osteoporosis, gastrointestinal symptoms (diarrhea, abdominal cramps, malabsorption”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Alvarez-Twose, 2012, Validation of the REMA score for predicting mast cell clonality and systemic mastocytosis in patients with systemic mast cell activation symptoms, Int Arch Allergy Immunol source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The diagnosis of anaphylaxis does not require the MCAS criteria.

    “The diagnosis of anaphylaxis does not require these MCAS criteria.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    In patients with severe recurrent symptoms and a diagnostic tryptase increase but no major improvement with conventional drugs, a provisional diagnosis of possibly MCAS may be established and further treatment introduced.

    “In these cases, a provisional diagnosis of “possibly MCAS” may be established and further treatment should be introduced.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    MC typing is recommended as a diagnostic approach to diagnose or exclude systemic mastocytosis in patients with MCA or MCAS.

    “Rather, MC typing is recommended as a diagnostic approach to diagnose or exclude SM in patients with MCA or MCAS (56-58).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [56] Alvarez-Twose, 2010, Clinical, biological, and molecular characteristics of clonal mast cell disorders presenting with systemic mast cell activation symptoms, J Allergy Clin Immunol source
    • cites [57] Alvarez-Twose, 2014, Nonaggressive systemic mastocytosis (SM) without skin lesions associated with insect-induced anaphylaxis shows unique features versus other indolent SM, J Allergy Clin Immunol source
    • cites [58] Matito, 2014, Anaphylaxis as a clinical manifestation of clonal mast cell disorders, Curr Allergy Asthma Rep source

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    MCAS is a well-defined condition that occurs primarily in patients with IgE-dependent allergies and/or mastocytosis, but may also occur in other conditions.

    “MCAS is a well-defined condition that occurs primarily in patients with IgE-dependent allergies and/or mastocytosis, but may also occur in a number of other conditions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    A diagnosis of MCAS is further supported by an event-related tryptase increase and a sustained prophylactic response to MC-stabilizing drugs or drugs directed against MC mediators.

    “A diagnosis of MCAS is further supported by demonstrating an event-related increase in tryptase and a sustained prophylactic response to MC-stabilizing drugs or drugs directed against MC mediators.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    MC typing is not recommended as a screening approach to define or quantify MCA.

    “Therefore, MC typing is not recommended as a screening approach to define or quantify MCA.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Response of symptoms to MC-stabilizing and/or anti-mediator-type drugs confirms the presence of MCAS.

    “the response of the symptoms to MC-stabilizing and/or anti-mediator-type drugs confirms the presence of MCAS.”
    Quote in the paperNot a substantial claim
26 of 26

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • MCAS is diagnosed when there is documented recurrent episodic occurrence of typical systemic symptoms produced by mast cell mediators and involving at least two organ systems.

    “documented recurrent episodic occurrence of typical systemic symptoms that are produced by MC mediators and involve at least 2 organ systems”

    From Why the 20% + 2 Tryptase Formula Is a Diagnostic Gold Standard for Severe Systemic Mast Cell Activation and Mast Cell Activation Syndrome (2019) · cites this paper as [22]

    The “Symptoms Produced by Systemic MCA” section describes severe, recurrent symptoms affecting more than one organ or tissue, supporting the symptom pattern in the claim. But “Consensus Criteria and Classification of MCAS” says diagnosis also requires biochemical evidence of mast-cell involvement and a response to mediator-targeting treatment; the symptoms alone do not establish MCAS. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Serum tryptase levels serve as the most specific marker and gold standard for measuring MC burden (sBT) as well as MCA and thus MCAS (sAT over sBT).

    “Serum tryptase levels serve as the most speci fi c marker and gold standard for measuring the MC burden (sBT) as well as MCA and thus MCAS (sAT over sBT).”

    From Selecting the Right Criteria and Proper Classification to Diagnose Mast Cell Activation Syndromes: A Critical Review (2021) · cites this paper as [30]

    The Laboratory Assessments section (page not available in our copy) says a substantial event-related rise in serum tryptase above baseline is specific for mast-cell activation and can serve as an MCAS criterion. It does not establish baseline tryptase as a gold-standard measure of mast-cell burden; the section on symptoms that do not meet MCAS criteria also cautions that elevated baseline tryptase occurs in several other conditions. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • The Vienna consensus criteria remain valid and were reconfirmed in 2019 with minor modifications.

    “These criteria remain valid and were recon fi rmed in 2019 with minor modi fi cations.”

    From Selecting the Right Criteria and Proper Classification to Diagnose Mast Cell Activation Syndromes: A Critical Review (2021) · cites this paper as [30]

    The “Consensus Criteria and Classification of MCAS” section applies existing consensus criteria and says all three must be met, supporting their continued validity. Our copy does not identify them as the Vienna criteria or say they were reconfirmed in 2019 with minor modifications; searches for those terms found no such passage. Page numbers were unavailable. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The ECNM proposed two algorithms for the recognition of underlying SM disorders in patients presenting with anaphylaxis.

    “The ECNM proposed two algorithms for the recognition of underlying SM disorders in patient presenting with anaphylaxis.”

    From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [62]

    The Abstract and “Proposed Diagnostic Algorithm for Patients with Suspected MCAS” section describe an algorithm that includes checking for underlying systemic mastocytosis, including occult disease. They do not describe two ECNM algorithms specifically for recognizing underlying SM in patients presenting with anaphylaxis; the proposed algorithm is for suspected MCAS more broadly. Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • For adult patients with MIS, BM biopsy is generally recommended regardless of other findings.

    “For adult patients with MIS, BM biopsy is generally recommended regardless of other findings.”

    From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [62]

    In the ‘Proposed Diagnostic Algorithm for Patients with Suspected MCAS’ section (page unavailable), the paper says a bone marrow investigation may confirm systemic mastocytosis in patients with indirect signs of it. It does not recommend bone marrow biopsy for all adults with MIS regardless of other findings. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting guidance on PGD2 elevation without a tryptase rise

    Minor

    One passage allows MCAS to be considered when PGD2 rises substantially despite normal tryptase, while the summary says a selective mediator rise without a tryptase increase is not associated with MCAS.

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Authors
Valent, P., Akin, C., Bonadonna, P., Hartmann, K., Brockow, K., Niedoszytko, M., Nedoszytko, B., Siebenhaar, F., Sperr, W. R., Oude Elberink, J. N. G., Butterfield, J. H., Alvarez-Twose, I., Sotlar, K., Reiter, A., Kluin-Nelemans, H. C., Hermine, O., Gotlib, J., Broesby-Olsen, S., Orfao, A., Horny, H.-P., Triggiani, M., Arock, M., Schwartz, L. B., & Metcalfe, D. D.
Affiliations
  • Medical University of Vienna (AT)
  • University of Michigan (US)
  • Azienda Ospedaliera Universitaria Integrata Verona (IT)
  • University of Lübeck (DE)
  • Technical University of Munich (DE)
  • Gdańsk Medical University (PL)
  • Charité - Universitätsmedizin Berlin (DE)
  • Mayo Clinic (US)
  • Paracelsus Medical University (AT)
  • Heidelberg University (DE)
  • Université Paris Cité (FR)
  • Stanford Cancer Institute
  • Pathologisches Institut (DE)
  • University of Salerno (IT)
  • Pitié-Salpêtrière Hospital (FR)
  • Virginia Commonwealth University (US)
  • National Institutes of Health (US)
Corresponding author
Valent, Peter
ORCID
Venue
The Journal of Allergy and Clinical Immunology: In Practice
Publisher
Elsevier BV
Published
2019-04
Volume
7
Issue
4
Pages
1125-1133.e1
ISSN
2213-2198 (ISSN-L)
DOI
10.1016/j.jaip.2019.01.006
PMC
PMC6643056
OpenAlex
W2914596877
Cited by
220
References
87
Citations by year
2026: 17 · 2025: 15 · 2024: 21 · 2023: 22 · 2022: 37 · 2021: 53 · 2020: 28 · 2019: 22 · 2014: 1
FWCI
11.25
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Allergy and Clinical Immunology In Practice (publishedVersion)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion, other-oa)
  • PubMed (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
  • PubMed Central (submittedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
  • edoc (University of Basel) (submittedVersion)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
Funders
  • National Institute of Allergy and Infectious Diseases
  • Austrian Science Fund (F4701-B20, F4704-B20)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
  • Health Sciences › Medicine › Rheumatology › Urticaria and Related Conditions
  • Health Sciences › Medicine › Physiology › Asthma and respiratory diseases
Keywords
mast cell activation syndrome, mast cell activation, diagnostic algorithm, misdiagnosis, systemic mastocytosis, severe allergy, differential diagnosis, unnecessary referrals
MeSH terms
Algorithms, Diagnosis, Differential, Humans, Hypersensitivity, Immediate, Mastocytosis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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