Cited by 225Mast cells and histamineFood Allergy and Anaphylaxis ResearchAsthma and respiratory diseases

The DOI matches its Crossref record; 86 of the 87 references it cites were found in a registry or an index; 66 of the 133 sources its claims cite were checked for support.

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, Sperr, Wolfgang R., Oude Elberink, Joanna N.G., Butterfield, Joseph H., Alvarez-Twose, Ivan, Sotlar, Karl, Reiter, Andreas, Kluin-Nelemans, Hanneke C., Hermine, Olivier, Gotlib, Jason, Broesby-Olsen, Sigurd, Orfao, Alberto, Horny, Hans-Peter, Triggiani, Massimo, Arock, Michel, Schwartz, Lawrence B., Metcalfe, Dean D.·2019·The Journal of Allergy and Clinical Immunology: In Practice

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…

Overview

AI snapshot

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.

Verification

Claims the paper makes

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

Show all 27 claims

  • Probably not a substantial claim. 12
  • It may state two separate claims as one. 18
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?

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.

1 of 1

Citations

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Metadata

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 (US)
  • Pathologisches Institut (DE)
  • University of Salerno (IT)
  • Pitié-Salpêtrière Hospital (FR)
  • Virginia Commonwealth University (US)
  • National Institutes of Health (US)
Corresponding author
Valent, Peter
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)
OpenAlex
W2914596877
Cited by
225
References
87
Citations by year
2026: 21 · 2025: 17 · 2024: 21 · 2023: 24 · 2022: 36 · 2021: 53 · 2020: 28 · 2019: 22
FWCI
2.89
Type
journal article
Language
en
Open access
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 (acceptedVersion)
  • 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 › Immunology and Allergy › Food Allergy and Anaphylaxis Research
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › 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, Proto-Oncogene Proteins c-kit, Mastocytosis, Systemic, Tryptases

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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.

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