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Cited by 45Mast cells and histamineFood Allergy and Anaphylaxis ResearchAsthma and respiratory diseases

Mast cell activation syndrome: Current understanding and research needs

Open access
Castells, Mariana, Giannetti, Matthew P., Hamilton, Matthew J., Novak, Peter, Pozdnyakova, Olga, Nicoloro-SantaBarbara, Jennifer, Jennings, Susan V., Francomano, Clair +16 more·2024·Journal of Allergy and Clinical Immunology
DOI 10.1016/j.jaci.2024.05.025PMC PMC11881543
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Abstract

Mast cell activation syndrome (MCAS) is a term applied to several clinical entities that have gained increased attention from patients and medical providers. Although several descriptive publications about MCAS exist, there are many gaps in knowledge, resulting in confusion about this clinical syndrome. Whether MCAS is a primary syndrome or exists as a constellation of symptoms in the context of known inflammatory, allergic, or clonal disorders associated with systemic mast cell activation is not well understood. More importantly, the underlying mechanisms and pathways that lead to mast cell activation in MCAS patients remain to be elucidated. Here we summarize the known literature, identify gaps in knowledge, and highlight research needs. Covered topics include contextualization of MCAS and MCAS-like endotypes and related diagnostic evaluations; mechanistic research; management of typical and refractory symptoms; and MCAS-specific education for patients and health care providers.

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Crossref · 10.1016/j.jaci.2024.05.025

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 52 cited sources checked · 0 supported · 0 flagged

  • Findingnone given

    No randomized trials have demonstrated that a particular MCAS phenotype or MC mediator level is associated with a specific treatment response.

    “No randomized trials have been conducted to demonstrate that a particular phenotype or MC mediator level is associated with a specific treatment response.”
    Quote in the paperSubstantial claim
  • Premisecitation

    An event-related increase in serum tryptase over baseline is the most specific marker of mast cell activation.

    “The event-related increase in serum tryptase levels over baseline is the most specific marker of MCA.6–8”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6] De Schryver, 2016, Tryptase levels in children presenting with anaphylaxis: temporal trends and associated factors, J Allergy Clin Immunol source

      Not checked in the free run.

    • cites [7] Baretto, 2017, Validation of international consensus equation for acute serum total tryptase in mast cell activation: a perioperative perspective, Allergy source

      Not checked in the free run.

    • cites [8] Valent, 2019, Why the 20% + 2 tryptase formula is a diagnostic gold standard for severe systemic mast cell activation and mast cell activation syndrome, Int Arch Allergy Immunol source

      Not checked in the free run.

  • Premisenone given

    Other mast cell-derived mediators that may reflect MCA include event-related increases in blood histamine, urine N-methyl histamine, leukotriene E4, prostaglandin D2, and 11β-PGF2α.

    “Other MC-derived mediators, which may reflect MCA, include an event-related increase in blood histamine, urine N-methyl histamine, leukotriene E4, prostaglandin D2 (PGD2), and a PGD2 metabolite, 11β-PGF2α(Fig 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fig 2

      Not checked in the free run.

  • Premisereasoning

    The absence of a serum tryptase increase does not rule out mast cell involvement, MCAS, or anaphylaxis.

    “The absence of an increase in serum tryptase does not preclude MC involvement, MCAS, or anaphylaxis”
    Quote in the paperSubstantial claim
  • Premisecitation

    Recent systematic evaluations of suspected MCAS patients found that less than 5% met strict criteria for primary or idiopathic MCAS.

    “Recent studies that attempted to systematically evaluate individuals with suspected MCAS showed that only a small fraction (<5%) of patients met strict criteria for primary or idiopathic MCAS,11,12”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] Zaghmout, 2024, Low prevalence of idiopathic mast cell activation syndrome among 703 patients with suspected mast cell disorders, J Allergy Clin Immunol Pract source

      Not checked in the free run.

    • cites [12] Buttgereit, 2022, Idiopathic mast cell activation syndrome is more often suspected than diagnosed—a prospective real-life study, Allergy source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 9
  • May combine two claims. 18

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

    Premisecitation

    Local and less severe forms of mast cell activation do not meet MCAS criteria.

    “In contrast, local and less severe forms of MCA do not fulfill the MCAS criteria.2”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Valent, 2022, Global classification of mast cell activation disorders: an ICD-10-CM–adjusted proposal of the ECNM-AIM Consortium, J Allergy Clin Immunol Pract source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    The 2022 consensus diagnostic criteria for MCAS were developed by consensus from literature review and expert opinion, have been validated, and are considered standard.

    “These criteria were developed by consensus based on literature review and expert opinion, have been validated, and are considered standard.6–9”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [6] De Schryver, 2016, Tryptase levels in children presenting with anaphylaxis: temporal trends and associated factors, J Allergy Clin Immunol source

      Not checked in the free run.

    • cites [7] Baretto, 2017, Validation of international consensus equation for acute serum total tryptase in mast cell activation: a perioperative perspective, Allergy source

      Not checked in the free run.

    • cites [8] Valent, 2019, Why the 20% + 2 tryptase formula is a diagnostic gold standard for severe systemic mast cell activation and mast cell activation syndrome, Int Arch Allergy Immunol source

      Not checked in the free run.

    • cites [9] Valent, 2022, Mast cell activation syndromes: Collegium Internationale Allergologicum update 2022, Int Arch Allergy Immunol source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    MCAS is defined by severe recurrent systemic symptoms related to mast cell activation that resemble anaphylaxis.

    “MCAS is defined by severe recurrent systemic symptoms related to MCA, which resemble anaphylaxis.8,9,13”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [8] Valent, 2019, Why the 20% + 2 tryptase formula is a diagnostic gold standard for severe systemic mast cell activation and mast cell activation syndrome, Int Arch Allergy Immunol source

      Not checked in the free run.

    • cites [9] Valent, 2022, Mast cell activation syndromes: Collegium Internationale Allergologicum update 2022, Int Arch Allergy Immunol source

      Not checked in the free run.

    • cites [13] Valent, 2019, Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome, J Allergy Clin Immunol Pract source

      Not checked in the free run.

    • Rests on an assumption: Symptoms attributed to MCAS are caused by mast cell activation.

  • May combine two claims.

    Premisecitation

    An acute tryptase/BST ratio exceeding 1.6 is an optimized diagnostic rule with high sensitivity and specificity in SM and HαT, but the 20% of baseline + 2 ng/mL formula should be applied to cover all basal tryptase ranges.

    “A ratio of acute tryptase/BST exceeding 1.6 provides an optimized diagnostic rule with high sensitivity and specificity in SM and HαT, but in order to cover all disorders (all ranges of basal tryptase), the 20% of baseline + 2 ng/mL formula should be applied.19”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Mateja, 2022, Defining baseline variability of serum tryptase levels improves accuracy in identifying anaphylaxis, J Allergy Clin Immunol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Atypical mast cell activation symptoms may be associated with serum elevation of IL-6 and are observed in patients with acute reactions to monoclonal antibodies and chemotherapy.

    “These atypical symptoms may be associated with serum elevation of IL-6 and are observed in patients with acute reactions to monoclonal antibodies and chemotherapy.15”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Jakubovic, 2020, Drug hypersensitivity in the fast lane, Ann Allergy Asthma Immunol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    New phenotypes of non-IgE-mediated mast cell activation have been described with atypical symptoms such as fever, chills, chest or back pain, and hypertension, possibly triggered by cytokines released from mast cells.

    “New phenotypes of non–IgE-mediated MCA have been described14 in which atypical symptoms of MCA, such as fever, chills, chest or back pain, and hypertension, may be present, which might be triggered by cytokines released from MC.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Castells, 2017, Diagnosis and management of anaphylaxis in precision medicine, J Allergy Clin Immunol source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Mast cell activation syndromes are characterized by recurrent episodes of systemic symptoms linked to the release of mast cell-derived mediators.

    “Mast cell activation syndromes (MCASs) are characterized by recurrent episodes of systemic symptoms associated with the release of mast cell (MC)-derived mediators (Fig 1).1,2”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Akin, 2010, Mast cell activation syndrome: proposed diagnostic criteria, J Allergy Clin Immunol source

      Not checked in the free run.

    • cites [2] Valent, 2022, Global classification of mast cell activation disorders: an ICD-10-CM–adjusted proposal of the ECNM-AIM Consortium, J Allergy Clin Immunol Pract source

      Not checked in the free run.

    • Rests on an assumption: Symptoms attributed to MCAS are caused by mast cell activation.

  • May combine two claims.

    Premisecitation

    Advantages of urine testing include real-time collection and at-home performance without relying on acute care facilities.

    “Advantages of urine testing include real-time collectionand all diagnostic MCAS criteria are fulfilled and at-home performance, without relying on acute care facilities.21”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Butterfield, 2022, Nontryptase urinary and hematologic biomarkers of mast cell expansion and mast cell activation: status, 2022, J Allergy Clin Immunol Pract source

      Not checked in the free run.

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

    Premisecitation

    Proposed thresholds for increases above baseline include urinary N-methylhistamine >400 μg/g Cr and 11β-PGF2α >3500 ng/d.

    “Recently a range has been proposed for increases above baseline and includes urinary N-methylhistamine >400 μg/g Cr and 11β-PGF2α>3500 ng/d.21”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Butterfield, 2022, Nontryptase urinary and hematologic biomarkers of mast cell expansion and mast cell activation: status, 2022, J Allergy Clin Immunol Pract source

      Not checked in the free run.

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

    Interpretationnone given

    The lack of evidence-based diagnostic guidelines, paucity of correlative diagnostic parameters, inconsistent symptomatology, limited physician knowledge, and lack of coordinated physician networks collectively create challenges for patients and providers.

    “The lack of evidence-based diagnostic guidelines, a paucity of correlative diagnostic parameters, inconsistent symptomatology, limited physician knowledge, and lack of coordinated physician networks collectively present challenges for both patients and providers.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    HαT has been associated with connective tissue abnormalities, chronic musculoskeletal pain, and/or POTS-like symptoms, and over half reported neuropsychiatric diagnoses.

    “HαT was associated with connective tissue abnormalities, chronic musculoskeletal pain, and/or POTS-like symptoms, and over half reported neuropsychiatric diagnoses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Omalizumab has been reported to reduce anaphylaxis frequency and severity in case reports and noncontrolled small case series of SM patients, and similar effects have been reported in retrospective analyses of symptomatic HαT individuals referred for MCAD.

    “Omalizumab has been reported to reduce the frequency and severity of anaphylaxis in case reports and noncontrolled small case series of patients with SM, and in retrospective analyses of symptomatic individuals with HαT referred for MCAD, a similar effect has been reported.18,67”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [18] Giannetti, 2021, Hereditary alpha-tryptasemia in 101 patients with mast cell activation–related symptomatology including anaphylaxis, Ann Allergy Asthma Immunol source

      Not checked in the free run.

    • cites [67] Broesby-Olsen, 2018, Omalizumab prevents anaphylaxis and improves symptoms in systemic mastocytosis: efficacy and safety observations, Allergy source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a study of 493 POTS patients (86% female), only 7.2% had BST ≥8 ng/mL and only 3.6% had BST >11.4 ng/mL.

    “In a recent study of 493 patients with POTS (of which 86% were female), only 7.2% of individuals had a BST level of ≥8 ng/mL, and only 3.6% had a BST level of >11.4 ng/mL.55”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Huang, 2021, The prevalence of hereditary alpha-tryptasemia in patients diagnosed with POTS via tilt table testing, J Allergy Clin Immunol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MCAS has been reported with congenital connective tissue disorders such as hypermobility EDS and dysautonomia such as POTS or autonomic failure, for which an autoimmune association has been suggested.

    “MCAS has been reported in conjunction with congenital connective tissue disorders (such as hypermobility EDS) and dysautonomia (as in patients with POTS or autonomic failure),17,52,53 for which an association with autoimmunity has been suggested.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [17] Lyons, 2016, Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number, Nat Genet source

      Not checked in the free run.

    • cites [52] Lyons, 2014, Mendelian inheritance of elevated serum tryptase associated with atopy and connective tissue abnormalities, J Allergy Clin Immunol source

      Not checked in the free run.

    • cites [53] Abonia, 2013, High prevalence of eosinophilic esophagitis in patients with inherited connective tissue disorders, J Allergy Clin Immunol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Almost three quarters of an MCAD sample reported clinically meaningful depressive symptoms, and most had substantially more symptoms than can be ascribed to MCAS.

    “In fact, almost three quarters of the sample reported clinically meaningful levels of depressive symptoms, and most have substantially more symptoms than can be ascribed to MCAS.74”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] Nicoloro-SantaBarbara, 2022, Depression, psychosocial correlates, and psychosocial resources in individuals with mast cell activation syndrome, J Health Psychol source

      Not checked in the free run.

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

    Premisecitation

    MCA and MCAD impose a substantial burden on patients and their families, supporting the need for patient and caregiver education.

    “MCA and MCAD also impose a substantial burden on patients and their families, supporting the need for patient and caregiver education.71”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Jennings, 2014, The mastocytosis society survey on mast cell disorders: patient experiences and perceptions, J Allergy Clin Immunol Pract source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Human studies provide evidence for the role of mast cells and MCA in rhinitis, asthma, urticaria, food allergy, and anaphylaxis, but evidence for their role in neurologic and psychiatric symptoms associated with MCAS is limited.

    “Human studies have provided evidence of the role of MCs and MCA in rhinitis, asthma, urticaria, food allergy, and anaphylaxis, but there is limited evidence of the role of MCs in neurologic and psychiatric symptoms associated to MCAS.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a study of 69 patients with POTS-like symptoms, 29 (65%) of 44 patients who also reported MCA symptoms had elevations of MC biomarkers (52% histamine, 36% prostaglandins, 9% tryptase), while none without MCA symptoms had mediator elevation.

    “A recent study of 69 patients with postural orthostatic tachycardia syndrome (POTS)-like symptoms found that 29 (65%) of 44 patients who also reported MCA symptoms had elevations of MC biomarkers (52% histamine in plasma or urine, 36% prostaglandins in plasma or urine, and 9% tryptase), while none of those without symptoms of MCA had elevation of mediators.25”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Kohno, 2021, Mast cell activation disorder and postural orthostatic tachycardia syndrome: a clinical association, J Am Hearth Assoc

      Not checked in the free run.

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

    Interpretationnone given

    Misattribution of symptoms unrelated to abnormal MC activity as MCAS can lead to inappropriate treatments, misplaced hope, and failure to better understand alternative diagnoses.

    “Furthermore, misattribution of symptoms un-related to abnormal MC activity, as MCAS can lead to inappropriate treatments, misplaced hope, and failure to better understand alternative diagnoses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    HαT is enriched in patients with SM, Hymenoptera-allergic patients with severe anaphylaxis, and patients with idiopathic anaphylaxis.

    “HαT is enriched in patients with SM,42,43 in Hymenoptera-allergic patients with severe anaphylaxis,44,45 and in patients with idiopathic anaphylaxis.42,43,45,46”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [42] Lyons, 2017, TPSAB1 genotype and effects of pro-tryptases on human mast cell–associated disorders, J Allergy Clin Immunol source

      Not checked in the free run.

    • cites [43] Greiner, 2021, Hereditary α tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis, Blood source

      Not checked in the free run.

    • cites [44] Selb, 2021, Routine KIT p.D816V screening identifies clonal mast cell disease in patients with Hymenoptera allergy regularly missed using baseline tryptase levels alone, J Allergy Clin Immunol source

      Not checked in the free run.

    • cites [45] Lyons, 2021, Heritable risk for severe anaphylaxis associated with increased α-tryptase–encoding germline copy number at TPSAB1, J Allergy Clin Immunol source

      Not checked in the free run.

    • cites [46] Sordi, 2023, Disease correlates and clinical relevance of hereditary α-tryptasemia in patients with systemic mastocytosis, J Allergy Clin Immunol source

      Not checked in the free run.

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

    Interpretationnone given

    MCASs comprise an array of syndromes and diseases with different phenotypes and a central pathophysiologic mechanism of local and/or systemic MCA that may affect many aspects of an individual's life.

    “MCASs comprise an array of syndromes and diseases presenting with different phenotypes with the central pathophysiologic mechanism of local and/or systemic MCA, which may affect many aspects of an individual’s life.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Symptoms attributed to MCAS are caused by mast cell activation.

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

    Premisenone given

    Female sex is overrepresented in idiopathic MCAS, underscoring the need for research on underlying mechanisms and genetic/hormonal alterations in MCA.

    “Female sex is overrepresented in idiopathic MCAS, underscoring the need for research regarding the underlying mechanisms and genetic/hormonal alterations in MCA.”
    Quote in the paperNot a substantial claim
22 of 22

  • The paper relies on this without support.

    Symptoms attributed to MCAS are caused by mast cell activation.

    “Mast cell activation syndromes (MCASs) are characterized by recurrent episodes of systemic symptoms associated with the release of mast cell (MC)-derived mediators (Fig 1).1,2”
    “MCAS is defined by severe recurrent systemic symptoms related to MCA, which resemble anaphylaxis.8,9,13”
1 of 1

The citation lists haven’t been fetched yet

References 77 · Cited by 45

Research works printed but not linked: 2

  1. Kohno, 2021, Mast cell activation disorder and postural orthostatic tachycardia syndrome: a clinical association, J Am Hearth Assoc, 10
  2. Weinstock, 2018, Successful treatment of postural orthostatic tachycardia and mast cell activation syndromes using naltrexone, immunoglobulin and antibiotic treatment, BMJ Case Rep, 2018

Authors
Castells, M., Giannetti, M. P., Hamilton, M. J., Novak, P., Pozdnyakova, O., Nicoloro-SantaBarbara, J., Jennings, S. V., Francomano, C., Kim, B., Glover, S. C., Galli, S. J., Maitland, A., White, A., Abonia, J. P., Slee, V., Valent, P., Butterfield, J. H., Carter, M., Metcalfe, D. D., Akin, C., Lyons, J. J., Togias, A., Wheatley, L., & Milner, J. D.
Affiliations
  • Brigham and Women's Hospital (US)
  • Mast Cell Disease Society (US)
  • Riley Hospital for Children (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Tulane University (US)
  • Stanford Medicine (US)
  • Scripps Health (US)
  • Cincinnati Children's Hospital Medical Center (US)
  • Ludwig Boltzmann Institute for Hematology and Oncology (AT)
  • Mayo Clinic (US)
  • National Institutes of Health (US)
  • University of Michigan (US)
  • University of California San Diego (US)
  • Columbia University Irving Medical Center (US)
Corresponding author
Castells, Mariana
ORCID
Venue
Journal of Allergy and Clinical Immunology
Publisher
Elsevier BV
Published
2024-08
Volume
154
Issue
2
Pages
255-263
ISSN
0091-6749 (ISSN-L)
DOI
10.1016/j.jaci.2024.05.025
PMC
PMC11881543
OpenAlex
W4399392441
Cited by
45
References
77
Citations by year
2026: 26 · 2025: 18 · 2024: 1
FWCI
1.99
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Allergy and Clinical Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Pfizer
  • Celgene
  • Division of Intramural Research, National Institute of Allergy and Infectious Diseases
  • Novavax
  • Moderna
  • University of Oxford
  • Foundation for Biomedical Research and Innovation
  • AOP Orphan
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (OT2HL156812)
  • National Institute of Allergy and Infectious Diseases (SI2 AI138586, R00AI138586)
  • NHLBI Division of Intramural Research
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 › Physiology › Asthma and respiratory diseases
Keywords
mast cell activation syndrome, mast cell activation, diagnostic assessment, pathophysiological mechanisms, refractory symptoms, symptom management, patient education, health care provider education
MeSH terms
Animals, Humans, Mast Cells, Mastocytosis, Syndrome

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