Mast cell activation syndrome: Proposed diagnostic criteria

doi:10.1016/j.jaci.2010.08.035

Journal of Allergy and Clinical Immunology

Volume 126, Issue 6, December 2010, Pages 1099-1104.e4

https://doi.org/10.1016/j.jaci.2010.08.035 Get rights and content

The term mast cell activation syndrome (MCAS) is finding increasing use as a diagnosis for subjects who present with signs and symptoms involving the dermis, gastrointestinal track, and cardiovascular system frequently accompanied by neurologic complaints. Such patients often have undergone multiple extensive medical evaluations by different physicians in varied disciplines without a definitive medical diagnosis until the diagnosis of MCAS is applied. However, MCAS as a distinct clinical entity has not been generally accepted, nor do there exist definitive criteria for diagnosis. Based on current understanding of this disease “syndrome” and on what we do know about mast cell activation and resulting pathology, we will explore and propose criteria for its diagnosis. The proposed criteria will be discussed in the context of other disorders involving mast cells or with similar presentations and as a basis for further scientific study and validation.

Section snippets

Historical perspective

In the late 1980s, the existence of “mast cell activation disorders” apparently associated with sudden synchronous mediator release in the absence of evidence of mast cell proliferation began to be discussed in the literature.³ The possibility of such disorders, which would have as their basis activated mast cells, was considered at a consensus conference to classify variants of systemic mastocytosis. To quote, “There also may be unknown diseases of mast cell activation, in which mast cells

Mast cells and mediators

Mast cells are derived from hematopoietic stem cells and undergo terminal differentiation in tissues.¹⁶ They are found concentrated in locations, such as the mucosal and endothelial surfaces, where tissues interface with the external environment. This is consistent with the current understanding of mast cells as sentinels of innate and adaptive immune systems. Although the exact role of mast cells in maintaining a healthy homeostatic state is yet to be understood, mast cells most often come to

Classification of diseases associated with mast cell proliferation/activation

Mast cells play a critical role in the genesis or perpetuation of a number of clinical diseases ranging from those associated with an intrinsic or primary defect in mast cells, such as occurs in mastocytosis, to diseases in which mast cells are recruited through a non–mast cell–dependent, extrinsic mechanism, resulting in a disease associated with “secondary” mast cell activation (Table I).

Proposed criteria for the diagnosis of idiopathic MCAS

The presence of a distinct idiopathic MCAS (Table I), when MMAS has been eliminated, has not been universally accepted. Despite the absence of a consensus for objective guidelines for diagnosis, this syndrome is assigned to some patients with a variable number of unexplained signs and symptoms (see Table E1) and with an otherwise negative diagnostic workup result.

We therefore propose that the diagnosis of MCAS is appropriate when primary and secondary diseases associated with mast cell

Summary

We believe that these recommendations for the diagnosis and management of MCAS form a starting point toward a global classification of mast cell disorders in general and MCAS in specific. To be generally acceptable, this classification scheme must be validated and modified by findings from prospective multicenter clinical studies.

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Using differential mobility spectrometry to improve the specificity of targeted measurements of 2,3-dinor 11β-Prostaglandin F2α
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2,3-dinor 11β-Prostaglandin F2α (BPG) is an arachidonic acid derivative and the most abundant metabolic byproduct of prostaglandin D2, which is released during mast cell activation. Therefore, measurements of BPG in urine using liquid chromatography-tandem mass spectrometry (LC-MS/MS) provide a noninvasive method for evaluation and management of mast cell disorders. Measurements obtained by LC-MS/MS exhibit a high prevalence of chromatographic interferences resulting in challenges with optimal determination of BGP. In this investigation, differential mobility spectrometry (DMS) is utilized to overcome the limitations of current testing.
Urine samples were extracted using an automated solid-phase extraction method. Samples were then analyzed with and without DMS devices installed on two commercially available mass spectrometry platforms to assess the benefits of DMS. Following promising results from a preliminary analytical evaluation, LC-DMS-MS/MS measurements of BPG in urine were fully validated to assess the analytical implications of using this technology.
The addition of DMS devices to the LC-MS/MS systems evaluated in this investigation significantly reduced interferences observed in the chromatograms. Concomitantly, DMS reduced the number of discordant quantifier/qualifier fragment ion results that significantly exceeded the ± 20 % limits, suggesting greater analytical specificity. The validation studies yielded low interday imprecision, with %CVs less than 6.5 % across 20 replicate measurements. Validation studies assessing other aspects of analytical performance also met acceptance criteria.
Incorporating DMS devices greatly improved the specificity of BPG measurements by LC-MS/MS, as evidenced by the comparison of chromatograms and fragment ion results. Validation studies showed exceptional performance for established analytical metrics, indicating that this technology can be used to minimize the impact of interferences without adversely impacting other aspects of analytical or clinical performance.
Mast cells in the autonomic nervous system and potential role in disorders with dysautonomia and neuroinflammation
2024, Annals of Allergy, Asthma and Immunology
Mast cells (MC) are ubiquitous in the body, and they are critical for not only in allergic diseases but also in immunity and inflammation, including having potential involvement in the pathophysiology of dysautonomias and neuroinflammatory disorders. MC are located perivascularly close to nerve endings and sites such as the carotid bodies, heart, hypothalamus, the pineal gland, and the adrenal gland that would allow them not only to regulate but also to be affected by the autonomic nervous system (ANS). MC are stimulated not only by allergens but also many other triggers including some from the ANS that can affect MC release of neurosensitizing, proinflammatory, and vasoactive mediators. Hence, MC may be able to regulate homeostatic functions that seem to be dysfunctional in many conditions, such as postural orthostatic tachycardia syndrome, autism spectrum disorder, myalgic encephalomyelitis/chronic fatigue syndrome, and Long-COVID syndrome. The evidence indicates that there is a possible association between these conditions and diseases associated with MC activation. There is no effective treatment for any form of these conditions other than minimizing symptoms. Given the many ways MC could be activated and the numerous mediators released, it would be important to develop ways to inhibit stimulation of MC and the release of ANS-relevant mediators.
Dilemma of Mast Cell Activation Syndrome: Overdiagnosed or Underdiagnosed?
2024, Journal of Allergy and Clinical Immunology: In Practice
World Health Organization Classification and Diagnosis of Mastocytosis: Update 2023 and Future Perspectives
2023, Immunology and Allergy Clinics of North America
Management of Mediator Symptoms, Allergy, and Anaphylaxis in Mastocytosis
2023, Immunology and Allergy Clinics of North America
Histamine elevation in familial Mediterranean fever: A study from the Juvenile Inflammatory Rheumatism cohort
2023, European Journal of Internal Medicine
Familial Mediterranean Fever (FMF) is the most frequent monogenic autoinflammatory disease (AID). Some patients have persistent symptoms despite colchicine intake. Mast cells (MC) are innate immune cells involved in inflammatory conditions including AID. Their activation is responsible for various symptoms such as abdominal pain, bloating and pruritus.
Our objective was to evaluate features of a systemic MC activation in FMF adult patients.
FMF adult patients prospectively filled a MC activation survey and usual MC mediators (tryptase and histamine in whole blood, plasma and urine) were measured. They were compared with a healthy control group (HC) and a systemic mastocytosis (SM) group. When digestive biopsies were realized during follow-up, MC infiltration in digestive mucosa was analyzed in FMF, in comparison with SM, Crohn disease (CD) and normal biopsies.
Forty-four FMF patients, 44 HC and 44 SM patients were included. Thirty-one (70%) FMF patients had symptoms of mast cell activation, versus 14 (32%) in the HC group (p = 0.0006). Thirty (68%) FMF patients had at least one elevated MC mediator: mainly whole blood histamine, in 19 (43%) and urinary histamine, in 14 (32%), which were significantly higher than in HC subjects. MC infiltration was comparable in FMF digestive biopsies, biopsies of CD and normal biopsies but was lower than in SM biopsies.
FMF patients show frequent symptoms of MC activation and an increase of blood or urinary histamine never described before in this disease. This suggests an implication of MC and possibly basophils in FMF pathophysiology.

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: Supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, and grants #P21173-B13 and #SFB-F01820 of the Fonds zur Förderung der Wissenschaftlichen Forschung in Österreich (FWF).

: Disclosure of potential conflict of interest: C. Akin receives research support from the Food Allergy Initiative, has provided legal consultation/expert witness testimony in cases related to anaphylaxis, and is on the Medical Advisory Board for the Mastocytosis Society. P. Valent receives research support from Novartis and Bristol-Myers Squibb. D. D. Metcalfe receives research support from the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, and is a member of the Editorial Board for the World Allergy Organization.

^∗: Dr Akin is currently affiliated with the Department of Medicine, Division of Rheumatology, Allergy and Immunology, Brigham and Women’s Hospital, Boston, Mass.

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Reviews and feature articleMast cell activation syndrome: Proposed diagnostic criteria

Section snippets

Historical perspective

Mast cells and mediators

Classification of diseases associated with mast cell proliferation/activation

Proposed criteria for the diagnosis of idiopathic MCAS

Summary

Endocrinol Metab Clin North Am

J Allergy Clin Immunol

Blood

Cell Signal

Lancet

J Allergy Clin Immunol

Blood

Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Reviews and feature article
Mast cell activation syndrome: Proposed diagnostic criteria