Mast cell activation syndrome

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Mast cell activation syndrome
Specialty Immunology (Allergy)

Mast cell activation syndrome (MCAS) is a term referring to one of two types of mast cell activation disorder (MCAD); the other type is idiopathic MCAD. [1] MCAS is an immunological condition in which mast cells inappropriately and excessively release chemical mediators, resulting in a range of chronic symptoms, sometimes including anaphylaxis or near-anaphylaxis attacks. [2] [3] [4] Primary symptoms include cardiovascular, dermatological, gastrointestinal, neurological and respiratory problems. [3]

Contents

MCAS is an umbrella term that describes a set of symptoms; it is not a specific diagnosis. [1] [5] Multiple diagnostic schemes for MCAS have been proposed. MCAS has often been misdiagnosed, especially as medical professionals and patients don’t understand that symptoms can wax or wane, and it can be a seemingly slow buildup with symptoms occurring in multiple organ systems before anaphylaxis type episodes; most doctors are not trained to recognize its symptoms nor know much about what to do with it; after all, it was only in 2010 that diagnostic criteria was formalized. [6]

Signs and symptoms

MCAS can present with a wide range of symptoms in multiple body systems, these symptoms may range from digestive discomfort to chronic pain, mental issues as well as an anaphylactic reaction. Symptoms typically wax and wane over time, varying in severity and duration. Many signs and symptoms are the same as those for mastocytosis, because both conditions result in too many mediators released by mast cells. [7] It has many overlapping characteristics with recurrent idiopathic anaphylaxis, although there are distinguishing symptoms, specifically hives and angioedema. [8] The condition may be mild until exacerbated by stressful life events, or symptoms may develop and slowly trend worse with time. MCAS symptoms are common in long COVID. [9]

Common symptoms include: [10]

Causes

There are many causes of mast cell activation, including allergy. Genetics may play a role. In particular, Mutations of the KIT gene (which codes for the KIT protein that regulates cell growth and specifically ), specifically around codon 816 with the common one being asp816val, have been suspected to be associated with MCAS and is also associated to most systemic mastocytosis patients. [11] [12] It has been found that MCAS patients tend to have a wider range of KIT mutations around all domains of the protein and multiple at the same time rather than a single one, which could be a potential cause of the heterogeneity of the presenting symptoms of MCAS. Symptoms of MCAS are caused by excessive chemical mediators released by mast cells. [13] Mediators include leukotrienes, histamines, prostaglandin, and tryptase. [14]

Pathophysiology

Mast cell activation can be localized or systemic, but a diagnosis of MCAS requires systemic symptoms. [15] [16] Some examples of tissue specific consequences of mast cell activation include urticaria, allergic rhinitis, and wheezing. Systemic mast cell activation presents with symptoms involving two or more organ systems (skin: urticaria, angioedema, and flushing; gastrointestinal: nausea, vomiting, diarrhea, and abdominal cramping; cardiovascular: hypotensive syncope or near syncope and tachycardia; respiratory: wheezing; naso-ocular: conjunctival injection, pruritus, and nasal stuffiness). This can result from the release of mediators from a specific site, such as the skin or mucosal tissue, or activation of mast cells around the vasculature. [17]

Diagnosis

MCAS is often difficult to identify due to the heterogeneity of symptoms and the "lack of flagrant acute presentation". [10] Many of the numerous symptoms are non-specific in nature. Diagnostic criteria were proposed in 2010 [3] and revised in 2019. [16] Mast cell activation was assigned an ICD-10 code (D89.40, along with subtype codes D89.41-43 and D89.49) in October 2016. [18]

According to the American Academy of Allergy, Asthma, and Immunology (AAAI), the most precise method of diagnosing MCAS is through a bone marrow biopsy and aspirate. [16] This method is commonly used to diagnose systemic mastocytosis, and the presence of SM increases the possibility of subsequently having MCAS. In addition, other common laboratory tests including KIT-D816X mutational analysis and flow cytometry analysis seeking co-expression of CD117 and CD25 are also commended for diagnosing clonal MCAS. [19]

Although different diagnostic criteria are published, a commonly used strategy to diagnose patients is to use all three of the following:[ citation needed ]

  1. Symptoms consistent with chronic/recurrent mast cell release:
    Recurrent abdominal pain, diarrhea, flushing, itching, nasal congestion, coughing, chest tightness, wheezing, lightheadedness (usually a combination of some of these symptoms is present)
  2. Laboratory evidence of mast cell mediator (elevated serum tryptase, N-methyl histamine, prostaglandin D2 or 11-beta- prostaglandin F2 alpha, leukotriene E4 and others)
  3. Improvement in symptoms with the use of medications that block or treat elevations in these mediators

According to the British Medical Journal Best Practices, a diagnosis of MCAS is confirmed by evidence of a significant rise in a mast cell marker (e.g., serum tryptase) during acute episodes and a positive clinical response to a medication that targets a mast cell mediator. It is important to then evaluate the MCAS subtype: primary (clonal), secondary (usually associated with IgE-dependent allergy), or idiopathic. [20] For a diagnosis of MCAS to be confirmed:

  1. There must be recurrent, acute episodes of symptoms/signs associated with secreted mast cell mediators that affect two or more organ systems at the same time
  2. A transient rise in a mast cell mediator (e.g., tryptase) must be confirmed during these acute episodes
  3. The symptoms must respond to drugs that either target released mast cell mediators or suppress mast cell activation (e.g., antihistamine, H2 antagonist, leukotriene receptor antagonist, cromolyn).

In most cases, MCAS presents with recurrent episodes of anaphylaxis.

The World Health Organization has not published diagnostic criteria.

Treatment

Pharmacological treatments include:

Prognosis

The prognosis of MCAS is uncertain. [16]

History

The condition was hypothesized by the pharmacologists Oates and Roberts of Vanderbilt University in 1991, and named in 2007, following a build-up of evidence featured in papers by Sonneck et al. [23] and Akin et al. [24] [7]

See also

Related Research Articles

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Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, allergic asthma, and anaphylaxis. Symptoms may include red eyes, an itchy rash, sneezing, coughing, a runny nose, shortness of breath, or swelling. Note that food intolerances and food poisoning are separate conditions.

<span class="mw-page-title-main">Anaphylaxis</span> Life-threatening allergic reaction

Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the following: an itchy rash, throat closing due to swelling that can obstruct or stop breathing; severe tongue swelling that can also interfere with or stop breathing; shortness of breath, vomiting, lightheadedness, loss of consciousness, low blood pressure, and medical shock. These symptoms typically start in minutes to hours and then increase very rapidly to life-threatening levels. Urgent medical treatment is required to prevent serious harm and death, even if the patient has used an epipen or has taken other medications in response, and even if symptoms appear to be improving.

<span class="mw-page-title-main">Mastocytosis</span> Medical condition

Mastocytosis, a type of mast cell disease, is a rare disorder affecting both children and adults caused by the accumulation of functionally defective mast cells and CD34+ mast cell precursors.

<span class="mw-page-title-main">Eosinophilia</span> Blood condition

Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds 5×108/L (500/μL). Hypereosinophilia is an elevation in an individual's circulating blood eosinophil count above 1.5 × 109/L (i.e. 1,500/μL). The hypereosinophilic syndrome is a sustained elevation in this count above 1.5 × 109/L (i.e. 1,500/μL) that is also associated with evidence of eosinophil-based tissue injury.

<span class="mw-page-title-main">Mast cell</span> Cell found in connective tissue

A mast cell is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a part of the immune and neuroimmune systems. Mast cells were discovered by Paul Ehrlich in 1877. Although best known for their role in allergy and anaphylaxis, mast cells play an important protective role as well, being intimately involved in wound healing, angiogenesis, immune tolerance, defense against pathogens, and vascular permeability in brain tumors.

<span class="mw-page-title-main">Immunoglobulin E</span> Immunoglobulin E (IgE) Antibody

Immunoglobulin E (IgE) is a type of antibody that has been found only in mammals. IgE is synthesised by plasma cells. Monomers of IgE consist of two heavy chains and two light chains, with the ε chain containing four Ig-like constant domains (Cε1–Cε4). IgE is thought to be an important part of the immune response against infection by certain parasitic worms, including Schistosoma mansoni, Trichinella spiralis, and Fasciola hepatica. IgE is also utilized during immune defense against certain protozoan parasites such as Plasmodium falciparum. IgE may have evolved as a defense to protect against venoms.

<span class="mw-page-title-main">Omalizumab</span> Monoclonal antibody medication

Omalizumab, sold under the brand name Xolair, is an injectable medication to treat severe persistent allergic forms of asthma, nasal polyps, urticaria (hives), and immunoglobulin E-mediated food allergy.

<span class="mw-page-title-main">Aspirin-exacerbated respiratory disease</span> Chronic inflammatory disease affecting the sinuses and lungs

Aspirin-exacerbated respiratory disease (AERD), also called NSAID-exacerbated respiratory disease (N-ERD) or historically aspirin-induced asthma and Samter's Triad, is a long-term disease defined by three simultaneous symptoms: asthma, chronic rhinosinusitis with nasal polyps, and intolerance of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). Compared to aspirin tolerant patients, AERD patients' asthma and nasal polyps are generally more severe. Reduction or loss of the ability to smell is extremely common, occurring in more than 90% of people with the disease. AERD most commonly begins in early- to mid-adulthood and has no known cure. While NSAID intolerance is a defining feature of AERD, avoidance of NSAIDs does not affect the onset, development or perennial nature of the disease.

<span class="mw-page-title-main">Tryptase</span> Class of enzymes

Tryptase is the most abundant secretory granule-derived serine proteinase contained in mast cells and has been used as a marker for mast cell activation. Club cells contain tryptase, which is believed to be responsible for cleaving the hemagglutinin surface protein of influenza A virus, thereby activating it and causing the symptoms of flu.

<span class="mw-page-title-main">Ketotifen</span> Antihistamine medication

Ketotifen is an antihistamine medication and a mast cell stabilizer used to treat allergic conditions such as conjunctivitis, asthma, and urticaria (hives). Ketotifen is available in ophthalmic and oral forms: the ophthalmic form relieves eye itchiness and irritation associated with seasonal allergies, while the oral form helps prevent systemic conditions such as asthma attacks and allergic reactions. In addition to treating allergies, ketotifen has shown efficacy in managing systemic mast cell diseases such as mastocytosis and mast cell activation syndrome (MCAS), which involve abnormal accumulation or activation of mast cells throughout the body. Ketotifen is also used for other allergic-type conditions like atopic dermatitis (eczema) and food allergies.

<span class="mw-page-title-main">Soy allergy</span> Type of food allergy caused by soy

Soy allergy is a type of food allergy. It is a hypersensitivity to ingesting compounds in soy, causing an overreaction of the immune system, typically with physical symptoms, such as gastrointestinal discomfort, respiratory distress, or a skin reaction. Soy is among the eight most common foods inducing allergic reactions in children and adults. It has a prevalence of about 0.3% in the general population.

<span class="mw-page-title-main">Milk allergy</span> Type of food allergy caused by milk

Milk allergy is an adverse immune reaction to one or more proteins in cow's milk. Symptoms may take hours to days to manifest, with symptoms including atopic dermatitis, inflammation of the esophagus, enteropathy involving the small intestine and proctocolitis involving the rectum and colon. However, rapid anaphylaxis is possible, a potentially life-threatening condition that requires treatment with epinephrine, among other measures.

<span class="mw-page-title-main">Mast cell leukemia</span> Medical condition

Mast cell leukemia is an extremely aggressive subtype of acute myeloid leukemia that usually occurs de novo but can, rarely, evolve from transformation of chronic myeloid leukemia into the more aggressive acute myeloid leukemia. In a small proportion of cases, acute mast cell leukemia may evolve from a more progressive form of systemic mastocytosis. The diagnosis of acute mast cell leukemia by the WHO criteria includes the requirement for a prevalence of 20% neoplastic mast cells in marrow and 10% in blood. If the mast cells represent less than 10% of blood cells, the tumor is called "aleukemic" mast cell leukemia.

<span class="mw-page-title-main">TPSB2</span> Protein-coding gene in the species Homo sapiens

Tryptase beta-2, also known as tryptase II, is a proteolytic enzyme that in humans is encoded by the TPSB2 gene.

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Peter Valent is an Austrian hematologist and stem cell researcher. Since 1990 he leads a research group at the Medical University of Vienna. From 2002 he coordinates the European Competence Network on Mastocytosis and since 2008 he is Scientific Director of the Ludwig Boltzmann Institute for Hematology and Oncology of the Ludwig Boltzmann Society in Austria.

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References

  1. 1 2 Valent P, Hartmann K, Bonadonna P, Gülen T, Brockow K, Alvarez-Twose I, Hermine O, Niedoszytko M, Carter MC, Hoermann G, Butterfield JH, Lyons JJ, Sperr WR, Greiner G, Sotlar K (2022-05-24). "Global Classification of Mast Cell Activation Disorders: An ICD-10-CM-Adjusted Proposal of the ECNM-AIM Consortium". The Journal of Allergy and Clinical Immunology. In Practice. 10 (8): 1941–1950. doi:10.1016/j.jaip.2022.05.007. hdl: 10261/296655 . ISSN   2213-2201. PMID   35623575. S2CID   249073293.
  2. ↑ Valent P (April 2013). "Mast cell activation syndromes: definition and classification". Allergy. 68 (4): 417–24. doi: 10.1111/all.12126 . PMID   23409940. S2CID   43636053.
  3. 1 2 3 Akin C, Valent P, Metcalfe DD (December 2010). "Mast cell activation syndrome: Proposed diagnostic criteria". The Journal of Allergy and Clinical Immunology. 126 (6): 1099–104.e4. doi:10.1016/j.jaci.2010.08.035. PMC   3753019 . PMID   21035176.
  4. ↑ Akin C (May 2015). "Mast cell activation syndromes presenting as anaphylaxis". Immunology and Allergy Clinics of North America. 35 (2): 277–85. doi:10.1016/j.iac.2015.01.010. PMID   25841551.
  5. ↑ Gülen T, Akin C, Bonadonna P, Siebenhaar F, Broesby-Olsen S, Brockow K, Niedoszytko M, Nedoszytko B, Oude Elberink HN, Butterfield JH, Sperr WR, Alvarez-Twose I, Horny HP, Sotlar K, Schwaab J (November 2021). "Selecting the Right Criteria and Proper Classification to Diagnose Mast Cell Activation Syndromes: A Critical Review". The Journal of Allergy and Clinical Immunology. In Practice. 9 (11): 3918–3928. doi:10.1016/j.jaip.2021.06.011. hdl: 10261/268013 . ISSN   2213-2201. PMID   34166845. S2CID   235634993.
  6. ↑ Vacheron N, McClinton T, Lynch-Smith DJ, Umberger R (April 8, 2020). "Mast cell activation syndrome". J Am Assoc Nurse Pract. 33 (7) (7): 545–552. doi:10.1097/JXX.0000000000000396. PMID   32282570.
  7. 1 2 3 [ better source needed ]Afrin LB, Molderings GJ (February 2014). "A concise, practical guide to diagnostic assessment for mast cell activation disease". World Journal of Hematology. 3 (1): 1–7. doi: 10.5315/wjh.v3.i1 .
  8. 1 2 3 4 5 6 Frieri M (June 2018). "Mast Cell Activation Syndrome". Clinical Reviews in Allergy & Immunology. 54 (3): 353–365. doi:10.1007/s12016-015-8487-6. PMID   25944644. S2CID   5723622.
  9. ↑ Davis HE, McCorkell L, Vogel JM, Topol EJ (2023-01-13). "Long COVID: major findings, mechanisms and recommendations". Nature Reviews. Microbiology. 21 (3): 133–146. doi:10.1038/s41579-022-00846-2. ISSN   1740-1534. PMC   9839201 . PMID   36639608.
  10. 1 2 [ better source needed ]Afrin L (2013). "Presentation, Diagnosis, and Management of Mast Cell Activation Syndrome.". Mast Cells: Phenotypic Features, Biological Functions and Role in Immunity. Nova Science. pp. 155–232. Archived from the original on 2018-08-18. Retrieved 2015-10-13.
  11. ↑ Afrin L (2013). "Prevention, diagnosis, and management of mast cell activation syndrome.". In Murray D (ed.). Mast cells: Phenotypic features, biological functions and role in immunity. Nova Sciences Publishers. pp. 155–231. ISBN   978-1-62618-166-3.
  12. ↑ Molderings GJ, Kolck UW, Scheurlen C, Brüss M, Homann J, Von Kügelgen I (January 2007). "Multiple novel alterations in Kit tyrosine kinase in patients with gastrointestinally pronounced systemic mast cell activation disorder". Scandinavian Journal of Gastroenterology. 42 (9): 1045–1053. doi:10.1080/00365520701245744. ISSN   0036-5521. PMID   17710669.
  13. ↑ Molderings GJ, Meis K, Kolck UW, Homann J, Frieling T (2010-12-01). "Comparative analysis of mutation of tyrosine kinase kit in mast cells from patients with systemic mast cell activation syndrome and healthy subjects". Immunogenetics. 62 (11): 721–727. doi:10.1007/s00251-010-0474-8. ISSN   1432-1211. PMID   20838788.
  14. ↑ Akin C (August 2017). "Mast cell activation syndromes". The Journal of Allergy and Clinical Immunology. 140 (2): 349–355. doi:10.1016/j.jaci.2017.06.007. ISSN   1097-6825. PMID   28780942.
  15. ↑ Hartmann K, Escribano L, Grattan C, Brockow K, Carter MC, Alvarez-Twose I, Matito A, Broesby-Olsen S, Siebenhaar F, Lange M, Niedoszytko M, Castells M, Oude Elberink JN, Bonadonna P, Zanotti R (January 2016). "Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology". The Journal of Allergy and Clinical Immunology. 137 (1): 35–45. doi: 10.1016/j.jaci.2015.08.034 . ISSN   1097-6825. PMID   26476479.
  16. 1 2 3 4 Weiler CR, Austen KF, Akin C, et al. (October 2019). "AAAAI Mast Cell Disorders Committee Work Group Report: Mast cell activation syndrome (MCAS) diagnosis and management". The Journal of Allergy and Clinical Immunology. 144 (4): 883–896. doi: 10.1016/j.jaci.2019.08.023 . PMID   31476322.
  17. ↑ Akin C (August 2017). "Mast cell activation syndromes". The Journal of Allergy and Clinical Immunology. 140 (2): 349–355. doi: 10.1016/j.jaci.2017.06.007 . PMID   28780942.
  18. ↑ "Mast Cell Disease ICD-10 Codes". TMS - The Mast Cell Disease Society, Inc. Retrieved 2024-03-21.
  19. ↑ Afrin LB, Ackerley MB, Bluestein LS, Brewer JH, Brook JB, Buchanan AD, Cuni JR, Davey WP, Dempsey TT, Dorff SR, Dubravec MS, Guggenheim AG, Hindman KJ, Hoffman B, Kaufman DL (2021-05-01). "Diagnosis of mast cell activation syndrome: a global "consensus-2"". Diagnosis. 8 (2): 137–152. doi: 10.1515/dx-2020-0005 . ISSN   2194-802X. PMID   32324159.
  20. ↑ Mast cell activation syndrome, Last reviewed: 5 Dec 2023
  21. 1 2 3 4 5 6 Castells M, Butterfield J (April 2019). "Mast Cell Activation Syndrome and Mastocytosis: Initial Treatment Options and Long-Term Management". The Journal of Allergy and Clinical Immunology: In Practice. 7 (4): 1097–1106. doi:10.1016/j.jaip.2019.02.002. PMID   30961835.
  22. ↑ Finn DF, Walsh JJ (September 2013). "Twenty-first century mast cell stabilizers". British Journal of Pharmacology. 170 (1): 23–37. doi:10.1111/bph.12138. PMC   3764846 . PMID   23441583. A diverse range of mast cell stabilizing compounds have been identified in the last decade from; natural, biological and synthetic sources to drugs already in clinical uses for other indications. Although in many cases, the precise mode of action of these molecules is unclear, all of these substances have demonstrated mast cell stabilization activity and therefore may have potential therapeutic use in the treatment of allergic and related diseases where mast cells are intrinsically involved. Table 1: Naturally occurring mast cell stabilizers
  23. ↑ Sonneck K, Florian S, Müllauer L, Wimazal F, Födinger M, Sperr WR, Valent P (2007). "Diagnostic and subdiagnostic accumulation of mast cells in the bone marrow of patients with anaphylaxis: Monoclonal mast cell activation syndrome". International Archives of Allergy and Immunology. 142 (2): 158–64. doi:10.1159/000096442. PMID   17057414. S2CID   25058981.[ non-primary source needed ]
  24. ↑ Akin C, Scott LM, Kocabas CN, Kushnir-Sukhov N, Brittain E, Noel P, Metcalfe DD (October 2007). "Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with 'idiopathic' anaphylaxis". Blood. 110 (7): 2331–3. doi:10.1182/blood-2006-06-028100. PMC   1988935 . PMID   17638853.[ non-primary source needed ]
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