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, a type of white blood cell, inappropriately and excessively release chemical mediators, such as histamine, 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] [5]

Contents

Based on the 2022 criteria, the following three diagnostic criteria needs to be met in order to be diagnosed with Mast Cell Activation Syndrome (MCAS) [6] ,

  1. Symptoms: You have severe, recurring symptoms involving at least two organ systems (e.g., skin, stomach, lungs, or heart). These symptoms must be linked to mast cell chemicals such histamine being released such as itching, throat tightening, and wheezing. Other symptoms can be found below.
  2. Lab tests: During a flare-up of symptoms, your body shows an increase in mast cell chemicals beyond normal levels. These chemicals can include tryptase, histamine, etc.
  3. Treatment response: Your symptoms improve significantly when you take medications that either block the effects of mast cell chemicals such as antihistamines or they must suppress mast cell activation directly such as anti-IgE treatments.

Signs and symptoms

Because degranulation events can be triggered in various locations within the body, 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, or full-scale anaphylactic reactions. 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. [5] [7]

Common symptoms include: [8]

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), 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. [5] [9] [10] It has been found that people with MCAS 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. [11] Mediators include leukotrienes, histamines, prostaglandin, and tryptase. [12]

Pathophysiology

Mast cell activation syndrome can be categorized into three subclasses depending on the trigger which "activates" the degranulation of cells. In Primary MCAS, researchers theorize that the threshold for chemical mediator release, also called degranulation, is lower, meaning it takes less outside stimulation to cause a reaction. [13] Other research has demonstrated that some patients, specifically those with Monoclonal Mast Cell Activation Disorder and those with Mastocytosis have something of an 'overpopulation' of mast cells in the bone marrow, which leads to stronger response when triggered. [14] Secondary MCAS is far more common, and involve an unclear etiology, though not directly related to monoclonal cells. In these cases, reactions occur as a result of IgE-mediated (an environmental allergen, such as food or medication and non-IgE-mediated (such as exercise) mechanisms. [15] Idiopathic MCAS occurs in patients who have an unremarkable workup, including a benign bone marrow biopsy, which suggests that there are no allergic causes or clonal mast cell diseases [15]

Mast cell activation can be localized or systemic, but a diagnosis of MCAS requires systemic symptoms. [16] [17] 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. [18]

Diagnosis

MCAS is often difficult to identify due to the heterogeneity of symptoms and the "lack of flagrant acute presentation". [8] Many of the numerous symptoms are non-specific in nature. Diagnostic criteria were proposed in 2010 [3] and revised in 2019. [17] Mast cell activation was assigned an ICD-10 code (D89.40, along with subtype codes D89.41-43 and D89.49) in October 2016. [19]

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. [17] 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. [20]

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

The World Health Organization has not published diagnostic criteria.

Treatment

Pharmacological treatments include:

Prognosis

The prognosis of MCAS is uncertain. [17]

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. [24] and Akin et al. [25] [7]

See also

Related Research Articles

<span class="mw-page-title-main">Allergy</span> Immune system response to a substance that most people tolerate well

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.

Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of the 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">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 Friedrich von Recklinghausen and later rediscovered 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">Basophil</span> Type of white blood cell

Basophils are a type of white blood cell. Basophils are the least common type of granulocyte, representing about 0.5% to 1% of circulating white blood cells. They are the largest type of granulocyte. They are responsible for inflammatory reactions during immune response, as well as in the formation of acute and chronic allergic diseases, including anaphylaxis, asthma, atopic dermatitis and hay fever. They also produce compounds that coordinate immune responses, including histamine and serotonin that induce inflammation, and heparin that prevents blood clotting, although there are less than that found in mast cell granules. Mast cells were once thought to be basophils that migrated from the blood into their resident tissues, but they are now known to be different types of cells.

<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">Food allergy</span> Hypersensitivity reaction to a food

A food allergy is an abnormal immune response to food. The symptoms of the allergic reaction may range from mild to severe. They may include itchiness, swelling of the tongue, vomiting, diarrhea, hives, trouble breathing, or low blood pressure. This typically occurs within minutes to several hours of exposure. When the symptoms are severe, it is known as anaphylaxis. A food intolerance and food poisoning are separate conditions, not due to an immune response.

<span class="mw-page-title-main">Type I hypersensitivity</span> Type of allergic reaction

Type I hypersensitivity, in the Gell and Coombs classification of allergic reactions, is an allergic reaction provoked by re-exposure to a specific type of antigen referred to as an allergen. Type I is distinct from type II, type III and type IV hypersensitivities. The relevance of the Gell and Coombs classification of allergic reactions has been questioned in the modern-day understanding of allergy, and it has limited utility in clinical practice.

<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">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">Urticaria pigmentosa</span> Most common form of cutaneous mastocytosis

Urticaria pigmentosa (also known as generalized eruption of cutaneous mastocytosis (childhood type) ) is the most common form of cutaneous mastocytosis. It is a rare disease caused by excessive numbers of mast cells in the skin that produce hives or lesions on the skin when irritated.

<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">Solitary mastocytoma</span> Medical condition

Solitary mastocytoma, also known as cutaneous mastocytoma, may be present at birth or may develop during the first weeks of life, originating as a brown macule that urticates on stroking. Solitary mastocytoma is a round, erythematous, indurated lesion measuring 1-5 cm in diameter. It can be mildly itchy or asymptomatic and develops over time. Predilection is the head and neck, followed by the trunk, extremities, and flexural areas.

One of the most prevalent forms of adverse drug reactions is cutaneous reactions, with drug-induced urticaria ranking as the second most common type, preceded by drug-induced exanthems. Urticaria, commonly known as hives, manifests as weals, itching, burning, redness, swelling, and angioedema—a rapid swelling of lower skin layers, often more painful than pruritic. These symptoms may occur concurrently, successively, or independently. Typically, when a drug triggers urticaria, symptoms manifest within 24 hours of ingestion, aiding in the identification of the causative agent. Urticaria symptoms usually subside within 1–24 hours, while angioedema may take up to 72 hours to resolve completely.

<span class="mw-page-title-main">Chronic spontaneous urticaria</span> Medical condition

Chronic spontaneous urticaria(CSU) also known as Chronic idiopathic urticaria(CIU) is defined by the presence of wheals, angioedema, or both for more than six weeks. The most common symptoms of chronic spontaneous urticaria are angioedema and hives that are accompanied by itchiness.

Kounis syndrome is defined as acute coronary syndrome caused by an allergic reaction or a strong immune reaction to a drug or other substance. It is a rare syndrome with authentic cases reported in 130 males and 45 females, as reviewed in 2017; however, the disorder is suspected of being commonly overlooked and therefore much more prevalent. Mast cell activation and release of inflammatory cytokines as well as other inflammatory agents from the reaction leads to spasm of the arteries leading to the heart muscle or a plaque breaking free and blocking one or more of those arteries.

Exercise-induced anaphylaxis is a rare condition in which anaphylaxis, a serious or life-threatening allergic response, is brought on by physical activity. Approximately 5–15% of all reported cases of anaphylaxis are thought to be exercise-induced.

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.

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

Fish allergy is an immune hypersensitivity to proteins found in fish. Symptoms can be either rapid or gradual in onset. The latter can take hours to days to appear. The former may include anaphylaxis, a potentially life-threatening condition which requires treatment with epinephrine. Other presentations may include atopic dermatitis or inflammation of the esophagus. Fish is one of the eight common food allergens which are responsible for 90% of allergic reactions to foods: cow's milk, eggs, wheat, shellfish, peanuts, tree nuts, fish, and soy beans.

Lirentelimab is a humanized nonfucosylated monoclonal antibody that targets sialic acid-binding Ig-like lectin 8 (SIGLEC8). In a randomized clinical trial, lirentelimab was found to improve eosinophil counts and symptoms in individuals with eosinophilic gastritis and duodenitis. Adverse reactions include infusion reactions, which are mild to moderate and typically occur following the first infusion.

References

  1. ↑ 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. Archived from the original on 2023-02-11. Retrieved 2023-02-10.
  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. 1 2 3 Conway AE, Verdi M, Shaker MS, Bernstein JA, Beamish CC, Morse R, Madan J, Lee MW, Sussman G, Al-Nimr A, Hand M, Albert DA (March 2024). "Beyond Confirmed Mast Cell Activation Syndrome: Approaching Patients With Dysautonomia and Related Conditions". J Allergy Clin Immunol Pract. 12 (7): 1738–1750. doi:10.1016/j.jaip.2024.03.019. PMID   38499084.
  6. ↑ Castells M, Giannetti MP, Hamilton MJ, Novak P, Pozdnyakova O, Nicoloro-SantaBarbara J, Jennings SV, Francomano C, Kim B, Glover SC, Galli SJ, Maitland A, White A, Abonia JP, Slee V (August 2024). "Mast cell activation syndrome: Current understanding and research needs". Journal of Allergy and Clinical Immunology. 154 (2): 255–263. doi:10.1016/j.jaci.2024.05.025. ISSN   0091-6749.
  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 [ 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.
  9. ↑ 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.
  10. ↑ 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. Archived from the original on 2023-03-27. Retrieved 2023-11-18.
  11. ↑ 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.
  12. ↑ 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. Archived from the original on 2023-01-30. Retrieved 2023-02-10.
  13. ↑ 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.
  14. ↑ Weiler, Austen, Akin, Barkoff, Bernstein, Bonadonna, Butterfield, Carter, Fox, Maitland, Pongdee, Mustafa, Ravi, Tobin, Vliagoftis, Schwartz (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 – via JACI.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. 1 2 Gulen T (January 2024). "Using the Right Criteria for MCAS". Current Allergy and Asthma Reports. 24 (2): 39–51. doi:10.1007/s11882-024-01126-0. PMC   10866766 . PMID   38243020 – via PubMed.
  16. ↑ 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.
  17. 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.
  18. ↑ 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.
  19. ↑ "Mast Cell Disease ICD-10 Codes". TMS - The Mast Cell Disease Society, Inc. Archived from the original on 2024-03-21. Retrieved 2024-03-21.
  20. ↑ 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.
  21. 1 2 3 4 5 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.
  22. 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.
  23. ↑ 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 Archived 2020-11-02 at the Wayback Machine
  24. ↑ 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 ]
  25. ↑ 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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