Activation of tissue mast cells (MCs) and their abnormal growth and accumulation in various organs are typically found in primary MC disorders also referred to as mastocytosis. However, increasing numbers of patients are now being informed that their clinical findings are due to MC activation (MCA) that is neither associated with mastocytosis nor with a defined allergic or inflammatory reaction. In other patients with MCA, MCs appear to be clonal cells, but criteria for diagnosing mastocytosis are not met. A working conference was organized in 2010 with the aim to define criteria for diagnosing MCA and related disorders, and to propose a global unifying classification of all MC disorders and pathologic MC reactions. This classification includes three types of ‘MCA syndromes’ (MCASs), namely primary MCAS, secondary MCAS and idiopathic MCAS. MCA is now defined by robust and generally applicable criteria, including (1) typical clinical symptoms, (2) a substantial transient increase in serum total tryptase level or an increase in other MC-derived mediators, such as histamine or prostaglandin D2, or their urinary metabolites, and (3) a response of clinical symptoms to agents that attenuate the production or activities of MC mediators. These criteria should assist in the identification and diagnosis of patients with MCAS, and in avoiding misdiagnoses or overinterpretation of clinical symptoms in daily practice. Moreover, the MCAS concept should stimulate research in order to identify and exploit new molecular mechanisms and therapeutic targets.

Keywords:
Tryptase, Mast cells, Mast cell activation syndrome, Allergy, Anaphylaxis
1.
Rivera J, Gilfillan AM: Molecular regulation of mast cell activation. J Allergy Clin Immunol 2006;117:1214–1225.
2.
Metcalfe DD: Mast cells and mastocytosis. Blood 2008;112:946–956.
3.
Galli SJ, Grimbaldeston M, Tsai M: Immunomodulatory mast cells: negative, as well as positive, regulators of immunity. Nat Rev Immunol 2008;8:478–486.
4.
Austen KF: Systemic anaphylaxis in the human being. N Engl J Med 1974;291:661–664.
5.
Serafin WE, Austen KF: Mediators of immediate hypersensitivity reactions. N Engl J Med 1987;317:30–34.
6.
Simons FE: Anaphylaxis. J Allergy Clin Immunol 2010;125:S161–S181.
7.
Webb LM, Lieberman P: Anaphylaxis: a review of 601 cases. Ann Allergy Asthma Immunol 2006;97:39–43.
8.
Lieberman P: Epidemiology of anaphylaxis. Curr Opin Allergy Clin Immunol 2008;8:316–320.
9.
Peavy RD, Metcalfe DD: Understanding the mechanisms of anaphylaxis. Curr Opin Allergy Clin Immunol 2008;8:310–315.
10.
Golden DB: What is anaphylaxis? Curr Opin Allergy Clin Immunol 2007;7:331–336.
11.
Finkelman FD, Boyce JA, Vercelli D, Rothenberg ME: Key advances in mechanisms of asthma, allergy, and immunology in 2009. J Allergy Clin Immunol 2010;125:312–318.
12.
Metcalfe DD: Differential diagnosis of the patient with unexplained flushing/anaphylaxis. Allergy Asthma Proc 2000;21:21–24.
13.
Alvarez-Twose I, González de Olano D, Sánchez-Muñoz L, Matito A, Esteban-López MI, Vega A, et al: Clinical, biological, and molecular characteristics of clonal mast cell disorders presenting with systemic mast cell activation symptoms. J Allergy Clin Immunol 2010;125:1269.e.2–1278.e2.
14.
González de Olano D, de la Hoz Caballer B, Núñez López R, Sánchez Muñoz L, Cuevas Agustín M, Diéguez MC, Alvarez Twose I, Castells MC, Escribano Mora L: Prevalence of allergy and anaphylactic symptoms in 210 adult and pediatric patients with mastocytosis in Spain: a study of the Spanish network on mastocytosis (REMA). Clin Exp Allergy 2007;37:1547–1555.
15.
Bonadonna P, Perbellini O, Passalacqua G, Caruso B, Colarossi S, Dal Fior D, Castellani L, Bonetto C, Frattini F, Dama A, Martinelli G, Chilosi M, Senna G, Pizzolo G, Zanotti R: Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels. J Allergy Clin Immunol 2009;123:680–686.
16.
Metcalfe DD, Schwartz LB: Assessing anaphylactic risk? Consider mast cell clonality. J Allergy Clin Immunol 2009;123:687–688.
17.
Donker ML, Bakker NA, Jaspers WJ, Verhage AH: Two patients with osteoporosis: initial presentation of systemic mastocytosis. J Bone Miner Metab 2008;26:199–202.
18.
Valent P, Akin C, Escribano L, Fodinger M, Hartman K, Metcalfe DD, et al: Standards and standardization in mastocytosis: consensus statement on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest 2007;37:435–453.
19.
Ruëff F, Dugas-Breit S, Przybilla B: Stinging Hymenoptera and mastocytosis. Curr Opin Allergy Clin Immunol 2009;9:338–342.
20.
Akin C: Anaphylaxis and mast cell disease: what is the risk? Curr Allergy Asthma Rep 2010;10:34–38.
21.
Akin C, Valent P, Metcalfe DD: Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol 2010;126:1099–1104.
22.
Schwartz LB, Bradford TR, Rouse C, Irani AM, Rasp G, Van der Zwan JK, Van der Linden PW: Development of a new, more sensitive immunoassay for human tryptase: use in systemic anaphylaxis. J Clin Immunol 1994;14:190–204.
23.
Schwartz LB, Sakai K, Bradford TR, Ren S, Zweiman B, Worobec AS, Metcalfe DD: The alpha form of human tryptase is the predominant type present in blood at baseline in normal subjects and is elevated in those with systemic mastocytosis. J Clin Invest 1995;96:2702–2710.
24.
Schwartz LB, Irani AM: Serum tryptase and the laboratory diagnosis of systemic mastocytosis. Hematol Oncol Clin North Am 2000;14:641–657.
25.
Morel AM, Delaage MA: Immunoanalysis of histamine through a novel chemical derivatization. J Allergy Clin Immunol 1988;82:646–654.
26.
Awad JA, Morrow JD, Roberts LJ: Detection of the major urinary metabolite of prostaglandin D2 in the circulation: demonstration of elevated levels in patients with disorders of systemic mast cell activation. J Allergy Clin Immunol 1994;93:817–824.
27.
Hogan AD, Schwartz LB: Markers of mast cell degranulation. Methods 1997;13:43–52.
28.
Di Lorenzo G, Pacor ML, Vignola AM, Profita M, Esposito-Pellitteri M, Biasi D, Corrocher R, Caruso C: Urinary metabolites of histamine and leukotrienes before and after placebo-controlled challenge with ASA and food additives in chronic urticaria patients. Allergy 2002;57:1180–1186.
29.
van Toorenenbergen AW, Oranje AP: Comparison of serum tryptase and urine N-methylhistamine in patients with suspected mastocytosis. Clin Chim Acta 2005;359:72–77.
30.
Butterfield JH, Weiler CR: Prevention of mast cell activation disorder-associated clinical sequelae of excessive prostaglandin D2 production. Int Arch Allergy Immunol 2008;147:338–343.
31.
van der Donk EM, Blok W, Kok PT, Bruijnzeel PL: Leukotriene C4 formation by enriched human basophil preparations from normal and asthmatic subjects. Prostaglandins Leukot Essent Fatty Acids 1991;44:11–17.
32.
Sonneck K, Florian S, Müllauer L, Wimazal F, Födinger M, Sperr WR, Valent P: Diagnostic and subdiagnostic accumulation of mast cells in the bone marrow of patients with anaphylaxis: monoclonal mast cell activation syndrome. Int Arch Allergy Immunol 2007;142:158–164.
33.
Akin C, Scott LM, Kocabas CN, Kushnir-Sukhov N, Brittain E, Noel P, Metcalfe DD: Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with ‘idiopathic’ anaphylaxis. Blood 2007;110:2331–2333.
34.
Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB, Marone G, Nuñez R, Akin C, Sotlar K, Sperr WR, Wolff K, Brunning RD, Parwaresch RM, Austen KF, Lennert K, Metcalfe DD, Vardiman JW, Bennett JM: Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res 2001;25:603–625.
35.
Horny HP, Valent P: Diagnosis of mastocytosis: general histopathological aspects, morphological criteria, and immunohistochemical findings. Leuk Res 2001;25:543–551.
36.
Arock M, Valent P: Pathogenesis, classification and treatment of mastocytosis: state of the art in 2010 and future perspectives. Expert Rev Hematol 2010;3:497–516.
37.
Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, Motala C, Ortega Martell JA, Platts-Mills TA, Ring J, Thien F, Van Cauwenberge P, Williams HC: Revised nomenclature for allergy for global use: report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol 2004;113:832–836.
38.
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al: Second symposium on the definition and management of anaphylaxis: summary report – Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 2006;117:391–397.
39.
Costa JJ, Demetri GD, Harrist TJ, Dvorak AM, Hayes DF, Merica EA, et al: Recombinant human stem cell factor (kit ligand) promotes human mast cell and melanocyte hyperplasia and functional activation in vivo. J Exp Med 1996;183:2681–2686.
40.
Jordan JH, Schernthaner GH, Fritsche-Polanz R, Sperr WR, Födinger M, Chott A, et al: Stem cell factor-induced bone marrow mast cell hyperplasia mimicking systemic mastocytosis (SM): histopathologic and morphologic evaluation with special reference to recently established SM-criteria. Leuk Lymphoma 2002;43:575–582.
41.
Valent P, Horny H-P, Li CY, Longley JB, Metcalfe DD, Parwaresch RM, Bennett JM: Mastocytosis; in Jaffe ES, Harris NL, Stein H, Vardiman JW (eds): World Health Organization (WHO) Classification of Tumours. Pathology and Genetics. Tumours of Haematopoietic and Lymphoid Tissues.Lyon, IARC Press, 2001, pp 291–302.
42.
Horny HP, Akin C, Metcalfe DD, Escribano L, Bennett JM, Valent P, Bain BJ: Mastocytosis (mast cell disease); in Swerdlow, SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (eds): World Health Organization (WHO) Classification of Tumours. Pathology and Genetics. Tumours of Haematopoietic and Lymphoid Tissues. Lyon, IARC Press, 2008, pp 54–63.
43.
Valent P, Sperr WR, Samorapoompichit P, Geissler K, Lechner K, Horny HP, Bennett JM: Myelomastocytic overlap syndromes: biology, criteria, and relationship to mastocytosis. Leuk Res 2001;25:595–602.
44.
Valent P, Samorapoompichit P, Sperr WR, Horny HP, Lechner K: Myelomastocytic leukemia: myeloid neoplasm characterized by partial differentiation of mast cell-lineage cells. Hematol J 2002;3:90–94.
45.
Sperr WR, Jordan JH, Baghestanian M, Kiener HP, Samorapoompichit P, Semper H, et al: Expression of mast cell tryptase by myeloblasts in a group of patients with acute myeloid leukemia. Blood 2001;98:2200–2209.
46.
Arredondo AR, Gotlib J, Shier L, Medeiros B, Wong K, Cherry A, et al: Myelomastocytic leukemia versus mast cell leukemia versus systemic mastocytosis associated with acute myeloid leukemia: a diagnostic challenge. Am J Hematol 2010;85:600–606.
47.
Castells MC, Irani AM, Schwartz LB: Evaluation of human peripheral blood leukocytes for mast cell tryptase. J Immunol 1987;138:2184–2189.
48.
Samorapoompichit P, Kiener HP, Schernthaner GH, Jordan JH, Agis H, Wimazal F, et al: Detection of tryptase in cytoplasmic granules of basophils in patients with chronic myeloid leukemia and other myeloid neoplasms. Blood 2001;98:2580–2583.
49.
Garcia-Montero AC, Jara-Acevedo M, Teodosio C, Sanchez ML, Nunez R, Prados A, et al: KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood 2006;108:2366–2372.
50.
Bodemer C, Hermine O, Palmérini F, Yang Y, Grandpeix-Guyodo C, Leventhal PS, et al: Pediatric mastocytosis is a clonal disease associated with D816V and other activating c-KIT mutations. J Invest Dermatol 2010;130:804–815.
51.
Daley T, Metcalfe DD, Akin C: Association of the Q576R polymorphism in the interleukin-4 receptor α-chain with indolent mastocytosis limited to the skin. Blood 2001;98:880–882.
52.
Nedoszytko B, Niedoszytko M, Lange M, van Doormaal J, Gleń J, Zabłotna M, et al: Interleukin-13 promoter gene polymorphism -1112C/T is associated with the systemic form of mastocytosis. Allergy 2009;64:287–294.
53.
Murphy S, Kelly HW: Cromolyn sodium: a review of mechanisms and clinical use in asthma. Drug Intell Clin Pharm 1987;21:22–35.
54.
Chin KW, Garriga MM, Metcalfe DD: The histamine content of oriental foods. Food Chem Toxicol 1989;27:283–287.
55.
Maintz L, Novak N: Histamine and histamine intolerance. Am J Clin Nutr 2007;85:1185–1196.
56.
Schwelberger HG: Histamine intolerance: a metabolic disease? Inflamm Res 2010;59:219–221.
57.
Valent P, Arock M, Bischoff SC, Bühring HJ, Brockow K, Escribano L, et al: The European Competence Network on Mastocytosis (ECNM). Wien Klin Wochenschr 2004;116:647–651.
58.
Vadas P, Gold M, Perelman B, Liss GM, Lack G, Blyth T, et al: Platelet-activating factor, PAF acetylhydrolase, and severe anaphylaxis. N Engl J Med 2008;358:28–35.
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