Top

Current Allergy and Asthma Reports

Published in:

Open Access 03-02-2024 | Anaphylaxis

Reversible Elevation of Tryptase Over the Individual's Baseline: Why is It the Best Biomarker for Severe Systemic Mast Cell Activation and MCAS?

Authors: Peter Valent, Cem Akin, Michel Arock

Published in: Current Allergy and Asthma Reports | Issue 3/2024

Abstract

Purpose of Review

Mast cell (MC) activation syndromes (MCAS) are conditions defined by recurrent episodes of severe systemic anaphylaxis or similar systemic events triggered by MC-derived mediators that can be measured in biological fluids. Since some symptoms of MC activation may occur due to other, non-MC etiologies and lead to confusion over diagnosis, it is of crucial importance to document the involvement of MC and their products in the patients´ symptomatology.

Recent Findings

The most specific and generally accepted marker of severe systemic MC activation is an event-related, transient increase in the serum tryptase level over the individual baseline of the affected individual. However, baseline concentrations of serum tryptase vary among donors, depending on the genetic background, age, kidney function, and underlying disease. As a result, it is of critical importance to provide a flexible equation that defines the diagnostic increase in tryptase qualifying as MCAS criterion in all patients, all situations, and all ranges of baseline serum tryptase. In 2012, the consensus group proposed the 120% + 2 ng/ml formula, which covers the great majority of groups, including cases with low, normal, or elevated basal serum tryptase level.

Summary

This formula has been validated in subsequent studies and has proven to be a robust and consistent diagnostic criterion of MCAS. The present article is discussing the impact of this formula and possible limitations as well as alternative markers and mediators that may be indicative of MCAS.

Metcalfe DD. Mast cells and mastocytosis. Blood. 2008;112:946–56.PubMedPubMedCentralCrossRef

Galli SJ, Tsai M. IgE and mast cells in allergic disease. Nat Med. 2012;18:693–704.PubMedPubMedCentralCrossRef

Theoharides TC, Valent P, Akin C. Mast cells, mastocytosis, and related disorders. N Engl J Med. 2015;373:163–72.PubMedCrossRef

• Valent P, Akin C, Hartmann K, Nilsson G, Reiter A, Hermine O, et al. Mast cells as a unique hematopoietic lineage and cell system: From Paul Ehrlich’s visions to precision medicine concepts. Theranostics. 2020;10:10743–68. This article describes that the mast cell system forms a unique hematopoietic cell lineage with unique features and unique functional properties in health and disease.PubMedPubMedCentralCrossRef

• Valent P, Akin C, Sperr WR, Horny HP, Arock M, Metcalfe DD, Galli SJ. New insights into the pathogenesis of mastocytosis: emerging concepts in diagnosis and therapy. Annu Rev Pathol. 2023;18:361–86. Comprehensive review on the pathogenesis and pathology of mast cells in patients with mast cell proliferative disorders (mastocytosis) and mast cell activation disorders.PubMedCrossRef

Metcalfe DD, Peavy RD, Gilfillan AM. Mechanisms of mast cell signaling in anaphylaxis. J Allergy Clin Immunol. 2009;124:639–46.PubMedPubMedCentralCrossRef

Kalesnikoff J, Galli SJ. Anaphylaxis: mechanisms of mast cell activation. Chem Immunol Allergy. 2010;95:45–66.PubMedCrossRef

Lieberman P. Mechanisms of anaphylaxis beyond classically mediated antigen- and IgE-induced events. Ann Allergy Asthma Immunol. 2017;118:246–8.PubMedCrossRef

Galli SJ, Gaudenzio N, Tsai M. Mast cells in inflammation and disease: recent progress and ongoing concerns. Annu Rev Immunol. 2020;38:49–77.PubMedCrossRef

10.

Schwartz LB. Tryptase from human mast cells: biochemistry, biology and clinical utility. Monogr Allergy. 1990;27:90–113.PubMed

11.

Schwartz LB. Tryptase, a mediator of human mast cells. J Allergy Clin Immunol. 1990;86:594–8.PubMedCrossRef

12.

• Schwartz LB, Lewis RA, Austen KF. Tryptase from human pulmonary mast cells. Purification and characterization J Biol Chem. 1981;256:11939–43. Isolation and biochemical characterization of human tryptase from tissue mast cells.PubMed

13.

Jogie-Brahim S, Min HK, Fukuoka Y, Xia HZ, Schwartz LB. Expression of alpha-tryptase and beta-tryptase by human basophils. J Allergy Clin Immunol. 2004;113:1086–92.PubMedCrossRef

14.

Schwartz LB, Min HK, Ren S, Xia HZ, Hu J, Zhao W, et al. Tryptase precursors are preferentially and spontaneously released, whereas mature tryptase is retained by HMC-1 cells, Mono-Mac-6 cells, and human skin-derived mast cells. J Immunol. 2003;170:5667–73.PubMedCrossRef

15.

Fukuoka Y, Schwartz LB. The B12 anti-tryptase monoclonal antibody disrupts the tetrameric structure of heparin-stabilized beta-tryptase to form monomers that are inactive at neutral pH and active at acidic pH. J Immunol. 2006;176:3165–72.PubMedCrossRef

16.

Skarbø BR, Vinnes EW, Wentzel-Larsen T, Sylte MS, Apelseth TO. Estimating the within-subject (CVI) and between-subject (CVG) biological variation of serum tryptase. Immun Inflamm Dis. 2022;10: e578.PubMedCrossRef

17.

Chovanec J, Tunc I, Hughes J, Halstead J, Mateja A, Liu Y, et al. Genetically defined individual reference ranges for tryptase limit unnecessary procedures and unmask myeloid neoplasms. Blood Adv. 2023;7:1796–810.PubMedCrossRef

18.

• Valent P, Hoermann G, Bonadonna P, Hartmann K, Sperr WR, Broesby-Olsen S, et al. The normal range of baseline tryptase should be 1 to 15 ng/mL and covers healthy individuals with HαT. J Allergy Clin Immunol Pract. 2023;11:3010–20. Description of biological ranges of basal serum tryptase in healthy subjects, including cohorts with or without carriers of hereditary alpha tryptasemia.PubMedCrossRef

19.

Sperr WR, Jordan JH, Fiegl M, Escribano L, Bellas C, Dirnhofer S, et al. Serum tryptase levels in patients with mastocytosis: correlation with mast cell burden and implication for defining the category of disease. Int Arch Allergy Immunol. 2002;128:136–41.PubMedCrossRef

20.

Sperr WR, Stehberger B, Wimazal F, Baghestanian M, Schwartz LB, Kundi M, et al. Serum tryptase measurements in patients with myelodysplastic syndromes. Leuk Lymphoma. 2002;43:1097–105.PubMedCrossRef

21.

Sperr WR, El-Samahi A, Kundi M, Girschikofsky M, Winkler S, Lutz D, et al. Elevated tryptase levels selectively cluster in myeloid neoplasms: a novel diagnostic approach and screen marker in clinical hematology. Eur J Clin Invest. 2009;39:914–23.PubMedCrossRef

22.

Valent P, Sperr WR, Sotlar K, Reiter A, Akin C, Gotlib J, et al. The serum tryptase test: an emerging robust biomarker in clinical hematology. Expert Rev Hematol. 2014;7:683–90.PubMedPubMedCentralCrossRef

23.

•• Schwartz LB, Metcalfe DD, Miller JS, Earl H, Sullivan T. Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. N Engl J Med. 1987;316:1622–6. First description that an event-related elevation of serum tryptase over the individual´s baseline is a robust biochemical marker of anaphylaxis.PubMedCrossRef

24.

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;96:2702–10.PubMedPubMedCentralCrossRef

25.

Schwartz HJ. Elevated serum tryptase in exercise-induced anaphylaxis. J Allergy Clin Immunol. 1995;95:917–9.PubMedCrossRef

26.

Schwartz LB. Diagnostic value of tryptase in anaphylaxis and mastocytosis. Immunol Allergy Clin North Am. 2006;26:451–63.PubMedCrossRef

27.

Lin RY, Schwartz LB, Curry A, Pesola GR, Knight RJ, Lee HS, et al. Histamine and tryptase levels in patients with acute allergic reactions: An emergency department-based study. J Allergy Clin Immunol. 2000;106:65–71.PubMedCrossRef

28.

• Schwartz LB, Yunginger JW, Miller J, Bokhari R, Dull D. Time course of appearance and disappearance of human mast cell tryptase in the circulation after anaphylaxis. J Clin Invest. 1989;83:1551–5. Detailed analysis of the time course of serum tryptase levels before, during, and after an anaphylactic event in patients suffering from anaphylaxis.PubMedPubMedCentralCrossRef

29.

• Akin C, Valent P, Metcalfe DD. Mast cell activation syndrome: Proposed diagnostic criteria. J Allergy Clin Immunol. 2010;126:1099–104. This manuscript presents a first proposal for diagnostic criteria and a classification of mast cell activation syndromes.PubMedPubMedCentralCrossRef

30.

Hamilton MJ, Hornick JL, Akin C, Castells MC, Greenberger NJ. Mast cell activation syndrome: a newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol. 2011;128:147-52.e2.PubMedCrossRef

31.

•• Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Carter MC, et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol. 2012;157:215–25. This manuscript provides definitions, diagnostic criteria, and a classification of mast cell activation syndromes in a consensus proposal.PubMedCrossRef

32.

Valent P. Mast cell activation syndromes: definition and classification. Allergy. 2013;68:417–24.PubMedCrossRef

33.

Valent P, Akin C, Bonadonna P, Hartmann K, Brockow K, Niedoszytko M, et al. Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome. J Allergy Clin Immunol Pract. 2019;7:1125-33.e1.PubMedPubMedCentralCrossRef

34.

• Valent P, Hartmann K, Bonadonna P, Gülen T, Brockow K, Alvarez-Twose I, et al. Global classification of mast cell activation disorders: an ICD-10-CM-adjusted proposal of the ECNM-AIM consortium. J Allergy Clin Immunol Pract. 2022;10:1941–50. This manuscript provides a global classification and diagnostic criteria for mast cell activation disorders, including mast cell activation syndromes (MCAS) and mast cell activation disorders/conditions in which MCAS criteria are not fulfilled.PubMedCrossRef

35.

Butterfield JH. Increased excretion of mast cell mediator metabolites during mast cell activation syndrome. J Allergy Clin Immunol Pract. 2023;11:2542–6.PubMedCrossRef

36.

Chollet MB, Akin C. Hereditary alpha tryptasemia is not associated with specific clinical phenotypes. J Allergy Clin Immunol. 2022;149:728-35.e2.PubMedCrossRef

37.

González-de-Olano D, Navarro-Navarro P, Muñoz-González JI, Sánchez-Muñoz L, Henriques A, de-Andrés-Martín A, et al. Clinical impact of the TPSAB1 genotype in mast cell diseases: A REMA study in a cohort of 959 individuals. Allergy. 2024.

38.

• Lyons JJ, Yu X, Hughes JD, Le QT, Jamil A, Bai Y, et al. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nat Genet. 2016;48:1564–9. This manuscript describes that increased TPSAB1 gene copy numbers are often found in individuals with an elevated basal serum tryptase level.PubMedPubMedCentralCrossRef

39.

Lyons JJ, Stotz SC, Chovanec J, Liu Y, Lewis KL, Nelson C, et al. A common haplotype containing functional CACNA1H variants is frequently coinherited with increased TPSAB1 copy number. Genet Med. 2018;20:503–12.PubMedCrossRef

40.

• Sabato V, Chovanec J, Faber M, Milner JD, Ebo D, Lyons JJ. First identification of an inherited TPSAB1 quintuplication in a patient with clonal mast cell disease. J Clin Immunol. 2018;38:457–9. This manuscript describes multiple TPSAB1 gene copy numbers in a family with mast cell activation symptoms and one case with clonal mast cell disease.PubMedCrossRef

41.

Lyons JJ, Chovanec J, O’Connell MP, Liu Y, Šelb J, Zanotti R, et al. Heritable risk for severe anaphylaxis associated with increased α-tryptase-encoding germline copy number at TPSAB1. J Allergy Clin Immunol. 2020;S0091–6749(20):31029.

42.

•• Greiner G, Sprinzl B, Górska A, Ratzinger F, Gurbisz M, Witzeneder N, et al. Hereditary α tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis. Blood. 2021;137:238–47. This manuscript describes an association between systemic mastocytosis (SM), severe mediator-related symptoms and hereditary alpha tryptasemia (HαT). In addition, this manuscript shows that the prevalence of HαT is significantly higher in SM compared to healthy controls or patients with other hematologic neoplasms.PubMedCrossRef

43.

Dugas-Breit S, Schöpf P, Dugas M, Schiffl H, Ruëff F, Przybilla B. Baseline serum levels of mast cell tryptase are raised in hemodialysis patients and associated with severity of pruritus. J Dtsch Dermatol Ges. 2005;3:343–7.PubMedCrossRef

44.

Jesky MD, Stringer SJ, Fenton A, Ng KP, Yadav P, Ndumbo M, et al. Serum tryptase concentration and progression to end-stage renal disease. Eur J Clin Invest. 2016;46:460–74.PubMedCrossRef

45.

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;183:2681–6.PubMedCrossRef

46.

• 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;98:2200–9. This manuscript describes that tryptase is produced in immature myeloid blast cells in patients with acute myeloid leukemia (AML) and that in some of the AML patients, basal serum tryptase levels may be clearly elevated or even very high.PubMedCrossRef

47.

Sperr WR, Mitterbauer M, Mitterbauer G, Kundi M, Jäger U, Lechner K, Valent P. Quantitation of minimal residual disease in acute myeloid leukemia by tryptase monitoring identifies a group of patients with a high risk of relapse. Clin Cancer Res. 2005;11:6536–43.PubMedCrossRef

48.

Valent P, Bonadonna P, Hartmann K, Broesby-Olsen S, Brockow K, Butterfield JH, et al. 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. 2019;180:44–51.PubMedCrossRef

49.

Boehm T, Reiter B, Ristl R, Petroczi K, Sperr W, Stimpfl T, Valent P, Jilma B. Massive release of the histamine-degrading enzyme diamine oxidase during severe anaphylaxis in mastocytosis patients. Allergy. 2019;74:583–93.PubMedCrossRef

50.

Valent P, Akin C, Nedoszytko B, Bonadonna P, Hartmann K, Niedoszytko M, et al. Diagnosis, classification and management of mast cell activation syndromes (MCAS) in the era of personalized medicine. Int J Mol Sci. 2020;21(23):9030.PubMedPubMedCentralCrossRef

51.

Matito A, Escribese MM, Longo N, Mayorga C, Luengo-Sánchez O, Pérez-Gordo M, et al. Clinical approach to mast cell activation syndrome: a practical overview. J Investig Allergol Clin Immunol. 2021;31:461–70.PubMedCrossRef

52.

Mateja A, Wang Q, Chovanec J, Kim J, Wilson KJ, Schwartz LB, et al. Defining baseline variability of serum tryptase levels improves accuracy in identifying anaphylaxis. J Allergy Clin Immunol. 2022;149:1010-17.e10.PubMedCrossRef

53.

• Baretto RL, Beck S, Heslegrave J, Melchior C, Mohamed O, Ekbote A. Validation of international consensus equation for acute serum total tryptase in mast cell activation: a perioperative perspective. Allergy. 2017;72:2031–4. This manuscript confirms the value of the 120%+2 ng/mL equation in patients with perioperative mast cell activation-related events (anaphylaxis).PubMedCrossRef

54.

Ebo DG, De Puysseleyr LP, Van Gasse AL, Elst J, Poorten MV, Faber MA, et al. Mast cell activation during suspected perioperative hypersensitivity: a need for paired samples analysis. J Allergy Clin Immunol Pract. 2021;9:3051-59.e1.PubMedCrossRef

55.

Wongkaewpothong P, Pacharn P, Sripramong C, Boonchoo S, Piboonpocanun S, Visitsunthorn N, et al. The utility of serum tryptase in the diagnosis of food-induced anaphylaxis. Allergy Asthma Immunol Res. 2014;6:304–9.PubMedPubMedCentralCrossRef

56.

De Schryver S, Halbrich M, Clarke A, La Vieille S, Eisman H, Alizadehfar R, et al. Tryptase levels in children presenting with anaphylaxis: temporal trends and associated factors. J Allergy Clin Immunol. 2016;137:1138–42.PubMedCrossRef

57.

Dua S, Dowey J, Foley L, Islam S, King Y, Ewan P, Clark AT. Diagnostic value of tryptase in food allergic reactions: a prospective study of 160 adult peanut challenges. J Allergy Clin Immunol Pract. 2018;6:1692-98.e1.PubMedCrossRef

58.

González de Olano D, de la Hoz Caballer B, Núñez López R, Sánchez Muñoz L, Cuevas Agustín M, Diéguez MC, et al. 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;37:1547–55.

59.

Bonadonna P, Perbellini O, Passalacqua G, Caruso B, Colarossi S, Dal Fior D, et al. Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels. J Allergy Clin Immunol. 2009;123:680–6.PubMedCrossRef

60.

Akin C. Anaphylaxis and mast cell disease: what is the risk? Curr Allergy Asthma Rep. 2010;10:34–8.PubMedCrossRef

61.

Brockow K, Jofer C, Behrendt H, Ring J. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients. Allergy. 2008;63:226–32.PubMedCrossRef

62.

Watkins J, Wild G. Improved diagnosis of anaphylactoid reactions by measurement of serum tryptase and urinary methylhistamine. Ann Fr Anesth Reanim. 1993;12:169–72.PubMedCrossRef

63.

Keyzer JJ, de Monchy JG, van Doormaal JJ, van Voorst Vader PC. Improved diagnosis of mastocytosis by measurement of urinary histamine metabolites. N Engl J Med. 1983;309:1603–5.PubMedCrossRef

64.

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;93:817–24.PubMedCrossRef

65.

Ono E, Taniguchi M, Mita H, Akiyama K. Salicylamide-induced anaphylaxis: increased urinary leukotriene E4 and prostaglandin D2 metabolite. Allergy. 2008;63:480–2.PubMedCrossRef

66.

Ravi A, Butterfield J, Weiler CR. Mast cell activation syndrome: improved identification by combined determinations of serum tryptase and 24-hour urine 11β-prostaglandin2α. J Allergy Clin Immunol Pract. 2014;2:775–8.PubMedCrossRef

67.

Vysniauskaite M, Hertfelder HJ, Oldenburg J, Dreßen P, Brettner S, Homann J, Molderings GJ. Determination of plasma heparin level improves identification of systemic mast cell activation disease. PLoS ONE. 2015;10: e0124912.PubMedPubMedCentralCrossRef

Title: Reversible Elevation of Tryptase Over the Individual's Baseline: Why is It the Best Biomarker for Severe Systemic Mast Cell Activation and MCAS?
Authors: Peter Valent
Cem Akin
Michel Arock
Publication date: 03-02-2024
Publisher: Springer US
Keywords: Anaphylaxis
Anaphylaxis
Systemic Mastocytosis
Mastocytosis
Biomarkers
Published in: Current Allergy and Asthma Reports / Issue 3/2024
Print ISSN: 1529-7322
Electronic ISSN: 1534-6315
DOI: https://doi.org/10.1007/s11882-024-01124-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Reversible Elevation of Tryptase Over the Individual's Baseline: Why is It the Best Biomarker for Severe Systemic Mast Cell Activation and MCAS?

Abstract

Purpose of Review

Recent Findings

Summary

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose of Review

Recent Findings

Summary

Please log in to get access to this content

Other articles of this Issue 3/2024

Precautionary Allergen Labeling: Avoidance for All?

The Natural History and Risk Factors for the Development of Food Allergies in Children and Adults

Epidemiology and the Growing Epidemic of Food Allergy in Children and Adults Across the Globe

Psychosocial Impact of Food Allergy on Children and Adults and Practical Interventions

Multidisciplinary Decision-Making—ITAlian Consensus After Two Years of Real Practice on the Management of Severe Uncontrolled CRSwNP by Biologics (ITACA Study)