Mast cell activation syndrome (MCAS) is a condition characterized by recurrent episodes of clinically relevant, systemic, severe reactions to mast cell (MC)-derived mediators released in the context of anaphylaxis or another acute MC-related event. It is important to document MC involvement in these reactions in order to establish the diagnosis MCAS. The most specific and reliable marker of systemic MC activation is an acute and substantial event-related (transient) increase in the serum tryptase level over the individual’s baseline value. However, the baseline level of tryptase varies depending on the underlying disease and the genetic background. For example, an estimated 3–5% of healthy individuals exhibit duplications or multiple copies of the TPSAB1 gene encoding for alpha-tryptase, and over 30% of all patients with myeloid neoplasms, including mastocytosis, have elevated basal tryptase levels. Therefore, it is of utmost importance to adjust the event-related diagnostic (MCAS-confirming) increase in tryptase over the individual baseline in a robust approach. To address this challenge, the 20% + 2 formula was proposed by the consensus group in 2012. Since then, this approach has been validated in clinical practice by independent groups and found to be sound. In the current article, we discuss the emerging importance and value of the 20% + 2 formula in clinical practice and its role as a criterion of severe systemic MC activation and MCAS.

Mast cells (MCs) are tissue-resident multifunctional effector cells of the immune system [1-3]. These cells produce not only an array of pro-inflammatory mediators and cytokines, including histamine, cysteinyl leukotrienes and prostaglandins, but also various proteases and certain proteoglycans such as heparin [1-3]. During and following anaphylactic degranulation, usually triggered through IgE receptor cross-linking by an allergen, MC release their granular mediators. MC activation and degranulation can also be induced by other triggers or by an IgE-independent hypersensitivity reaction [1-6].

Tryptases are serine proteases that are preferentially produced and stored in MC [7, 8]. In fact, tryptases account for >20% of the total protein content in tissue MC [9]. Whereas mature tryptases are mostly stored in the heparin-containing metachromatic granules of human MC, the precursor forms (pro-tryptases) are released spontaneously and constantly from resting MC [10, 11]. Based on a constant release rate in the steady state and the chemical and biological stability of tryptases, the resulting basal serum tryptase level is remarkably consistent in healthy individuals. The serum tryptase level also remains stable in various reactive processes. However, during and shortly after a severe anaphylactic event where MC release large amounts of tryptase, the serum tryptase level increases substantially over the individual’s baseline (Fig. 1) [12-17]. Thereafter, the tryptase level returns to baseline, which may take several hours (up to 24 h), providing a reliable diagnostic window of about 2–4 h for laboratory investigations [18]. Although other MC-derived chemical mediators and their metabolites, like histamine, prostaglandin D2 (PGD2), and under certain circumstances heparin, may also serve as indicator(s) of MC activation, tryptase has been repeatedly described as the most specific and reliable biomarker of severe systemic MC activation in daily practice [12-18]. A summary of MC-related biomarkers that have been considered (and may be used) for the detection and quantification of MC activation in patients with anaphylaxis is provided in Table 1.

Table 1.

Biomarkers indicating systemic severe MC activation in patients

Biomarkers indicating systemic severe MC activation in patients
Biomarkers indicating systemic severe MC activation in patients
Fig. 1.

a Total serum tryptase concentrations in a patient with indolent systemic mastocytosis and bee venom allergy. The patient developed anaphylaxis (dyspnea, hypotension, tachycardia) 15 min after subcutaneous injection of 0.3 µg bee venom immunotherapy. Whereas his basal tryptase levels were stable before the reaction (40.1, 41.2 ng/mL) and the value returned to 43.2 ng/mL 16 h after the reaction, the tryptase level in the serum obtained within 2 h after anaphylaxis increased to 71.3 ng/mL. This level exceeded the diagnostic threshold by plus 20% + 2 ng/mL (41.2 + 8.24 + 2 ng/mL = 51.44 ng/mL) and thus qualified as MCAS criterion. b Patients with mastocytosis with mild clinical symptoms not resembling MCAS (no MCAS – left panel) and those with severe clinical symptoms resembling MCAS (MCAS-like – right panel) were examined for their serum tryptase levels post or prior to the event and at or shortly after the event (E). As visible, a diagnostic increase in tryptase was only captured in those with a severe anaphylactic (MCAS-like) event (E). MCAS, mast cell activation syndrome; PPE, post or prior to the event.

Fig. 1.

a Total serum tryptase concentrations in a patient with indolent systemic mastocytosis and bee venom allergy. The patient developed anaphylaxis (dyspnea, hypotension, tachycardia) 15 min after subcutaneous injection of 0.3 µg bee venom immunotherapy. Whereas his basal tryptase levels were stable before the reaction (40.1, 41.2 ng/mL) and the value returned to 43.2 ng/mL 16 h after the reaction, the tryptase level in the serum obtained within 2 h after anaphylaxis increased to 71.3 ng/mL. This level exceeded the diagnostic threshold by plus 20% + 2 ng/mL (41.2 + 8.24 + 2 ng/mL = 51.44 ng/mL) and thus qualified as MCAS criterion. b Patients with mastocytosis with mild clinical symptoms not resembling MCAS (no MCAS – left panel) and those with severe clinical symptoms resembling MCAS (MCAS-like – right panel) were examined for their serum tryptase levels post or prior to the event and at or shortly after the event (E). As visible, a diagnostic increase in tryptase was only captured in those with a severe anaphylactic (MCAS-like) event (E). MCAS, mast cell activation syndrome; PPE, post or prior to the event.

Close modal

Systemic MC activation is commonly found in severe anaphylactic reactions [1-6]. In most patients, an IgE-dependent allergy or another hypersensitivity disorder is identified. In severe cases, a MC activation syndrome (MCAS) may be diagnosed [19-22]. Patients with MCAS fulfill specific criteria (see below) and are classified based on the underlying disease. Thus, MCAS is divided into (i) primary (mono/clonal) MCAS, where monoclonal KIT-mutated MC can be detected, (ii) secondary MCAS, where an allergic or other reactive inflammatory disease process may be identified as a trigger of MC activation, and (iii) idiopathic MCAS, where neither MC clonality nor an underlying allergic or other inflammatory or toxic disease process is diagnosed [19-22].

MCAS criteria have been widely accepted and applied in daily practice, mostly in the context of sudden hypotension and shock or other signs of severe anaphylaxis, but also in the context of less severe symptoms where these criteria may not be fulfilled (exclusion of MCAS) [23, 24]. Based on the recommendations of the EU/US consensus group, MCAS is diagnosed when the following criteria apply: (i) documented recurrent episodic occurrence of typical systemic symptoms that are produced by MC mediators and involve at least 2 organ systems, (ii) an event-related transient elevation of the serum tryptase level by at least 20% over the individual baseline plus 2 ng/mL absolute (e.g., from 15 ng/mL to at least + 3 + 2 ≥20 ng/mL or from 41.2 ng/mL to at least + 8.24 + 2 ≥52 ng/mL; Fig. 1) within a 2–4 h window after the reaction, and (iii) a documented clinically meaningful response to drugs that either target MC-derived mediators (e.g., H1 antihistamines or antileukotrienes) and/or suppress MC activation (e.g., cromoglycate, ketotifen, or omalizumab) [19, 21, 22].

Although these criteria are generally accepted and their application has been validated, there remains an ongoing discussion on their use and usefulness in daily practice. One concern relates to the 20% + 2 formula mentioned above. In particular, many users are not familiar with this approach and ask questions related to this formula and why it has been proposed in the MCAS context.

In the current article, we discuss these issues and explain why, where, when, and how this MCAS criterion is applied in routine medical practice and why it remains a most important diagnostic standard.

During the 2010 Working Conference on MC disorders where MCAS criteria were discussed and formulated, one of the deliberation points was the minimal increase in serum tryptase over the individual’s baseline that would meet the criterion of a significant systemic MC activation and would thus count as a diagnostic marker of MCAS [21]. In fact, although it was clear that tryptase is the biomarker of choice to define anaphylaxis and thus MCAS based on previous literature data and experience in specialized centers [12-18], a diagnostic threshold was missing.

The challenge was to define a minimal increase in tryptase over the individual’s baseline level that could be employed for all conditions and cases, namely, individuals with a low basal serum tryptase level (1–5 ng/mL), those with a slightly elevated basal tryptase (12–50 ng/mL), cases with markedly elevated basal tryptase (>50–200 ng/mL), and patients with very high tryptase levels (>200 ng/mL). Employing only an absolute amount of extra tryptase as criterion (e.g., plus extra 20 ng/mL) would fail in those who have very low basal tryptase levels (1–5 ng/mL) and in those with systemic mastocytosis (SM) with a tryptase level exceeding 100 or 200 ng/mL. Defining only a relative increase in tryptase as a criterion (e.g., by 10 or 20%) would fail in those who have low enzyme levels (below 10 ng/mL; e.g., an increase from 5 to 5.7 or even 6 cannot be regarded as a marker of severe systemic anaphylaxis).

It is also important to note that a persistently elevated serum tryptase concentration, like found in SM, is not indicative of MC activation but reflects the elevated body burden of MC. In other cases, a constantly increased basal release or an extra amount of alpha tryptase gene copies can lead to a persistently elevated basal tryptase – again, however, such persistently elevated tryptase is not an indication of systemic MC activation or MCAS.

After in-depth deliberations and based on shared practical experience, the faculty did come up with a consensus proposal and put forth the 20% + 2 formula during the Working Conference [21]. This formula defines a minimal diagnostic increase in tryptase over the individuals’ baseline that qualifies as solid indication and thus as criterion of severe systemic MC activation in all cohorts of patients, including those with very low or normal basal serum tryptase, those with slightly elevated basal tryptase, and those with highly elevated basal serum tryptase. The 20% + 2 formula was subsequently validated against the available literature and all retrospective cases published, and the formula was found to be applicable and robust both in the context of allergy and in the context of -mastocytosis (K.B., L.B., and P.V., unpublished observation) – see also Figure 1. Later, the 20% + 2 formula was further validated in independent case series – see below. Figure 1 shows typical examples of patients with anaphylaxis where the 20% + 2 formula worked out well.

The first question concerning the 20% + 2 formula is: how frequently is an elevated basal serum tryptase level (>11.4 ng/mL, as defined in the commercial assay) detected in daily practice in healthy individuals, in patients diagnosed with allergic/atopic disorders, chronic inflammatory diseases, hematologic disorders, and other diseases of internal medicine? The answer is: when taking the 11.4 threshold as denominator, an increased basal tryptase level is found frequently in otherwise healthy individuals (roughly 5–10% of the general population), in diverse reactive states, and in hematologic disorders, especially in myeloid malignancies (roughly 20–30%; Table 2) [25-31]. Thus, a number of genetic, inflammatory, and neoplastic conditions are associated with an increased basal serum tryptase level. These include tryptase gene replications such as hereditary alpha tryptasemia; chronic infections, such as helminth infections; renal insufficiency – especially hemodialysis patients; and myeloid neoplasms, including myelodysplastic syndromes, SM, acute myeloid leukemia, chronic myeloid leukemia (CML), and chronic eosinophilic leukemia [25-33].

Table 2.

Conditions associated with an elevated basal serum tryptase level

Conditions associated with an elevated basal serum tryptase level
Conditions associated with an elevated basal serum tryptase level

Depending on the underlying condition, basal tryptase levels can be slightly elevated, substantially elevated, or even highly elevated (Table 2). For example, most cases of hereditary alpha tryptasemia have slightly elevated tryptase (12–30 ng/mL) [30-33]. However, the tryptase level increases with gene copy number and can be up to 100 ng/mL in those who have multiple tryptase gene copies (P.V., P.B., and J.J.L., unpublished observation and [33]).

In patients with myeloid neoplasms, the range of tryptase is also broad (Table 2). In most patients with myelodysplastic syndromes or myeloproliferative syndromes, such as CML or chronic eosinophilic leukemia, serum tryptase levels are slightly elevated [27-29]. However, in some patients with acute myeloid leukemia, especially those with inv (16) or t(8;21), basal serum tryptase levels may increase to 100, over 200, or even 1,000 ng/mL (Table 2) [25]. Similarly, in patients with mastocytosis, especially in those who suffer from advanced SM, basal serum tryptase levels may exceed 200 or even 1,000 ng/mL [14, 16, 26]. Finally, as mentioned, there are a number of reactive conditions where serum tryptase levels are elevated, such as chronic kidney failure or chronic helminth infections [28, 34, 35]. All in all, the serum tryptase level can range substantially from subject to subject, both in the general, apparently healthy, population (due to genetic variability and gene copy number variation), in reactive inflammatory conditions, and in myeloid neoplasms. This variation in tryptase levels thus requires a flexible formula defining the minimal increase in tryptase during an MCAS screen in all instances.

The second question is whether one or more of these groups of individuals (healthy individuals or patients) with elevated basal tryptase have indeed an increased risk for developing MCAS. Here the answer is not simple. For example, there is some evidence that individuals with extra tryptase gene copies (hereditary alpha tryptasemia) are at increased risk to develop anaphylactic reactions, especially when a concomitant allergy is also present [30, 33, 36]. In the group of mastocytosis patients, the answer is clearer: in general, patients with SM have a higher risk to develop anaphylaxis and MCAS compared to otherwise healthy individuals or allergic patients without SM [37-44]. Patients with SM and a concomitant allergy have the highest risk to develop MCAS [40-42]. On the other hand, the risk of MCAS does not appear to increase with higher serum tryptase levels [43-46]. In fact, SM patients with a low basal tryptase level (below 30 ng/mL) can develop severe life-threatening anaphylaxis and thus MCAS in apparently a similar manner and frequency when compared to patients with SM with higher serum tryptase levels [43-47].

In myeloid neoplasms other than SM, the elevated tryptase level is often associated with an increase in immature MCs or immature basophils. Still, the risk for development of severe anaphylaxis is usually not greater than the risk found within the general population, thereby contrasting with the elevated risk in SM. However, CML patients can suffer from severe allergies and can rarely develop severe anaphylactic reactions resembling MCAS (P.V., unpublished observation). Whether in these patients, the large number of basophils play a pathologic role remains unknown.

Over the past few years, the 20% + 2 formula has been validated in patients with MC disorders as well as in patients without mastocytosis. In patients with SM, the 20% + 2 formula is a robust approach that safely discriminates between an anaphylactic event and less severe forms of MC activation not fulfilling MCAS criteria, independent of the variant of SM or the basal serum tryptase level (unpublished data and [48]). These data confirm previous studies that have shown that a substantial increase in tryptase is a reliable parameter to document MC activation during anaphylactic episodes [12, 16-18]. However, even in patients who do not suffer from an allergy or mastocytosis, an increase in the serum tryptase level is a most reliable biomarker of MC activation [13, 15, 49]. For example, it has been reported that the 20% + 2 formula is a robust equation for confirming suspected perioperative anaphylaxis during general anesthesia [49]. Moreover, the formula has been validated in children presenting to emergency departments with anaphylaxis [49]. By contrast, in cases with local MC activation or mild mediator-related symptoms, including a subset of food allergy-related reactions associated with GI tract exposure, the serum tryptase level remains near the individual’s baseline [48-52].

The documentation of a severe systemic MC activation and thus MCAS has also therapeutic implications, especially when other differential diagnoses have to be considered. In fact, MCAS patients often need immediate intensive therapy, such as anti-histamines, glucocorticosteroids, and/or epinephrine. In addition, depending on the underlying disease, such patients often receive MC stabilizers, KIT-targeting drugs, or immunotherapy.

Apart from tryptase, a number of other MC-derived compounds may serve as suitable parameters to document severe reactions following systemic MC activation. These substances include, among others, histamine and its metabolites, PGD2 and its metabolites, and heparin [53-58]. However, with the exception of heparin, these mediators are less specific for MC compared to tryptase (Table 1). Methods to determine these mediators are also much less available through widely distributed commercial assays. Some of these mediators have to be measured in 24-h urine samples collected under specific guidelines, including dietary restrictions, in order to obtain reliable results [53-57]. In addition, it remains unclear and undefined what minimal diagnostic increase in histamine (metabolites) or PGD2 metabolites qualifies as a robust indication and thus criterion of severe systemic MC activation and MCAS. Moreover, age-specific normal levels have not been established. Finally, most of these markers increase in a number of different reactive conditions and also in cases with mild mediator-related symptoms. Therefore, these markers may qualify as criteria for less severe forms of MC activation or as indicators of targets of therapeutic intervention (PGD2), but not as a robust criterion for MCAS.

More recently, diamino-oxidase, a histamine-degrading enzyme, has been described as a marker that increases in MCAS patients and has a similar specificity and time course compared to serum tryptase levels [48]. However, a validated test is not generally available, and it remains unknown whether diamino-oxidase is expressed and released from MCs during an anaphylactic reaction and thus is specific for MCAS.

The baseline level of serum tryptase varies considerably among apparently healthy individuals based on their genetic background and other factors. For example, the basal tryptase level is higher in cases of hereditary alpha tryptasemia compared to healthy individuals without an increase in TPSAB1 copy number. The basal tryptase level is also elevated and varies among patients with MC disorders and other myeloid neoplasms as well as in reactive (inflammatory) states. Since several of these conditions may also predispose for the development of MC activation-related events, it is of utmost importance to provide a valuable and simple tool to define a clinically meaningful, reliable increase of the tryptase level over the individual’s baseline through which a substantial (diagnostic) MC activation is safely documented. The 20% + 2 consensus equation is a sound tool to measure a clinically relevant increase in tryptase independent of the baseline level, including individuals with normal/low tryptase (<10 ng/mL), those with slightly elevated tryptase (<50 ng/mL) and those with clearly or even massively elevated tryptase. On the other hand, the tryptase test and the 20% + 2 formula are also robust in that mild forms and local forms of MC activation are usually not captured through this formula. All in all, the 20% + 2 formula remains a recommended gold standard in the evaluation of severe anaphylaxis and MCAS and thus a valid criterion of MCAS available as a clinical diagnostic tool. In the light of the many referrals of patients, this criterion is of even greater contemporary importance, as it helps in the evaluation to determine whether a patient is suffering from true MCAS.

We like to thank Dubravka Smiljkovic for skillful technical assistance. This study was supported in part by the Austrian Science Funds (FWF) projects F4701-B20 and F4704-B20. K.H. is supported by intramural funding of the University of Basel, Switzerland. D.D.M. is supported by the Division of Intramural Research, NIAID.

P.V.: (1). Research grant: Deciphera (2). Advisory Board and Honoraria: Novartis, Deciphera, Pfizer; P.B.: no conflict of interest to declare; K.H.: (1). Research grant: Euroimmun, (2). Advisory Boards and Honoraria: ALK-Abello, Blueprint, Deciphera, and Novartis; K.B.: Advisory board and Honoraria: Phadia (Thermo Fisher); S.B.-O.: Honoraria: Thermo Fisher, Blueprint, Novartis; J.H.B.: no conflict of interest to declare; M.T.: Advisory Board and Honoraria: Novartis, Patara, Deciphera, Blueprint; M.A.: (1). Research grant: Agensys Inc., Blueprint Medicine, Deciphera, (2). Advisory Board and Honoraria: Blueprint Medicine, Deciphera, Novartis; C.A.: (1). Honoraria: Novartis, Blueprint, (2). Research Grant: Blueprint. The authors declare that they have no other (additional) conflict of interest to declare in this project.

This study was supported in part by the Austrian Science Funds (FWF) projects F4701-B20 and F4704-B20. D.D.M., and J.J.L. are supported by the Division of Intramural Research, NIAID.

All authors contributed equally by discussing the available literature, unpublished data, and case reports. All authors contributed substantially writing and/or extensively reviewing parts of the manuscript. All authors approved the final version of the document.

1.
Metcalfe
DD
.
Mast cells and mastocytosis
.
Blood
.
2008
Aug
;
112
(
4
):
946
56
.
[PubMed]
0006-4971
2.
Galli
SJ
,
Tsai
M
.
IgE and mast cells in allergic disease
.
Nat Med
.
2012
May
;
18
(
5
):
693
704
.
[PubMed]
1078-8956
3.
Theoharides
TC
,
Valent
P
,
Akin
C
.
Mast cells, mastocytosis, and related disorders
.
N Engl J Med
.
2015
Jul
;
373
(
2
):
163
72
.
[PubMed]
0028-4793
4.
Metcalfe
DD
,
Peavy
RD
,
Gilfillan
AM
.
Mechanisms of mast cell signaling in anaphylaxis
.
J Allergy Clin Immunol
.
2009
Oct
;
124
(
4
):
639
46
.
[PubMed]
0091-6749
5.
Kalesnikoff
J
,
Galli
SJ
.
Anaphylaxis: mechanisms of mast cell activation
.
Chem Immunol Allergy
.
2010
;
95
:
45
66
.
[PubMed]
1660-2242
6.
Lieberman
P
.
Mechanisms of anaphylaxis beyond classically mediated antigen- and IgE-induced events
.
Ann Allergy Asthma Immunol
.
2017
Mar
;
118
(
3
):
246
8
.
[PubMed]
1081-1206
7.
Schwartz
LB
.
Tryptase from human mast cells: biochemistry, biology and clinical utility
.
Monogr Allergy
.
1990
;
27
:
90
113
.
[PubMed]
0077-0760
8.
Schwartz
LB
.
Tryptase, a mediator of human mast cells
.
J Allergy Clin Immunol
.
1990
Oct
;
86
(
4 Pt 2
):
594
8
.
[PubMed]
0091-6749
9.
Schwartz
LB
,
Lewis
RA
,
Austen
KF
.
Tryptase from human pulmonary mast cells. Purification and characterization
.
J Biol Chem
.
1981
Nov
;
256
(
22
):
11939
43
.
[PubMed]
0021-9258
10.
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
Jun
;
170
(
11
):
5667
73
.
[PubMed]
0022-1767
11.
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
Mar
;
176
(
5
):
3165
72
.
[PubMed]
0022-1767
12.
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
Jun
;
316
(
26
):
1622
6
.
[PubMed]
0028-4793
13.
Bosso
JV
,
Schwartz
LB
,
Stevenson
DD
.
Tryptase and histamine release during aspirin-induced respiratory reactions
.
J Allergy Clin Immunol
.
1991
Dec
;
88
(
6
):
830
7
.
[PubMed]
0091-6749
14.
Schwartz
LB
,
Sakai
K
,
Bradford
TR
,
Ren
S
,
Zweiman
B
,
Worobec
AS
, et al
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
Dec
;
96
(
6
):
2702
10
.
[PubMed]
0021-9738
15.
Schwartz
HJ
.
Elevated serum tryptase in exercise-induced anaphylaxis
.
J Allergy Clin Immunol
.
1995
Apr
;
95
(
4
):
917
9
.
[PubMed]
0091-6749
16.
Schwartz
LB
.
Diagnostic value of tryptase in anaphylaxis and mastocytosis
.
Immunol Allergy Clin North Am
.
2006
Aug
;
26
(
3
):
451
63
.
[PubMed]
0889-8561
17.
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
Jul
;
106
(
1 Pt 1
):
65
71
.
[PubMed]
0091-6749
18.
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
May
;
83
(
5
):
1551
5
.
[PubMed]
0021-9738
19.
Akin
C
,
Valent
P
,
Metcalfe
DD
.
Mast cell activation syndrome: proposed diagnostic criteria
.
J Allergy Clin Immunol
.
2010
Dec
;
126
(
6
):
1099
104.e4
.
[PubMed]
0091-6749
20.
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
Jul
;
128
(
1
):
147
152.e2
.
[PubMed]
0091-6749
21.
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
(
3
):
215
25
.
[PubMed]
1018-2438
22.
Valent
P
.
Mast cell activation syndromes: definition and classification
.
Allergy
.
2013
Apr
;
68
(
4
):
417
24
.
[PubMed]
0105-4538
23.
Valent
P
,
Akin
C
,
Bonadonna
P
,
Hartmann
K
,
Broesby-Olsen
S
,
Brockow
K
, et al
Mast cell activation syndrome: importance of consensus criteria and call for research
.
J Allergy Clin Immunol
.
2018
Sep
;
142
(
3
):
1008
10
.
[PubMed]
0091-6749
24.
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
Apr
;
7
(
4
):
1125
1133.e1
.
[PubMed]
2213-2198
25.
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
Oct
;
98
(
7
):
2200
9
.
[PubMed]
0006-4971
26.
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
Jun
;
128
(
2
):
136
41
.
[PubMed]
1018-2438
27.
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
May
;
43
(
5
):
1097
105
.
[PubMed]
1042-8194
28.
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 haematology
.
Eur J Clin Invest
.
2009
Oct
;
39
(
10
):
914
23
.
[PubMed]
0014-2972
29.
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
Oct
;
7
(
5
):
683
90
.
[PubMed]
1747-4086
30.
Lyons
JJ
,
Sun
G
,
Stone
KD
,
Nelson
C
,
Wisch
L
,
O’Brien
M
, et al
Mendelian inheritance of elevated serum tryptase associated with atopy and connective tissue abnormalities
.
J Allergy Clin Immunol
.
2014
May
;
133
(
5
):
1471
4
.
[PubMed]
0091-6749
31.
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
Dec
;
48
(
12
):
1564
9
.
[PubMed]
1061-4036
32.
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
Apr
;
20
(
5
):
503
12
.
[PubMed]
1098-3600
33.
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
May
;
38
(
4
):
457
9
.
[PubMed]
0271-9142
34.
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
May
;
3
(
5
):
343
7
.
[PubMed]
1610-0379
35.
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
May
;
46
(
5
):
460
74
.
[PubMed]
0014-2972
36.
Ruëff
F
,
Przybilla
B
,
Biló
MB
,
Müller
U
,
Scheipl
F
,
Aberer
W
, et al
Predictors of severe systemic anaphylactic reactions in patients with Hymenoptera venom allergy: importance of baseline serum tryptase-a study of the European Academy of Allergology and Clinical Immunology Interest Group on Insect Venom Hypersensitivity
.
J Allergy Clin Immunol
.
2009
Nov
;
124
(
5
):
1047
54
.
[PubMed]
0091-6749
37.
Oude Elberink
JN
,
de Monchy
JG
,
Kors
JW
,
van Doormaal
JJ
,
Dubois
AE
.
Fatal anaphylaxis after a yellow jacket sting, despite venom immunotherapy, in two patients with mastocytosis
.
J Allergy Clin Immunol
.
1997
Jan
;
99
(
1 Pt 1
):
153
4
.
[PubMed]
0091-6749
38.
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
Oct
;
37
(
10
):
1547
55
.
[PubMed]
0954-7894
39.
Niedoszytko
M
,
de Monchy
J
,
van Doormaal
JJ
,
Jassem
E
,
Oude Elberink
JN
.
Mastocytosis and insect venom allergy: diagnosis, safety and efficacy of venom immunotherapy
.
Allergy
.
2009
Sep
;
64
(
9
):
1237
45
.
[PubMed]
0105-4538
40.
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
Mar
;
123
(
3
):
680
6
.
[PubMed]
0091-6749
41.
Akin
C
.
Anaphylaxis and mast cell disease: what is the risk?
Curr Allergy Asthma Rep
.
2010
Jan
;
10
(
1
):
34
8
.
[PubMed]
1529-7322
42.
Bonadonna
P
,
Pagani
M
,
Aberer
W
,
Bilò
MB
,
Brockow
K
,
Oude Elberink
H
, et al
Drug hypersensitivity in clonal mast cell disorders: ENDA/EAACI position paper
.
Allergy
.
2015
Jul
;
70
(
7
):
755
63
.
[PubMed]
0105-4538
43.
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
Feb
;
63
(
2
):
226
32
.
[PubMed]
0105-4538
44.
Broesby-Olsen
S
,
Farkas
DK
,
Vestergaard
H
,
Hermann
AP
,
Møller
MB
,
Mortz
CG
, et al
Risk of solid cancer, cardiovascular disease, anaphylaxis, osteoporosis and fractures in patients with systemic mastocytosis: A nationwide population-based study
.
Am J Hematol
.
2016
Nov
;
91
(
11
):
1069
75
.
[PubMed]
0361-8609
45.
van Anrooij
B
,
van der Veer
E
,
de Monchy
JG
,
van der Heide
S
,
Kluin-Nelemans
JC
,
van Voorst Vader
PC
, et al
Higher mast cell load decreases the risk of Hymenoptera venom-induced anaphylaxis in patients with mastocytosis
.
J Allergy Clin Immunol
.
2013
Jul
;
132
(
1
):
125
30
.
[PubMed]
0091-6749
46.
Gülen
T
,
Ljung
C
,
Nilsson
G
,
Akin
C
.
Risk Factor Analysis of Anaphylactic Reactions in Patients With Systemic Mastocytosis
.
J Allergy Clin Immunol Pract
.
2017
Sep - Oct
;
5
(
5
):
1248
55
.
[PubMed]
2213-2198
47.
Zanotti
R
,
Lombardo
C
,
Passalacqua
G
,
Caimmi
C
,
Bonifacio
M
,
De Matteis
G
, et al
Clonal mast cell disorders in patients with severe Hymenoptera venom allergy and normal serum tryptase levels
.
J Allergy Clin Immunol
.
2015
Jul
;
136
(
1
):
135
9
.
[PubMed]
0091-6749
48.
Boehm
T
,
Reiter
B
,
Ristl
R
,
Petroczi
K
,
Sperr
W
,
Stimpfl
T
, et al
Massive release of the histamine-degrading enzyme diamine oxidase during severe anaphylaxis in mastocytosis patients
.
Allergy
.
2019
Mar
;
74
(
3
):
583
93
.
[PubMed]
0105-4538
49.
Baretto
RL
,
Beck
S
,
Heslegrave
J
,
Melchior
C
,
Mohamed
O
,
Ekbote
A
, et al
Validation of international consensus equation for acute serum total tryptase in mast cell activation: A perioperative perspective
.
Allergy
.
2017
Dec
;
72
(
12
):
2031
4
.
[PubMed]
0105-4538
50.
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
Apr
;
137
(
4
):
1138
42
.
[PubMed]
0091-6749
51.
Dua
S
,
Dowey
J
,
Foley
L
,
Islam
S
,
King
Y
,
Ewan
P
, et al
Diagnostic Value of Tryptase in Food Allergic Reactions: A Prospective Study of 160 Adult Peanut Challenges
.
J Allergy Clin Immunol Pract
.
2018
Sep - Oct
;
6
(
5
):
1692
1698.e1
.
[PubMed]
2213-2198
52.
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
Jul
;
6
(
4
):
304
9
.
[PubMed]
2092-7355
53.
Watkins
J
,
Wild
G
.
Improved diagnosis of anaphylactoid reactions by measurement of serum tryptase and urinary methylhistamine
.
Ann Fr Anesth Reanim
.
1993
;
12
(
2
):
169
72
.
[PubMed]
0750-7658
54.
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
Dec
;
309
(
26
):
1603
5
.
[PubMed]
0028-4793
55.
Awad
JA
,
Morrow
JD
,
Roberts
LJ
 2nd
.
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
May
;
93
(
5
):
817
24
.
[PubMed]
0091-6749
56.
Ono
E
,
Taniguchi
M
,
Mita
H
,
Akiyama
K
.
Salicylamide-induced anaphylaxis: increased urinary leukotriene E4 and prostaglandin D2 metabolite
.
Allergy
.
2008
Apr
;
63
(
4
):
480
2
.
[PubMed]
0105-4538
57.
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
Nov-Dec
;
2
(
6
):
775
8
.
[PubMed]
2213-2198
58.
Vysniauskaite
M
,
Hertfelder
HJ
,
Oldenburg
J
,
Dreßen
P
,
Brettner
S
,
Homann
J
, et al
Determination of plasma heparin level improves identification of systemic mast cell activation disease
.
PLoS One
.
2015
Apr
;
10
(
4
):
e0124912
.
[PubMed]
1932-6203

Edited by: H.-U. Simon, Bern.

Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.