Allergy

REVIEW ARTICLE

Mast cell activation syndromes: definition and

classification
P. Valent
Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria

To cite this article: Valent P. Mast cell activation syndromes: definition and classification. Allergy 2013; 68: 417–424.

Keywords Abstract
allergic reactions; classification; criteria; IgE;
mast cells.
Mast cell activation (MCA) occurs in a number of different clinical conditions,
including IgE-dependent allergies, other inflammatory reactions, and mastocyto-
Correspondence sis. MCA-related symptoms may be mild, moderate, severe, or even life-threaten-
Peter Valent, Department of Internal ing. The severity of MCA depends on a number of different factors, including
Medicine I, Division of Hematology and genetic predisposition, the number and releasability of mast cells involved in the
Hemostaseology, Medical University of reaction, the type of allergen, presence of specific IgE, and presence of certain
Vienna, W€ €rtel 18-20, A-1090
ahringer Gu comorbidities. In severe reactions, MCA can be documented by a substantial
Vienna, Austria. increase in the serum tryptase level above baseline. When symptoms are recur-
Tel.: 43 1 40400 6085
rent, are accompanied by an increase in mast cell–derived mediators in biological
Fax: 43 1 40400 4030
fluids, and are responsive to treatment with mast cell–stabilizing or mediator-tar-
E-mail: peter.valent@meduniwien.ac.at
geting drugs, the diagnosis of mast cell activation syndrome (MCAS) is appropri-
Accepted for publication 28 December 2012
ate. Based on the underlying condition, these patients can further be classified
into i) primary MCAS where KIT-mutated, clonal mast cells are detected, ii) sec-
DOI:10.1111/all.12126 ondary MCAS where an underlying inflammatory disease, often in the form of
an IgE-dependent allergy, but no KIT-mutated mast cells, is found, and iii) idio-
Edited by: Hans-Uwe Simon pathic MCAS, where neither an allergy or other underlying disease, nor KIT-
mutated mast cells are detectable. It is important to note that in many patients
This work was in part supported by a mast- with MCAS, several different factors act together to lead to severe or even life-
ocytosis grant of the Medical University of threatening anaphylaxis. Detailed knowledge about the pathogenesis and com-
Vienna.
plexity of MCAS, and thus establishing the exact final diagnosis, may greatly help
in the management and therapy of these patients.

Mast cells are tissue-fixed effector cells of allergic and other
inflammatory reactions (1–5). In common with blood
basophils, mast cells express high-affinity IgE-binding sites and
store numerous proinflammatory and vasoactive mediators in
their metachromatic granules (1–3). During a severe anaphy-
lactic reaction, allergen-induced cross-linking of IgE-binding
sites on mast cells is followed by an explosive release of gran-
ular mediators (1–3, 5–7). In addition, activated mast cells
release newly synthesized membrane-derived (lipid) mediators
of allergic reactions into the extracellular space. Blood
basophils also participate in allergic and other inflammatory
reactions in the same way as mast cells (1, 8, 9). However,
not all allergic reactions involve both cell types, even if the
reaction is systemic. In addition, some of the mediators rele-
vant to anaphylactic reactions are produced and released pri-
marily in mast cells but not in basophils, or only in blood
basophils but not in tissue mast cells.
The capacity of mast cells and basophils to release media-
tors of anaphylaxis in response to cell activation, also termed
‘releasability’, depends on a number of different factors,
including the primary underlying disease, number and type
of (pre)activated receptors and signaling cascades, and the
genetic background (9–13). The severity of an anaphylactic
reaction is determined by additional factors, including the
numbers of mast cells (and basophils) involved in the reac-
tion, presence and type of allergen, amount and type of IgE,
presence of comorbidities, the local microenvironment, and
the cytokine- and chemokine networks (14–17).
Mast cell activation (MCA) occurs in a number of differ-
ent pathologic conditions. Acute MCA is commonly seen in
allergic reactions and often leads to the clinical signs and
symptoms of anaphylaxis (1–7). Severe or even life-threaten-
ing MCA may occur when the burden of mast cells is high
and/or these cells are in an hyperactivated state. In these
cases, a MCA syndrome (MCAS) may be diagnosed.
Historically, clinical symptoms arising from MCA have
mostly been studied in the context of allergies or atopic dis-
orders (18–20). More recently, however, MCA has also been

Allergy 68 (2013) 417–424 © 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd 417
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Mast cell activation syndromes Valent

studied in the context of other diseases, including systemic
mastocytosis (21–25). During the past 3 years, criteria for
MCA and MCAS have been developed by a consensus panel
consisting of experts in the fields of allergy, dermatology,
hematology, pathology, and molecular medicine (25–27). In
the current review article, these criteria and the classification
of MCAS are discussed in light of new developments in the
field and the growing interest in the biology and implications
of MCA and MCAS.
Symptoms of mast cell activation (MCA)
The various symptoms of MCA are probably one of the
more frequently recorded and frequently treated symptoms in
daily practice in internal medicine. MCA-related symptoms
range from mild headache or abdominal cramping to severe
or even life-threatening anaphylaxis (Table 1). These symp-
toms are caused by a number of different vasoactive and pro-
inflammatory mediators that are released from MC when
these cells are activated by an allergen via IgE and IgE recep-
tors, or other trigger(s) (1–6, 28, 29). Correspondingly, the
severity of MCA correlates with the amount and type of
mediators released from mast cells during an anaphylactic
reaction. Well-recognized symptoms of immediate-type
allergy, suggestive of systemic MCA, include acute urticaria,
flushing, pruritus, headache, abdominal cramping and diar-
rhea, respiratory symptoms, and hypotension (Table 1).
Although none of these symptoms is absolutely specific for
MCA, most are typically found in these patients. Especially,
when occurring together in one patient at the same time,
these symptoms are suggestive of MCA and/or basophil acti-
vation. The likelihood of MCA is even higher when two or
more of these symptoms are recorded and respond to drugs
blocking mediator effects, mediator production, or mediator
release in mast cells. Indeed, the response to such drugs is
often helpful in daily practice and has therefore been pro-
posed as an additional criterion of MCA (27). This is of par-
ticular importance when symptoms are unusual or the
patient is suffering from another unrelated disease that may
provoke similar symptoms, mimicking MCA. An important
point is that many different mediators may be involved in
MCA-related symptoms (1–6, 28, 29) so that the final conclu-
sion the patient is not responding to antimediator therapy
should only be drawn after having applied several different
antimediator-type drugs. Likewise, severe hypotension may
be triggered by both histamine and prostaglandin D2,
derived from activated mast cells in the same patient, so that
the reaction can only be kept under control when administer-
ing histamine receptor blockers as well as a prostaglandin
synthesis inhibitor.
Another important aspect is that systemic MCA may also
present as a chronic and less severe reaction, but may still be
a challenge and relevant, clinically. Such symptoms are often
less specific and include headache and fatigue or nausea and
insomnia. Although these patients may not fulfill formal cri-
teria of severe systemic MCA (no MCA syndrome by defini-
tion), the symptoms should be recognized as clinically
relevant and should be treated appropriately using antimedia-
tor-type drugs or mast cell-stabilizing agents. On the other
hand, it is important to be aware of the fact that there are a
number of differential diagnoses that have to be considered
in these patients, including neurologic and even psychiatric
disorders.
Finally, MCA may occur as a local, nonsystemic, more or
less severe, event which may also represent a clinical chal-
lenge for the treating physician. Especially the local variant
of MCA that is associated with, or even triggered by, an ato-
pic disease or another chronic inflammatory disease may rep-
resent a major clinical problem. Although the criteria for
systemic MCA are usually not fulfilled in these patients, the

Table 1 Clinical symptoms typically found in patients suffering from mast cell activation (MCA)* and their impact in the evaluation of MCA
syndromes (MCAS)

Symptom(s)* Diagnostic impact in the evaluation of severe MCA ( = suspected MCA syndrome = MCAS)

Hypotension  shock Pathognomonic key finding in MCAS (other underlying diseases that could explain hypotension need to be excluded)
Tachycardia Tachycardia usually accompanies hypotension in MCAS
Diarrhea Usually accompanied by systemic symptoms of MCAS; in the absence of these, the diagnosis remains uncertain
Abdominal cramping Usually accompanied by systemic symptoms of MCAS; in the absence of these, the diagnosis remains uncertain
Nausea Usually accompanied by systemic symptoms of MCAS; in the absence of these, the diagnosis remains uncertain
Flushing Severe flushing may be an indicator of MCAS; in these cases; flushing is often accompanied by systemic symptoms
Pruritus Severe pruritus may be an indicator of MCAS; in these cases; flushing is often accompanied by systemic symptoms
Acute urticaria Severe acute urticaria may be an indicator of MCAS; in these cases, systemic symptoms are usually found
Angioedema Severe angioedema may be an indicator of MCAS and then is usually accompanied by systemic symptoms
Nasal congestion Diagnostic only in the context of other MCAS-related symptoms and the presence of other MCAS criteria
Wheezing Diagnostic only in the context of other MCAS-related symptoms and the presence of other MCAS criteria
Headache Diagnostic only in the context of other MCAS-related symptoms and the presence of other MCAS criteria
Neurologic symptoms Diagnostic only in the context of other MCAS-related symptoms and the presence of other MCAS criteria
Fatigue Diagnostic only in the context of other MCAS-related symptoms and the presence of other MCAS criteria

*All these symptoms can be triggered by mast cell-derived compounds. Therefore, an isolated symptom is not a typical finding in MCAS
patients. Rather, the likelihood of MCA, and thus MCAS, increases when two or more of these symptoms have been recorded and the
symptoms improve in response to therapy with antimediator-type drugs or mast cell-stabilizing agents.

418 Allergy 68 (2013) 417–424 © 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd

Valent
impact of local MCA in these conditions needs to be
acknowledged, and specific therapy using antimediator-type
drugs or mast cell-stabilizing agents is often required, with
recognition that the underlying disease is the primary target
of therapy.
All in all, MCA can be classified into severe and less severe
forms, into acute, episodic, and chronic variants, and into
systemic and local entities (Table 2).
Laboratory assessment of systemic MCA
In most reactions, MCA is followed by the release of pre-
formed and newly generated mediators of inflammation and
other mast cell–dependent compounds. In severe systemic
reactions, increased levels of mast cell–derived mediators are
measurable in biological fluids (serum, plasma, urine) in most
cases (30–35). Some of these mediators, like tryptase, are
rather specific for mast cells (36, 37). Other mediators are less
specific and also produced by other cell types. Whereas hista-
mine is released from mast cells and basophils in similar
quantities, tryptase is rather specific for mast cells, although
basophils can also express and release small quantities of the
enzyme (38–40). However, for routine purposes in clinical
immunology, a rapid increase in the serum tryptase level
from baseline is considered a specific and reliable parameter
of MCA. If no pretherapeutic baseline is available, the base-
line has to be assessed after complete recovery or in a symp-
tom-free interval (30–32, 41, 42). Most experts recommend
that baseline tryptase should be measured at least
24-48 h after complete resolution of all symptoms in these
patients. The other important question is: what is the mini-
mal increase in serum tryptase required to judge it as indica-
tive (proof) of MCA. The recent consensus proposal is that a
minimal increase in tryptase to plus 20% of baseline plus
absolute 2 ng/ml would meet the definition of MCA (27).
Table 2 Proposed variants of mast cell activation (MCA)*
Variants* Indicator/criterion
Severity
Mild MCA No therapy required
Moderate MCA Drug therapy required, but no need for
hospitalization
Severe MCA** Hospitalization required**
Organ system involvement
Local MCA Restricted to one organ, usually a local reaction
Systemic MCA Multiorgan involvement (in severe forms:
increase in serum tryptase found)
Frequency
Acute MCA Symptom(s) recorded once
Episodic MCA Recurrent symptoms
Chronic MCA Persistent symptoms
*Symptoms should always be described in detail in all patients
using the three levels of delineation – for example: severe acute
systemic MCA; or: moderate local, episodic form of MCA.
**These patients are usually suffering from a MCA syndrome
(MCAS).
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Mast cell activation syndromes
For example, if the baseline tryptase level was 5 ng/ml, an
increase to 10 ng/ml is suggestive of MCA [1(20%) + 2(abso-
lute) = every value above 8 (5 + 3) ng/ml].
Apart from tryptase, other mediators, when increasing
from baseline, may also serve as useful parameters of MCA.
These include, among others, histamine (plasma, urine), his-
tamine metabolites (urine), and prostaglandin D2 (43–47).
However, as mentioned, these mediators are less specific for
MCA compared with tryptase. Moreover, no criteria have
been proposed to define what minimal increase in these medi-
ators would count as a reliable indicator of systemic MCA.
Nevertheless, these mediators are helpful in the evaluation of
MCA patients and should therefore be recommended, at least
when the serum tryptase assay is not available or did not
show a convincing result.
Cellular assays have also been proposed to document mast
cell and basophil activation (48–51). Reliable and established
parameters of basophil and mast cell activation are CD63
and CD203c. Both determinants (antigens) are upregulated
on the surface of IgE receptor cross-linked mast cells and
basophils (48–53). However, whereas basophils are easily
accessible for repeated investigations, mast cells are not
accessible unless a tissue biopsy is performed.
Definition of MCA syndromes (MCAS) and related
criteria
The term MCAS should be applied when i) clinical signs of
severe recurrent (or chronic) systemic MCA are present, ii)
involvement of mast cells can be documented by biochemical
measurements (preferably increase in tryptase following the
20% + 2 formula), and iii) the symptoms respond to therapy
with mast cell-stabilizing agents or drugs directed against
mast cell mediator production, mediator release, or mediator
effects (24–27) (Fig. 1). All three criteria should be fulfilled
to establish the diagnosis of MCAS (27). However, in many
cases, only two or even one of these three criteria can be
documented. In the case of typical symptoms, the provi-
sional diagnosis of ‘possibly MCA/MCAS’ can be estab-
lished, and in acute cases, immediate treatment should be
introduced. For example, if a patient with known mastocy-
tosis is admitted because of an anaphylactic shock (without
signs of an underlying cardiovascular or infectious disease)
but does not respond to antihistamines and glucocorticoster-
oids but only to epinephrine, the diagnosis is suspected
MCAS, and treatment will continue with antimediator-type
and mast cell-stabilizing agents as well as intensive care
treatment. In other words, in certain situations, a lack of
response to antimediator-type drugs does not exclude the
presence of MCAS.
As mentioned above, MCA may also present as a less
severe or chronic condition. In these patients, not all criteria
of MCAS may be fulfilled even if the episodes are of clinical
relevance. In these cases, the condition should be called
MCA, or suspected MCA, without MCAS. The consensus
group has recommended that in patients with mastocytosis
(regardless of the variant), any type of MCA requiring ther-
apy should be marked with the diagnostic label ‘SY’
419

Mast cell activation syndromes
Signs and symptoms of MCA
Severity of
symptoms
Suspected MCAS
Documented elevation of serum total
tryptase or of other mast cell-derived
mediators, such as histamine or PGD2
Diagnosis: MCAS
Figure 1 Proposed diagnostic algorithm in patients with suspected
mast cell activation syndrome (MCAS). In the first step, symptoms
and signs of mast cell activation (MCA) are recorded, and clinical
and laboratory examinations have excluded the presence of another
underlying condition or disease that can mimic symptoms of MCA.
Based on the severity of symptoms, the diagnosis MCAS is sus-
pected. The case history is also essential in these cases and may
reveal the presence of a known systemic mastocytosis (SM) or a
known allergic or atopic disease (AD). In the next step, the physi-
cian documents MCA by serology. A substantial increase in the
appearing as a subscript in the final diagnosis (27, 54). These
patients include those who have and those who do not have
an overt MCAS. For example, in a patient with systemic
indolent mastocytosis (ISM) requiring continuous histamine
receptor blockers and glucocorticosteroids to control MCA-
related symptoms, the final diagnosis should be ISMSY
(or ISM-SY), even if the criteria of MCAS are not fulfilled
(or could not be documented) (54).
Underlying disorders and classification of MCAS
Mast cell activation syndrome usually develops on the basis
of a known underlying systemic disease, which can be an
IgE-dependent disorder, another inflammatory disease, or a
mast cell neoplasm (20–27). In most patients, the mast cell
neoplasm, if detected, is classified as systemic mastocytosis
(SM). In these patients, neoplastic mast cells usually carry
the activating KIT point mutation D816V (55–58). The
related mutant, KIT D816V, is considered to play a role in
the autonomous growth and expansion of neoplastic mast
cells (59, 60). In addition, KIT D816V has been discussed as
contributing to the enhanced releasability of mast cells in
SM, although this point is still a matter of discussion. An
important aspect is that KIT D816V is sometimes also
expressed in mast cells in patients with cutaneous mastocyto-
sis (CM) (61–63) or even in otherwise healthy individuals in
whom neither criteria for CM nor criteria for SM are fulfilled
(21–26). In these patients, the KIT-mutated mast cells may
contribute to the symptoms of MCAS in the same way as in
420 Allergy 68 (2013) 417–424 © 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd
13989995, 2013, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12126, Wiley Online Library on [06/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Valent
Clinical and laboratory examinations have excluded
other underlying conditions mimicking MCA/MCAS
Case history (e.g. SM or AD)
Symptoms respond to drugs targeting mast
cells, mast cell mediators or mediator effects
basal serum tryptase level or other mast cell–derived mediators
during an attack will support the conclusion the patient is suffering
from MCAS. An increase in serum tryptase to at least 20% above
baseline + additional 2 ng/ml (absolute) measured during or after
(within 4–12 h) a clinical episode(s) is indicative of severe MCA
(MCAS) (27). Finally, the physician will ask whether the symptoms
are responsive to drugs targeting mast cells (mast cell-stabilizing),
mast cell mediators, or mediator effects. If all these features are
fulfilled, the diagnosis of MCAS can be established based on rec-
ommendations provided by the consensus group (27).
SM. There are also other activating mutations in KIT that
have been reported to occur in SM or CM (61–63), and sev-
eral of these mutations may contribute to disease evolution
and/or manifestation of certain symptoms. However, com-
pared with KIT D816V, all these mutants are rarely found in
SM and CM, and their exact impact and role as trigger of
MCA remain at present unknown (61–63).
Based on the underlying disease and recognized etiology,
MCAS can be differentiated into primary MCAS, secondary
MCAS, and idiopathic MCAS (27). In primary MCAS, KIT-
mutated monoclonal mast cells usually expressing CD25, are
detectable, and the underlying disease may be SM or CM
(27). Even in the absence of SM and CM, a primary (mono-
clonal) MCAS with clonal mast cells can be diagnosed (27).
In these rare patients, the follow-up may reveal progression
to overt CM or SM. In secondary MCAS, most patients are
suffering from an IgE-dependent allergic disease. If neither
an allergic or other underlying inflammatory process nor a
monoclonal, KIT-mutated, mast cell population are detect-
able in a patient with MCAS, the diagnosis ‘idiopathic
MCAS’ should be established (Table 3).
The impact of comorbidities in patients with MCAS
As mentioned earlier, the severity of MCA is considered to
depend on a number of different factors, such as the number
of mast cells participating in the reaction, releasability, type
and amount of produced IgE, and the presence of activating
cytokines and chemokines. Whereas the underlying disease
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Valent Mast cell activation syndromes

Table 3 Variants of mast cell activation syndromes (MCAS)* and Table 4 Major differential diagnoses in patients with suspected
diagnostic features mast cell activation syndrome (MCAS)

MCAS variant Discriminating/diagnostic features Cardiovascular

Myocardial Infarction
Primary MCAS KIT D816V-mutated clonal mast cells are found Endocarditis/Endomyocarditis
(usually these mast cells express CD25)** Aortic Stenosis with Syncope
Secondary MCAS An underlying Allergy or Atopic Disorder Pulmonary Infarction
inducing MCA and thus MCAS is diagnosed, Endocrinologic
but no clonal mast cells are detectable*** Acute Hypothyroidism
Idiopathic MCAS MCAS criteria are fulfilled, but no underlying Acute Hypoglycemia
reactive disease, no allergen-specific IgE, and Adrenal Insufficiency
no clonal mast cells are detectable*** Hypopituitarism
Gastrointestinal Disorders (with Diarrhea + Dehydration)
*The classification of MCAS is described in detail in a recent con-
Acute Inflammatory Bowel Disease
sensus proposal (27).
VIP-secreting Tumor (VIPoma)
**Most of these patients suffer from cutaneous (CM) or systemic
Acute Episodes of Morbus Crohn or Colitis Ulcerosa
(SM) mastocytosis. However, in some of them, criteria for SM and
Food Intoxication
CM are not fulfilled.
Infectious Diseases
***In these patients, no mutation of KIT at codon 816 is found. If
Severe Bacterial or viral infections  septic shock
flow cytometry is available, the phenotype of mast cells should be
Acute Gastrointestinal Infection with Dehydration
established: the presence of CD25-negative mast cells (normal phe-
Acute Encephalitis/Meningitis
notype) supports the diagnosis of secondary or idiopathic MCAS.
Acute Parasitic Diseases (e.g. Acute Chagas Disease)
Neurologic/Central Nervous System (CNS) Disorders
Epilepsy
may be a primary mast cell disease, often presenting with CNS Tumors
excessive numbers of mast cells, or an IgE-dependent allergy, Other CNS Diseases
resulting in IgE-dependent release of allergic mediators from Intoxication
mast cells, the coexistence of both may represent a clinically Psychiatric conditions
serious, often life-threatening, situation (64). In addition, Skin Diseases
other comorbidities may be present that influence mast cell Hereditary or acquired Angioedema
releasability through cytokine exposure, the numbers of mast Pemphigus vulgaris
cells through KIT ligand exposure, or leukocyte activation Acute Lupus Erythematodes
triggered by chemokine effects. Some of the comorbidities Acute Toxic Dermatoses
represent classical combinations representing a high-risk situ- Hematologic – Acute Anemia  Hypovolemic Shock
ation for the occurrence of life-threatening MCA (anaphy- Acute Gastrointestinal Bleeding
laxis). One typical example is the presence of an allergy Massive Hypermenorrhea
against hymenoptera venom(s) in patients with mastocytosis Drug-induced Side Effects
(23, 65–68). In these patients, insect stings can lead to extre- Drug-induced Hypoglycemia
Drug-induced Hypotension
mely severe reactions, and cases of death have been reported
Drug-induced Diarrhea
in the literature (65–68). Another high-risk situation is the
Drug-Induced CNS Damage
combination of food allergy and mastocytosis. IgE-dependent
allergy against inhaled allergens and a coexisting severe bron- In most instances, symptoms of acute hypotension are recorded. If
chial disorder, for example a chronic bronchial infection, is additional MCA-mimicking symptoms, such as skin lesions, head-
another example. In all these situations, severe reactions need ache, and/or diarrhea are found, it is often difficult to separate from
to be addressed immediately and often result in hospitaliza- MCA and thus MCAS.
tion. To address all these high-risk conditions in a prophylac- VIP, vasoactive intestinal peptide.
tic manner, patients are advised to take continuous
(prophylactic) antimediator-type drugs, to carry additional severe infections (sepsis), dehydration, and other systemic
emergency drugs (glucocorticosteroids, epinephrin self injec- diseases (Table 4). Other differential diagnoses relate to
tor) with them, and to self-apply these drug on demand to organ-specific symptoms, such as diarrhea (gastrointestinal
bridge the time until the emergency team will arrive and diseases), skin rush (cutaneous diseases), or neurologic symp-
bring the situation under control. toms (neurologic or psychiatric diseases). In many cases, the
etiology remains uncertain until all relevant laboratory
parameters have been collected. The increase in serum tryp-
Differential diagnoses
tase is a reliable marker of MCA. In fact, tryptase levels do
A number of differential diagnoses have to be considered in not increase in unrelated conditions or disorders mentioned
patients with suspected MCA/MCAS (Table 4). In patients above. However, serum tryptase levels may increase in case
with severe hypotension and shock, differential diagnoses of a severe trauma. Moreover, when no pre-event value is
include cardiovascular disorders, endocrinologic disorders, available, it is important to note that a slightly elevated

Allergy 68 (2013) 417–424 © 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd 421
 13989995, 2013, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12126, Wiley Online Library on [06/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Mast cell activation syndromes Valent

serum tryptase (>15 ng/ml) may be detected in mastocytosis,
in other myeloid neoplasms, and in about 5% of the normal
(healthy) population. This means, an elevated tryptase level
alone is not indicative of MCA. Rather, only the increase in
the serum tryptase level above baseline measured in the same
patient when no symptoms are recorded, counts as a robust
indication of MCA, provided that clinical symptoms and the
response to therapy are also indicative of MCA (27, 30–32).
In the example mentioned above, this means that a second
tryptase sample has to be measured (at least 1–2 days) after
complete resolution of all symptoms, to confirm MCA using
the tryptase test.
Summary and future perspectives
Mast cell activation syndrome is a well-defined and impor-
tant clinical condition that may occur in a variety of underly-
ing diseases, including primary mast cell disorders,
IgE-dependent allergic and atopic diseases, and other hyper-
sensitivity or immunologic reactions. Using recently estab-
lished criteria, MCA can be diagnosed and documented in
clinical practice, which may assist in the diagnostic work-up
of these patients. When MCAS is diagnosed, the causative
agent(s) and final diagnosis should be established with recog-
nition that an underlying primary mast cell disease with
KIT-mutated neoplastic cells may be present. Based on the
etiology, MCAS is either a primary, a secondary, or an idio-
pathic condition. Notably, in MCAS patients, the pathogene-
sis may be complex, and the process of anaphylaxis be
triggered by several different factors. In most patients, an
IgE-dependent allergic disease is diagnosed. Less severe forms
of MCA or local forms of MCA that do not meet all criteria
of MCAS also exist and may also represent a clinical chal-
lenge. Several of these conditions need management and ther-
apy similar to patients with full-blown MCAS. In those
patients in whom no signs of MCA are found, additional
causes and alternative diagnoses have to be considered. For
the foreseeable future, recently emerging studies on MCAS
will lead to an increased understanding of the pathogenesis
and complexity of these conditions. This may in turn lead to
the development of improved or even personalized treatment
strategies, through which each single component of the dis-
ease, including neoplastic mast cells, IgE production, releas-
ability, and others, are addressed separately using
combinations of various targeted drugs. Whether this devel-
opment will lead to a significant improvement of MCAS
therapy and prognosis remains to be determined.
Author contribution
P.V. designed the concept and content of the study, collected
data, established the Tables, and wrote and approved the
manuscript.
Conflict of interest
The author has no conflict of interest to declare in this study
and manuscript.

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