Mast cell activation syndromes: definition and classification

Authors

  • P. Valent

    Corresponding author
    • Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria
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  • Edited by: Hans-Uwe Simon

  • This work was in part supported by a mastocytosis grant of the Medical University of Vienna.

Correspondence

Peter Valent, Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.

Tel.: 43 1 40400 6085

Fax: 43 1 40400 4030

E-mail: peter.valent@meduniwien.ac.at

Abstract

Mast cell activation (MCA) occurs in a number of different clinical conditions, including IgE-dependent allergies, other inflammatory reactions, and mastocytosis. MCA-related symptoms may be mild, moderate, severe, or even life-threatening. The severity of MCA depends on a number of different factors, including genetic predisposition, the number and releasability of mast cells involved in the reaction, the type of allergen, presence of specific IgE, and presence of certain comorbidities. In severe reactions, MCA can be documented by a substantial increase in the serum tryptase level above baseline. When symptoms are recurrent, are accompanied by an increase in mast cell–derived mediators in biological fluids, and are responsive to treatment with mast cell–stabilizing or mediator-targeting drugs, the diagnosis of mast cell activation syndrome (MCAS) is appropriate. Based on the underlying condition, these patients can further be classified into i) primary MCAS where KIT-mutated, clonal mast cells are detected, ii) secondary 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) idiopathic 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 with MCAS, several different factors act together to lead to severe or even life-threatening anaphylaxis. Detailed knowledge about the pathogenesis and complexity 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 anaphylactic reaction, allergen-induced cross-linking of IgE-binding sites on mast cells is followed by an explosive release of granular 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 relevant to anaphylactic reactions are produced and released primarily 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 mediators 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 reaction, 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 different 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-threatening 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 disorders [18-20]. More recently, however, MCA has also been 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 symptoms are caused by a number of different vasoactive and proinflammatory mediators that are released from MC when these cells are activated by an allergen via IgE and IgE receptors, 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 diarrhea, 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 activation. 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 proposed as an additional criterion of MCA [27]. This is of particular 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 conclusion 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 administering histamine receptor blockers as well as a prostaglandin synthesis inhibitor.

Table 1. Clinical symptoms typically found in patients suffering from mast cell activation (MCA)a and their impact in the evaluation of MCA syndromes (MCAS)
Symptom(s)aDiagnostic impact in the evaluation of severe MCA ( = suspected MCA syndrome = MCAS)
  1. a

    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.

Hypotension ± shockPathognomonic key finding in MCAS (other underlying diseases that could explain hypotension need to be excluded)
TachycardiaTachycardia usually accompanies hypotension in MCAS
DiarrheaUsually accompanied by systemic symptoms of MCAS; in the absence of these, the diagnosis remains uncertain
Abdominal crampingUsually accompanied by systemic symptoms of MCAS; in the absence of these, the diagnosis remains uncertain
NauseaUsually accompanied by systemic symptoms of MCAS; in the absence of these, the diagnosis remains uncertain
FlushingSevere flushing may be an indicator of MCAS; in these cases; flushing is often accompanied by systemic symptoms
PruritusSevere pruritus may be an indicator of MCAS; in these cases; flushing is often accompanied by systemic symptoms
Acute urticariaSevere acute urticaria may be an indicator of MCAS; in these cases, systemic symptoms are usually found
AngioedemaSevere angioedema may be an indicator of MCAS and then is usually accompanied by systemic symptoms
Nasal congestionDiagnostic only in the context of other MCAS-related symptoms and the presence of other MCAS criteria
WheezingDiagnostic only in the context of other MCAS-related symptoms and the presence of other MCAS criteria
HeadacheDiagnostic only in the context of other MCAS-related symptoms and the presence of other MCAS criteria
Neurologic symptomsDiagnostic only in the context of other MCAS-related symptoms and the presence of other MCAS criteria
FatigueDiagnostic only in the context of other MCAS-related symptoms and the presence of other MCAS criteria

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 criteria of severe systemic MCA (no MCA syndrome by definition), the symptoms should be recognized as clinically relevant and should be treated appropriately using antimediator-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 challenge for the treating physician. Especially the local variant of MCA that is associated with, or even triggered by, an atopic disease or another chronic inflammatory disease may represent a major clinical problem. Although the criteria for systemic MCA are usually not fulfilled in these patients, the 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).

Table 2. Proposed variants of mast cell activation (MCA)a
VariantsaIndicator/criterion
  1. a

    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.

  2. b

    These patients are usually suffering from a MCA syndrome (MCAS).

Severity
Mild MCANo therapy required
Moderate MCADrug therapy required, but no need for hospitalization
Severe MCAbHospitalization requiredb
Organ system involvement
Local MCARestricted to one organ, usually a local reaction
Systemic MCAMultiorgan involvement (in severe forms: increase in serum tryptase found)
Frequency
Acute MCASymptom(s) recorded once
Episodic MCARecurrent symptoms
Chronic MCAPersistent symptoms

Laboratory assessment of systemic MCA

In most reactions, MCA is followed by the release of preformed 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 histamine 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 baseline has to be assessed after complete recovery or in a symptom-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 minimal increase in serum tryptase required to judge it as indicative (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]. For example, if the baseline tryptase level was 5 ng/ml, an increase to 10 ng/ml is suggestive of MCA [1(20%) + 2(absolute) = 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), histamine 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 mediators 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 provisional diagnosis of ‘possibly MCA/MCAS’ can be established, and in acute cases, immediate treatment should be introduced. For example, if a patient with known mastocytosis is admitted because of an anaphylactic shock (without signs of an underlying cardiovascular or infectious disease) but does not respond to antihistamines and glucocorticosteroids 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.

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 suspected. 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 physician documents MCA by serology. A substantial increase in the 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 recommendations provided by the consensus group [27].

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 therapy should be marked with the diagnostic label ‘SY’ 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 mastocytosis (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 SM. There are also other activating mutations in KIT that have been reported to occur in SM or CM [61-63], and several of these mutations may contribute to disease evolution and/or manifestation of certain symptoms. However, compared 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 (monoclonal) 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 detectable in a patient with MCAS, the diagnosis ‘idiopathic MCAS’ should be established (Table 3).

Table 3. Variants of mast cell activation syndromes (MCAS)a and diagnostic features
MCAS variantDiscriminating/diagnostic features
  1. a

    The classification of MCAS is described in detail in a recent consensus proposal [27].

  2. b

    Most of these patients suffer from cutaneous (CM) or systemic (SM) mastocytosis. However, in some of them, criteria for SM and CM are not fulfilled.

  3. c

    In these patients, no mutation of KIT at codon 816 is found. If flow cytometry is available, the phenotype of mast cells should be established: the presence of CD25-negative mast cells (normal phenotype) supports the diagnosis of secondary or idiopathic MCAS.

Primary MCASKIT D816V-mutated clonal mast cells are found (usually these mast cells express CD25)b
Secondary MCASAn underlying Allergy or Atopic Disorder inducing MCA and thus MCAS is diagnosed, but no clonal mast cells are detectablec
Idiopathic MCASMCAS criteria are fulfilled, but no underlying reactive disease, no allergen-specific IgE, and no clonal mast cells are detectablec

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 may be a primary mast cell disease, often presenting with excessive numbers of mast cells, or an IgE-dependent allergy, resulting in IgE-dependent release of allergic mediators from mast cells, the coexistence of both may represent a clinically serious, often life-threatening, situation [64]. In addition, other comorbidities may be present that influence mast cell releasability through cytokine exposure, the numbers of mast cells through KIT ligand exposure, or leukocyte activation triggered by chemokine effects. Some of the comorbidities represent classical combinations representing a high-risk situation for the occurrence of life-threatening MCA (anaphylaxis). One typical example is the presence of an allergy against hymenoptera venom(s) in patients with mastocytosis [23, 65-68]. In these patients, insect stings can lead to extremely severe reactions, and cases of death have been reported in the literature [65-68]. Another high-risk situation is the combination of food allergy and mastocytosis. IgE-dependent allergy against inhaled allergens and a coexisting severe bronchial disorder, for example a chronic bronchial infection, is another example. In all these situations, severe reactions need to be addressed immediately and often result in hospitalization. To address all these high-risk conditions in a prophylactic manner, patients are advised to take continuous (prophylactic) antimediator-type drugs, to carry additional emergency drugs (glucocorticosteroids, epinephrin self injector) with them, and to self-apply these drug on demand to bridge the time until the emergency team will arrive and bring the situation under control.

Differential diagnoses

A number of differential diagnoses have to be considered in patients with suspected MCA/MCAS (Table 4). In patients with severe hypotension and shock, differential diagnoses include cardiovascular disorders, endocrinologic disorders, severe infections (sepsis), dehydration, and other systemic diseases (Table 4). Other differential diagnoses relate to organ-specific symptoms, such as diarrhea (gastrointestinal diseases), skin rush (cutaneous diseases), or neurologic symptoms (neurologic or psychiatric diseases). In many cases, the etiology remains uncertain until all relevant laboratory parameters have been collected. The increase in serum tryptase is a reliable marker of MCA. In fact, tryptase levels do not increase in unrelated conditions or disorders mentioned above. However, serum tryptase levels may increase in case of a severe trauma. Moreover, when no pre-event value is available, it is important to note that a slightly elevated 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.

Table 4. Major differential diagnoses in patients with suspected mast cell activation syndrome (MCAS)
  1. In most instances, symptoms of acute hypotension are recorded. If additional MCA-mimicking symptoms, such as skin lesions, headache, and/or diarrhea are found, it is often difficult to separate from MCA and thus MCAS.

  2. VIP, vasoactive intestinal peptide.

Cardiovascular
Myocardial Infarction
Endocarditis/Endomyocarditis
Aortic Stenosis with Syncope
Pulmonary Infarction
Endocrinologic
Acute Hypothyroidism
Acute Hypoglycemia
Adrenal Insufficiency
Hypopituitarism
Gastrointestinal Disorders (with Diarrhea + Dehydration)
Acute Inflammatory Bowel Disease
VIP-secreting Tumor (VIPoma)
Acute Episodes of Morbus Crohn or Colitis Ulcerosa
Food Intoxication
Infectious Diseases
Severe Bacterial or viral infections ± septic shock
Acute Gastrointestinal Infection with Dehydration
Acute Encephalitis/Meningitis
Acute Parasitic Diseases (e.g. Acute Chagas Disease)
Neurologic/Central Nervous System (CNS) Disorders
Epilepsy
CNS Tumors
Other CNS Diseases
Intoxication
Psychiatric conditions
Skin Diseases
Hereditary or acquired Angioedema
Pemphigus vulgaris
Acute Lupus Erythematodes
Acute Toxic Dermatoses
Hematologic – Acute Anemia ± Hypovolemic Shock
Acute Gastrointestinal Bleeding
Massive Hypermenorrhea
Drug-induced Side Effects
Drug-induced Hypoglycemia
Drug-induced Hypotension
Drug-induced Diarrhea
Drug-Induced CNS Damage

Summary and future perspectives

Mast cell activation syndrome is a well-defined and important clinical condition that may occur in a variety of underlying diseases, including primary mast cell disorders, IgE-dependent allergic and atopic diseases, and other hypersensitivity or immunologic reactions. Using recently established 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 recognition 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 idiopathic condition. Notably, in MCAS patients, the pathogenesis 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 challenge. Several of these conditions need management and therapy 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 disease, including neoplastic mast cells, IgE production, releasability, and others, are addressed separately using combinations of various targeted drugs. Whether this development 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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