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Mast Cell Activation Syndromes: Collegium Internationale Allergologicum Update 2022

Mast cell activation syndromes (MCASs) are defined by systemic severe and recurrent mast cell activation, usually in form of anaphylaxis, a substantial, event-related increase of the serum tryptase level beyond the individual’s baseline and a response of the symptomatology to drugs directed against mast cells, mast cell-derived mediators, or mediator effects. A number of predisposing genetic conditions, underlying allergic and other hypersensitivity states, and related comorbidities can contribute to the clinical manifestation of MCASs. These conditions include hereditary alpha tryptasemia, mastocytosis with an expansion of clonal KIT-mutated mast cells, atopic diathesis, and overt IgE-dependent and IgE-independent allergies. Several of these conditions have overlapping definitions and diagnostic criteria and may also develop concomitantly in the same patient. However, although criteria and clinical features overlap, each of these conditions is characterized by a unique constellation of variables and diagnostic criteria. Since two, three, or more conditions can coexist in the same patient, with obvious clinical implications, it is of crucial importance to diagnose the variant of MCAS precisely and to take all accompanying, underlying and potentially complicating conditions, and comorbidities into account when establishing the management plan. Indeed, most of these patients require multidisciplinary investigations and only a personalized treatment approach can lead to an optimal management plan providing an optimal quality of life and low risk of anaphylaxis.

IgE-independent allergies. Several of these conditions have overlapping definitions and diagnostic criteria and may also develop concomitantly in the same patient. However, although criteria and clinical features overlap, each of these conditions is characterized by a unique constellation of variables and diagnostic criteria. Since two, three, or more conditions can coexist in the same patient, with obvious clinical implications, it is of crucial importance to diagnose the variant of MCAS precisely and to take all accompanying, underlying and potentially complicating conditions, and comorbidities into account when establishing the management plan. Indeed, most of these patients require multidisciplinary investigations and only a personalized treatment approach can lead to an optimal management plan providing an optimal quality of life and low risk of anaphylaxis.
The capacity of MC and basophils to release mediators of allergy upon activation, often referred to as releasability, depends on a number of variables, including the genetic background, the nature and source of the allergen, additional cofactors (e.g., exercise, stress, alcohol, drugs), underlying diseases (e.g., infections) and contributing comorbidities, numbers of MC or basophils participating in the reaction, the type and amount of IgE, the cytokines and chemokines involved, and the signaling cascades that are activated upon ligand-induced activation [3][4][5][6][10][11][12][13][14]. MC activation (MCA) can be observed in a number of different pathologic conditions in children and adults. Acute MCA is quite often seen in patients suffering from allergic disorders with the most severe manifestation being anaphylaxis [1][2][3][4][5][6]. Severe or even life-threatening MCA may occur when the burden of MC is high and/or the involved MC are in a "hyperactivated" state, resulting in increased releasability [2-5, 8, 9]. In such events, the serum tryptase level increases substantially over the individual's baseline and returns to the individual's "preevent range" after several hours in the symptom-free interval [15][16][17].
When the resulting clinical symptoms are severe, systemic, and recurrent (recurrent anaphylaxis), an MCA syndrome (MCAS) may be diagnosed [18][19][20][21][22]. Depending on the etiology, MCAS can be divided into primary MCAS where clonal MC are detected, secondary MCAS where an IgE-related allergy, other allergic disorders (mediated by IgE-independent mechanism), or another reactive disease process triggering MCA is documented, and idiopathic MCAS where no underlying disease or etiology is identified [18][19][20][21][22]. Especially in patients with severe allergies and in those who suffer from mastocytosis and a concomitant allergy, the risk to develop an MCAS event is rather high and in several of these patients, such severe events of anaphylaxis may be life-threatening [20][21][22][23].
More recently, additional genetic features have been linked to an elevated risk to develop anaphylaxis and MCAS. One such factor is hereditary alpha tryptasemia (HαT), a genetic trait defined by extra copies of the TPSAB1 gene encoding for alpha tryptase, and an elevated basal serum tryptase concentration in most carriers [24][25][26]. In patients with systemic mastocytosis (SM), the HαT carrier status is associated with a high prevalence of severe mediator-related symptoms and with concomitant allergies [27,28]. Patients with SM who are HαT carriers and are also suffering from an IgE-dependent allergy may bear the highest risk to develop anaphylaxis and MCAS [26][27][28].
During the past few years, a discussion about the etiology, diagnosis, and optimal management of patients with MCAS has been initiated [8,[21][22][23]. This discussion is useful and may lead to a better appreciation and understanding of underlying or contributing mechanisms and to the development of improved strategies to therapeutically interfere with MCA, MC expansion, and abnormal signaling pathways in these cells. In the current manuscript, we discuss cellular, molecular, and mechanistic relationships between SM, MCAS, allergy, HαT, and atopic diathesis. In addition, we compare diagnostic criteria and discuss overlapping features defining these conditions. Finally, we discuss implications that arise from the observation that two or even more of these conditions can coexist in the same MCAS patient, which is a clear challenge in clinical practice and can only be addressed appropriately by developing individualized management strategies and personalized treatment approaches [22,23].

Clinical Manifestations and Laboratory Correlates of MCA
MCA may occur in a number of different physiologic and pathologic conditions. Acute MCA is commonly seen in various allergic reactions, other hypersensitivity reactions (e.g., intolerance) and toxic reactions against exogenous elicitors, such as venoms [4,8,9,[19][20][21][22][23]29]. The most common underlying condition is an overt IgEdependent allergic disorder. In these patients, severe, recurrent systemic MCA may lead to the clinical picture of anaphylaxis [2-5, 8, 9]. As mentioned before, serum total tryptase concentrations increase substantially above the Int Arch Allergy Immunol 2022;183:693-705 DOI: 10.1159/000524532 individual's baseline during an anaphylactic event in most of these patients, peak at around 2 h after the event, and return to baseline 4-12 h after complete resolution of symptoms [15][16][17].
Other mediators produced and stored in MC, such as histamine and its metabolites or PGD 2 and its metabolites, are also released from these cells during anaphylaxis and therefore increase in biological fluids (plasma, urine) during and shortly after an anaphylactic episode [30][31][32][33][34][35][36]. Compared to serum tryptase levels, these MC-dependent compounds may sometimes be more sensitive parameters (biomarkers) in allergic reactions and thus also detected as elevated in less severe or chronic forms of MCA but are clearly less specific for the MC lineage and less-well validated in MCAS contexts compared to tryptase.
Also very common are local forms of MCA, less severe (mild) MCA-dependent reactions, and conditions associated with chronic, but not acute, MCA. Related clinical symptoms are shown in Table 1. In these patients, MCA is usually more difficult to diagnose compared to acute severe systemic MCA. Examples are local allergic reactions to exogenous allergens and organ-related atopic disorders, such as allergic rhinoconjunctivitis, atopic dermatitis, urticaria, or allergic asthma [42][43][44][45][46].  In most of these patients, serum tryptase levels increase only slightly or do not increase over the individual's baseline. Even the other MC-dependent compounds mentioned above, although more sensitive, may not increase in biological fluids in these patients. Therefore, these cases often represent a clinical challenge as diagnostic criteria for MCA or an MCAS are not fulfilled and the involvement (and primary role) of other inflammatory effector cells apart from MC, such as basophils or eosinophils, cannot be excluded. The final diagnosis in these cases remains descriptive and MC involvement can only be discussed [22,47]. In most reports, these conditions are termed unspecified (unconfirmed) MCA disorders (unspecified).
In other patients, systemic severe MCA is detected, but the criteria for MCAS are not yet or not completely fulfilled. For example, patients may fulfill all clinical criteria and the serum tryptase level increase, but the increase over baseline does not fulfill the 120% + 2 ng/mL threshold. These patients are often termed "other MCA disorders" but cannot be called MCAS. In many cases, an IgEdependent allergy is diagnosed. In another group of patients, tryptase levels are constantly elevated and may point to an occult form of mastocytosis, another myeloid neoplasm, or HαT. In most cases, a HαT will be diag-nosed. However, the diagnosis of HαT per se or an IgEdependent allergy per se is not diagnostic for MCAS even if MCAS-like symptoms have been recorded [22,47]. Rather, MCAS can only be diagnosed in allergic patients when MCAS criteria are fulfilled and the same holds true for mastocytosis [18-20, 22, 47].

Diagnostic Criteria and Classification of MCAS
The diagnosis of MCAS has to be considered when symptoms of MCA are severe, systemic (involve more than 1 organ systems), and recurrent, usually in form of severe anaphylaxis, and the involvement of the MC lineage can be confirmed with certainty [18][19][20][21][22][23]. In principle, the diagnostic approach to these patients is simple and follows a step-wise approach (Fig. 1). In a first step, the physician asks for symptoms of MCA and anaphylaxis. Then, MCAS criteria are applied (Fig. 1). Based on diagnostic criteria proposed by the EU/US consensus group [19], the diagnosis MCAS can then be established when (a) typical clinical symptoms arising from recurrent acute systemic MCA (resembling recurrent anaphylaxis) have been documented, (b) MC-derived mediators increase substantially in the serum (tryptase) or urine (his- tamine or prostaglandin-D2 metabolites) over the individual's baseline (standard test: documented increase in serum tryptase levels following the 120% + 2 ng/mL formula), and c) the symptoms respond to drugs blocking MCA, MC mediators, mediator production, or mediator effects (Table 2) [18][19][20]. All of these 3 criteria must be fulfilled to conclude that the patient is suffering from MCAS ( Table 2). The clinical impact and robustness of these MCAS criteria have been confirmed in several validation studies and are regarded as widely accepted standard [48][49][50].   Depending on the etiology of MCAS, 3 major variants have been defined: primary (clonal = monoclonal) MCAS, secondary (reactive) MCAS, and idiopathic MCAS (Table 3) [19][20][21][22]47]. In patients with primary (monoclonal) MCAS, MC are (mono)clonal cells, often increase in number, and may appear hyper-reactive against IgE-dependent and/or IgE-independent triggers of anaphylaxis [19][20][21][22]. In most of these patients, MC display the KIT mutation D816V, and SM is diagnosed ( Table 2). In a few cases with KIT D816V+ MCAS, the criteria to diagnose SM are not (yet) fulfilled [51,52]. These patients are still regarded as primary MCAS, and in some of these cases, overt SM is diagnosed during follow-up. In patients with secondary MCAS, an IgE-dependent or IgE-independent allergic disease is usually identified as causative etiology [19][20][21][22][23]. If no underlying allergic or other reactive disease is detected and MC are normal (polyclonal) cells, the idiopathic form of MCAS is diagnosed (Table 3; Fig. 2) [19][20][21][22][23].
During the past few years, more and more studies have shown that two or even three variants of MCAS can coexist in the same patient and that these patients bear the highest risk for the development of life-threatening MCAS episodes [22,23]. For example, in patients with SM and an IgE-dependent allergy against bee or wasp venom, both the underlying SM and the underlying venom allergy may act as a trigger of anaphylaxis and thereby induce a mixed (primary + secondary) form of MCAS. Therefore, such combined (mixed) form of MCAS should always be considered in patients with severe anaphylaxis (Fig. 2)  In other patients, familial clustering of MCAS episodes is observed. Several of these patients are suffering from allergies and are carriers of HαT [53]. Currently, there is a discussion about the terminology of HαT+ cases fulfilling MCAS criteria. So far, the term "HαT+ MCAS" seems to be appropriate. Since the condition is based on a hereditary trait and familial clustering can occur, we are of the opinion that this form of MCAS may also be termed hereditary (or familial) MCAS when several (more than one) family members indeed fulfill all MCAS criteria (Fig. 2) [53]. The coexistence of HαT and other predisposing conditions, such as an insect venom allergy and/ or mastocytosis is associated with a high risk of severe anaphylactic reactions.

Predisposing Genetic Variants and Patterns and Clonal Disease States
A number of gene variants and genetic background patterns have been associated with the manifestation or severity of atopic states and overt allergic disorders. Several of the affected genes encode proteins physiologically involved in the regulation of MC development, such as KIT, IL-4, or IL-6, the production of IgE, and/or the regulation of expression of the IgE receptor on MC, where IL-4, the IL-4 receptors, and IL-13 may play a role [54][55][56]. Other genes (variants) encode for proteins that are produced in MC and/or other immune cells and are involved in the regulation of vascular stability or dysfunction, such as angiotensinogen, angiotensin-converting enzymes, or chymase [8,20,57,58].
Several hypotheses have been raised to explain the high prevalence of MCA and MCAS in patients with KIT D816V+ SM. The most important etiology may be KIT D816V-mediated autonomous expansion of MC [70]. Indeed, the burden of MC is usually high in these cases, and the KIT mutation D816V is a somatic defect that is detected not only in MC but also in immature proliferating MC progenitor cells that can divide and give rise to a larger number of neoplastic MC [71,72], whereas mature MC themselves are nonproliferating cells [73]. However, se-vere MCA and MCAS may also be found in patients with SM and a low serum tryptase level and thus a low MC burden [74].
The mutation-mediated activation of the KIT receptor has also been discussed as a trigger of MCA [69]. However, IgE-dependent activation and releasability of KIT D816V-transduced ROSA cells and KIT D816V+ bone marrow MC obtained from patients with SM did not result in (augmented) mediator release [75]. In addition, many patients with KIT D816V+ SM remain asymptomatic for their lifetime or at least for many years, even if the burden of KIT-mutated MC is very high. Therefore, the hypothesis has been raised that KIT D816V+ MC stay in a form of desensitization against MCA [75], and only additional triggers of MCA may in part overcome this "desensitization status." Indeed, in most symptomatic patients with KIT D816V+ SM and clear signs of MCA or MCAS, a concomitant allergy, nonallergic hypersensitivity, toxic reaction, or a hereditary predisposition is detected [26-28, 41, 64-69]. It is also worth noting that anaphylaxis has also been reported in cases with SM in the absence of KIT D816V or in those in whom neoplastic MC displayed other KIT mutations [76].
As mentioned before, HαT is a genetic trait that has been associated with an elevated basal serum tryptase concentration (most cases), an increased prevalence of SM, and an increased risk to develop severe mediatorrelated symptoms and MCAS in SM patients [24][25][26][27][28]. Interestingly, HαT is also more prevalent in patients with nonadvanced SM compared to patients with advanced SM. However, the most intriguing correlation is between HαT and the presence of severe mediator-related symptoms [26][27][28]. In these HαT carriers with SM and MCAS, a concomitant IgE-dependent allergy is also detected quite frequently. All in all, there seems to be a clinically relevant "high-risk complex" consisting of HαT, SM, and an IgE-dependent allergy (often against Hymenoptera venoms), and these patients apparently are at a very high risk to develop severe or even life-threatening anaphylaxis or even a combined (and most severe) form of MCAS (Fig. 2). It is also worth noting that patients with HαT appear to have slightly elevated numbers of bone marrow MC in the absence of SM [77]. Therefore, it may well be that HαT is a primary genetic factor that not only predisposes for MCA and MCAS but also for MC expansion and thereby also facilitates the development and evolution of KIT D816V+ SM.
There may be also other predisposing genetic variables and constellations that might play a role in the manifestation of anaphylaxis, MCA, and MCAS in patients with Valent [78,79]. A general atopic predisposition as well as epigenetic changes may also contribute to the development and severity of MCA and MCAS in these cases.

Comorbidities Contributing to MCA in Patients with SM and MCAS
In addition to the genetic variables discussed above, a number of comorbidities and other patient-related risk factors may contribute to the development and manifestation of MCA and anaphylaxis (MCAS) in SM. The most frequently recorded clinically relevant comorbidities are IgE-dependent allergies [19-21, 41, 64, 65]. Especially allergies against Hymenoptera (bee or wasp) venoms are well-known disorders that can cause MCA and MCAS in patients with SM [64,65,67,74]. However, also other IgEdependent and IgE-independent hypersensitivity reactions may complicate the clinical course in SM. Moreover, patients with SM may suffer from hypersensitivity to food, alcohol, medications, physical stimuli, or stress and may sometimes even develop an MCAS during exposure [13,80,81]. Some of these reactions may be aggravated or facilitated by the genetic background of the patient. For example, patients with HαT or the p.C492Y variant of the adhesion G-protein coupled receptor ADGRE2 (CD312) may react to vibration and develop "vibration urticaria" [82,83]. Chronic inflammatory disorders, auto-immune disorders, rheumatic diseases, neurologic diseases, and infectious diseases may also support MCA and may thus induce or trigger MCA and MCAS in these patients [3,8,9,65]. The cytokine storm that is often detected in these cases and the related signaling cascades may support the expansion and distribution of MC in various tissues but can also support MCA [3,8,9]. All in all, the complexity of the etiology underlying MCA in MCAS patients and the many disease-related and patientrelated cofactors are an emerging challenge in daily practice, both in diagnostic terms and also regarding optimal management.  Table 4 of this manuscript.
In the past few years, accumulating data have suggested that it is important to define the co-triggering underlying etiologies contributing to severe MCA-related symptoms in patients with MCAS. In addition, accumulating evidence suggest that MCAS patients require a multidisciplinary approach and patient-specific individualized treatment [23]. In the first step, the etiology and variant of MCAS need to be defined. In many patients with mastocytosis, a combined form of MCAS (primary plus secondary) is diagnosed as these patients may also suffer from an IgE-dependent allergy, for example, an allergy against bee or wasp venom. In some of these cases, additional predisposing conditions, such as an atopic predisposition (with elevated IgE) or HαT is documented (Fig. 2). It is worth noting that the HαT carrier status is found in nearly 20% of all cases with SM and is even more prevalent in symptomatic patients with SM (prevalence in the general population: around 5%) [26][27][28]. In other patients, additional underlying conditions and comorbidities, such as IgE-independent allergies, infections, or chronic tissue inflammation, may contribute to the development of MCAS episodes. Some of these coexisting conditions can be treated effectively with immunotherapy (e.g., Hymenoptera venom allergy), anti-infective drugs, or anti-inflammatory drugs. In those with massive tissue inflammation, corticosteroids may be required to suppress the inflammatory reactions and to avoid tissue damage. All in all, detailed knowledge about the category of MCAS and the underlying etiology should provide a solid basis for establishing a personalized management and treatment plan for (almost all) patients with MCAS (Fig. 3).
As mentioned, immunotherapy against bee or wasp venom is often recommended for MCAS patients with documented Hymenoptera (bee or wasp) venom allergy (Table 4). In those with SM and a documented bee or wasp venom allergy (mixed MCAS), life-long immunotherapy is standard (Table 4) [23,[84][85][86]. The recommendation to treat life-long in these patients is based on the observation that discontinuation of immunotherapy may be followed by new fatal anaphylactic episodes (MCAS relapse) [87]. For patients with an extremely high risk (genetic predisposition, recurrent anaphylaxis) or resistant disease with known involvement of IgE, IgE-depleting therapy (e.g., with omalizumab) may help to avoid MCAS events and/or to keep anaphylaxis under control [88][89][90]. Omalizumab may also be useful in combination with other anti-allergic drugs and may also suppress adverse reactions against venom immunotherapy in patient with SM [91][92][93].
Regardless of the variant of SM and underlying pathologies and conditions, all patients should receive basic therapy with histamine receptor-1 (HR1) and HR2 blocker and MC-stabilizing agents as needed [18][19][20][21][22][23]94]. In those with recurrent or resistant disease, additional corticosteroids may be required, especially when the symptoms are severe and persistent. These therapeutic maneuvers reduce the risk of occurrence of severe MCAS events. A most important and effective approach is the strict avoidance of any known or suspected triggers of anaphylaxis in these patients [19][20][21][22][23].
When the burden of MC is very high in SM and contributes to the severity of MCA and MCAS, MC-reducing (antineoplastic or targeted) drugs, such as cladribine (2-CdA) or novel KIT D816V-targeting tyrosine kinase inhibitors, such as midostaurin or avapritinib, may be considered as an experimental approach. This is especially recommended when MCAS events are recurrent and resistant against all conventional therapeutic maneuvers and the patient is suffering from smoldering or advanced SM. Indeed, these drugs are capable of reducing the MC burden in most patients with advanced SM, including aggressive SM and MC leukemia [95][96][97][98]. In addition, it has been shown that both drugs decrease the severity of mediator-related symptoms and improve the quality of life in these patients [95][96][97][98]. Midostaurin is also known to block IgE-mediated release of histamine from MC and basophils, which may also contribute to the clinical effi-cacy of this drug [99]. 2-CdA has also been described to suppress MC expansion and mediator-related symptoms in patients with smoldering or advanced SM [100][101][102][103].
Depending on the overall situation, underlying etiologies, and the responses to therapy, these drugs may also be administered in combination or in sequential application, with recognition of potential drug-drug interactions and accumulating side effects. For example, complete control of MCAS has been reported in MCAS patients with HαT+ smoldering SM, drug-resistant IgE-dependent allergies, and repeated life-threatening anaphylaxis after sequential therapy with 2-CdA to reduce MC numbers and omalizumab to bring IgE-dependent reactions under control [104]. However, even omalizumab and other anti-allergic drugs may not bring anaphylaxis under control in all patients. For these cases, novel experimental therapies need to be developed.

Summary and Future Perspectives
During the past few years, accumulating evidence suggests that a complex etiology with a number of underlying genetic patterns, somatic changes, and comorbidities as well as other patient-related factors and mechanisms contribute to the clinical picture and course of MCASs. Predisposing genetic features and patterns include HαT and an atopic diathesis. KIT-activating somatic mutations in KIT can lead to an enormous expansion of MC and the clinical picture of SM and may thus contribute to the severity of MCAS events in affected patients. The most prevalent and significant group of comorbidities inducing or triggering MCAS events in patients are IgE-dependent allergies. Most importantly, several of these predisposing and inducing conditions can coexist in 1 patient, leading to an exceptionally high risk to develop a combined and thus more severe MCAS. Highlighting examples are SM patients suffering from HαT and/or from Hymenoptera venom allergy. The risk of life-threatening MCAS events is exceptionally high in these cases. Based on this knowledge, we recommend that all patients with MCAS are examined for the presence of contributing genetic conditions and contributing comorbidities and pathologies. As a result, the diagnosis and prognostication of patients with MCAS will improve. In addition, our improving knowledge about underlying etiologies should pave the way for designing better therapeutic algorithms and the development of personalized treatment approaches for patients with primary, secondary, or combined MCASs.