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Anaphylaxis and Mast Cell Disorders

  • Theo Gülen
    Correspondence
    Correspondence author. Department of Respiratory Medicine and Allergy, K85, Karolinska University Hospital Huddinge, Stockholm SE-141 86, Sweden.
    Affiliations
    Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Huddinge

    Department of Medicine Solna, Immunology and Allergy Unit, Karolinska Institutet and Karolinska University Hospital

    Mastocytosis Centre Karolinska, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden
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  • Cem Akin
    Affiliations
    Department of Internal Medicine, Division of Allergy and Clinical Immunology, University of Michigan, Ann Arbor, MI, USA
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      Keywords

      Key points

      • Patients with mastocytosis have a high risk of developing severe anaphylaxis, not only when suffering from venom allergy but also in the absence of a clear trigger/allergy.
      • The severity and frequency of anaphylactic reactions in patients with mastocytosis may depend on hyperreleasability of mast cells due to their inherent state of hyperreactivity, and due to the potential influence of occult or overt IgE-dependent allergies.
      • Comprehensive management of patients with mastocytosis with anaphylaxis can be complex and requires special knowledge about disease pathogenesis and special considerations in prophylactic measures; patient care should therefore be implemented in specialized centers or in close collaboration with experts.

      Introduction

      Mast cells (MCs) are granulated, tissue-fixed effector cells that reside in almost all vascularized tissues.
      • Galli S.J.
      • Kalesnikoff J.
      • Grimbaldeston M.A.
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      Mast cells as "tunable" effector and immunoregulatory cells: recent advances.
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      • Galli S.J.
      • Tsai M.
      Mast cells: versatile regulators of inflammation, tissue remodeling, host defense and homeostasis.
      The multifunctional capacity of MCs originates from their ability to detect triggers of internal or external stress or danger, which leads to the release of a spectrum of mediators.
      • Valent P.
      • Akin C.
      • Hartmann K.
      • et al.
      Mast cells as a unique hematopoietic lineage and cell system: from Paul Ehrlich's visions to precision medicine concepts.
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      • Marone G.
      Mast cells: fascinating but still elusive after 140 years from their discovery.
      Both the number of MCs and their activation in the tissue increase with inflammation, but it remains elusive how the MC reactivity is regulated.
      MCs are well known for their role as the effector cells of immediate-type hypersensitivity reactions; however, they also play a crucial role in the pathogenesis of MC disorders, such as mastocytosis. MC activation may occur at the local level, such as in urticaria, or systemically with clinical signs and symptoms of anaphylaxis.
      • Valent P.
      • Akin C.
      • Hartmann K.
      • et al.
      Mast cells as a unique hematopoietic lineage and cell system: from Paul Ehrlich's visions to precision medicine concepts.
      ,
      • Galli S.J.
      • Tsai M.
      Mast cells in allergy and infection: versatile effector and regulatory cells in innate and adaptive immunity.
      ,
      • Kalesnikoff J.
      • Galli S.J.
      Anaphylaxis: mechanisms of mast cell activation.
      Although IgE-mediated reaction, through the cross-linking of IgE molecules bound to the MC surface by FcεRI receptors, is thought to be the most common pathway, non-IgE-mediated mechanisms involving activation of complement C3a/C5a receptors
      • Kalesnikoff J.
      • Galli S.J.
      Anaphylaxis: mechanisms of mast cell activation.
      ,
      • Iwaki S.
      • Tkaczyk C.
      • Metcalfe D.D.
      • et al.
      Roles of adaptor molecules in mast cell activation.
      or the Mas-related G protein receptor-X2 (MRGPRX2) have also been proposed.
      • Kelso J.M.
      MRGPRX2 signaling and skin test results.
      Upon activation, MCs release granule-stored and newly formed cell membrane-derived lipid mediators and cytokines into the extracellular space. These mediators include histamine, proteases, proteoglycans, eicosanoids, and cytokines such as tumor necrosis factor-α.
      • Gilfillan A.M.
      • Beaven M.A.
      Regulation of mast cell responses in health and disease.
      ,
      • Castells M.
      Mast cell mediators in allergic inflammation and mastocytosis.
      Blood basophils may also participate in allergic and other inflammatory reactions in the same way as MCs
      • Siracusa M.C.
      • Kim B.S.
      • Spergel J.M.
      • et al.
      Basophils and allergic inflammation.
      ,
      • Korošec P.
      • Gibbs B.F.
      • Rijavec M.
      • et al.
      Important and specific role for basophils in acute allergic reactions.
      ; nevertheless, not all hypersensitivity reactions involve both cell types, even if the reaction is systemic. Notably, some of the mediators involved in anaphylactic reactions are produced and released primarily by MCs, but not by basophils. Inappropriate release of MC mediators causes the so-called mast cell mediator-related symptoms.

      Anaphylaxis

      Anaphylaxis can be defined as an acute, severe, systemic hypersensitivity reaction and represents an example of excessive MC activation resulting in an abundant release of various mediators (see definition of anaphylaxis in Adriana G. Bagos-Estevez and Dennis K. Ledford’s article, “Anaphylaxis: Definition, Epidemiology, Diagnostic Challenges, Grading System,” in this issue). Anaphylaxis concurrently affects multiple organ systems and presents with a broad array of symptoms and signs. Data about the prevalence and incidence of anaphylaxis are limited and often inconsistent.
      • Lieberman P.
      • Camargo Jr., C.A.
      • Bohlke K.
      • et al.
      Epidemiology of anaphylaxis: findings of the American College of Allergy, Asthma and Immunology Epidemiology of Anaphylaxis Working Group.
      • Worm M.
      Epidemiology of anaphylaxis.
      • Panesar S.S.
      • Javad S.
      • de Silva D.
      • et al.
      The epidemiology of anaphylaxis in Europe: a systematic review.
      • Wood R.A.
      • Camargo Jr., C.A.
      • Lieberman P.
      • et al.
      Anaphylaxis in America: the prevalence and characteristics of anaphylaxis in the United States.
      • Decker W.W.
      • Campbell R.L.
      • Manivannan V.
      • et al.
      The etiology and incidence of anaphylaxis in Rochester, Minnesota: a report from the Rochester Epidemiology Project.
      It is, however, widely accepted that anaphylaxis is a relatively rare condition. Studies from the United Kingdom indicate an increase in hospital admissions due to anaphylaxis over the last 2 decades.
      • Sheikh A.
      • Hippisley-Cox J.
      • Newton J.
      • et al.
      Trends in national incidence, lifetime prevalence and adrenaline prescribing for anaphylaxis in England.
      The diagnosis of anaphylaxis is based on a constellation of different signs and symptoms, and the current diagnostic criteria require concurrent occurrence of a minimum of 2 organ systems that generally include the cutaneous, gastrointestinal (GI), respiratory, and cardiovascular systems
      • Sampson H.A.
      • Munoz-Furlong A.
      • Campbell R.L.
      • et al.
      Second symposium on the definition and management of anaphylaxis: summary report--second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium.
      ,
      • Simons F.E.
      • Ardusso L.R.
      • Bilo M.B.
      • et al.
      World allergy organization guidelines for the assessment and management of anaphylaxis.
      (Table 1). For information regarding the grading system, epidemiology, and differential diagnosis of anaphylaxis, see Adriana G. Bagos-Estevez and Dennis K. Ledford’s article, “Anaphylaxis: Definition, Epidemiology, Diagnostic Challenges, Grading System,” in this issue and Motosue and colleagues’ article, “Anaphylaxis: Epidemiology and Differential Diagnosis,” in this issue.
      Table 1Criteria for the diagnosis of anaphylaxis and related disorders of severe mast cell activation
      Data from Refs.
      • Sampson H.A.
      • Munoz-Furlong A.
      • Campbell R.L.
      • et al.
      Second symposium on the definition and management of anaphylaxis: summary report--second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium.
      ,
      • Simons F.E.
      • Ardusso L.R.
      • Bilo M.B.
      • et al.
      World allergy organization guidelines for the assessment and management of anaphylaxis.
      ,
      • Gulen T.
      • Hagglund H.
      • Dahlen B.
      • et al.
      Mastocytosis: the puzzling clinical spectrum and challenging diagnostic aspects of an enigmatic disease.
      ,
      • Valent P.
      • Akin C.
      • Metcalfe D.D.
      Mastocytosis 2016: updated WHO classification and novel emerging treatment concepts.
      ,
      • Valent P.
      • Akin C.
      • Bonadonna P.
      • et al.
      Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome.
      ,
      • Gülen T.
      • Akin C.
      • Bonadonna P.
      • et al.
      Selecting the right criteria and proper classification to diagnose mast cell activation syndromes: a critical review.
      DisorderDiagnostic Criteria
      AnaphylaxisAnaphylaxis is highly likely when any one of the following 3 criteria is fulfilled:
       1Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized hives, itching or flushing, swollen lips-tongue-uvula)

      AND at least one of the following:
      ARespiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak flow, hypoxia)
      BCardiovascular compromise (eg, hypotension, syncope, collapse, incontinence)
       2Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours):
      AInvolvement of the skin or mucosal tissue
      BRespiratory compromise
      CCardiovascular compromise
      DPersistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
       3Hypotension after exposure to a known allergen for that patient (minutes to several hours)
      SMDiagnosis requires presence of major and 1 minor criterion or presence of 3 minor criteria in extracutaneous organ biopsy specimens, preferably bone marrow:
       Major criterionMultifocal aggregates of MCs (≥15 MCs per cluster) in biopsy sections
       Minor criteria
      1In MC infiltrates in extracutaneous biopsy sections, >25% of the MCs (CD117+) are spindle shaped or have atypical morphology
      2Presence of an activating KIT mutation at codon 816, generally D816V, in bone marrow, blood, or other extracutaneous organ(s)
      3Detection of aberrant MC clones expressing CD117 with CD25 and/or CD2 in bone marrow or blood or another extracutaneous organs
      4Baseline serum tryptase persistently exceeds ≥20 ng/mL
      MMASDiagnosis requires presence of one or 2 minor criteria of SM:
       1Presence of an activating KIT mutation D816V, in bone marrow, blood, or other extracutaneous organ(s)

      AND/OR
       2Detection of aberrant MC clones expressing CD117 with CD25 in bone marrow or blood or another extracutaneous organ(s)
      MCASThree criteria are required to fulfill MCAS diagnosis:
       1Severe, episodic symptoms that are attributable to MC activation with concurrent involvement of at least 2 organs including skin, cardiovascular, gastrointestinal, and upper/lower respiratory systems
       2An event-related increase in serum tryptase above the individual’s sBT according to formula (≥sBT + 20% of sBT + 2 ng/mL)
       3Appropriate response to drugs directed against MC activation or effects of MC mediators to reduce/suppress symptoms
      Abbreviations: MCAS, mast cell activation syndromes; MMAS, monoclonal mast cell activation syndrome; sBT, serum baseline tryptase; SM, systemic mastocytosis.
      Thus, anaphylaxis presently remains a clinical entity and its understanding for an allergist remains limited with respect to factors determining severity and underlying intracellular effector mechanisms. Anaphylaxis comprises a heterogeneous group of conditions regarding the nature and route of exposure to triggers, organ involvement, severity, and time course. Hence, it would be reasonable to consider anaphylaxis as a syndrome, in which different phenotypes and endotypes may be described instead of defining the condition as a “single clinical entity.” For instance, food-induced systemic reaction is a leading cause of anaphylaxis in children, whereas venom- or drug-induced reactions account for most adult cases.
      • Wood R.A.
      • Camargo Jr., C.A.
      • Lieberman P.
      • et al.
      Anaphylaxis in America: the prevalence and characteristics of anaphylaxis in the United States.
      ,
      • Braganza S.C.
      • Acworth J.P.
      • McKinnon D.R.
      • et al.
      Paediatric emergency department anaphylaxis: different patterns from adults.
      • Vetander M.
      • Helander D.
      • Flodstrom C.
      • et al.
      Anaphylaxis and reactions to foods in children--a population-based case study of emergency department visits.
      • Worm M.
      • Eckermann O.
      • Dolle S.
      • et al.
      Triggers and treatment of anaphylaxis: an analysis of 4,000 cases from Germany, Austria and Switzerland.
      The distinctions not only are limited to triggers but also are applicable to the clinical manifestations. In addition, mortality occurs mostly in adult patients due to cardiovascular failure, whereas this manifestation is rare in children.
      • Moneret-Vautrin D.A.
      • Morisset M.
      • Flabbee J.
      • et al.
      Epidemiology of life-threatening and lethal anaphylaxis: a review.
      ,
      • Turner P.J.
      • Jerschow E.
      • Umasunthar T.
      • et al.
      Fatal anaphylaxis: mortality rate and risk factors.
      From this perspective, severe anaphylaxis (SA) seems to be a distinct anaphylaxis phenotype, because all these observations cannot be merely explained by a random phenomenon. At present, the clinical and biological features of SA are not yet well characterized, although these patients usually present with hypotension and/or loss of consciousness. It is therefore crucial to gain deep insight into the underlying mechanisms. In this regard, subjects with MC activation disorders (MCAD), including mastocytosis, provide a unique disease model to investigate specific features of SA, because the existing evidence indicates a strong association between these 2 conditions.
      • Gulen T.
      • Hagglund H.
      • Dahlen B.
      • et al.
      High prevalence of anaphylaxis in patients with systemic mastocytosis - a single-centre experience.
      • Gulen T.
      • Ljung C.
      • Nilsson G.
      • et al.
      Risk factor analysis of anaphylactic reactions in patients with systemic mastocytosis.
      • Brockow K.
      • Jofer C.
      • Behrendt H.
      • et al.
      Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients.

      Mast cell activation disorders

      MCAD refer to a heterogeneous group of conditions that may be caused by an increased number of MCs and/or hyperactive MCs.
      • Akin C.
      Mast cell activation disorders.
      These disorders can vary in severity, but common symptoms include often severe reactions to insect stings, and in rare cases to foods or drugs. MCAD comprise clonal (eg, mastocytosis) and nonclonal (idiopathic) variants.
      • Akin C.
      Mast cell activation disorders.
      Clonal MC disorders (CMD) are well-characterized by intrinsic MC defects, including KIT mutation D816V, and/or expression of aberrant MC receptors, which may cause a “hyperactive” state of MCs leading to excessive release of mediators. Fig. 1, schematically illustrates the wide spectrum of disorders related to MC activation.
      Figure thumbnail gr1
      Fig. 1Spectrum of disorders manifested by mast cell activation. These disorders encompass a broad and heterogeneous group of conditions that can range from very rare (eg, MCAS) to very common (eg, allergic disorders), some of which have an increased number of MCs and/or hyperactive MCs in various organs. It is essential to obtain accurate diagnosis due to the substantial overlapping in clinical presentation of these conditions. Please see the text for further discussion. MCAS, mast cell activation syndromes; IA, idiopathic anaphylaxis.

      Mastocytosis

      Mastocytosis is characterized by excessive accumulation, proliferation, and activation of abnormal MCs in several organs, including the skin, bone marrow, and GI tract.
      • Gulen T.
      • Hagglund H.
      • Dahlen B.
      • et al.
      Mastocytosis: the puzzling clinical spectrum and challenging diagnostic aspects of an enigmatic disease.
      ,
      • Valent P.
      • Akin C.
      • Metcalfe D.D.
      Mastocytosis 2016: updated WHO classification and novel emerging treatment concepts.
      The World Health Organization (WHO) introduced a classification of mastocytosis into 2 main groups: cutaneous mastocytosis (CM) and systemic mastocytosis (SM) involving at least 1 extracutaneous organ.
      • Gulen T.
      • Hagglund H.
      • Dahlen B.
      • et al.
      Mastocytosis: the puzzling clinical spectrum and challenging diagnostic aspects of an enigmatic disease.
      SM has been classified into several subgroups, with more than 85% of affected subjects having indolent SM (ISM) with a good prognosis (Box 1). The remaining 15% of affected subjects have more aggressive variants of the disease with a poor prognosis. According to the WHO diagnostic criteria, the diagnosis of SM requires the existence of a major and a minor criterion or 3 minor criteria on extracutaneous biopsy materials, most commonly from the bone marrow
      • Gulen T.
      • Hagglund H.
      • Dahlen B.
      • et al.
      Mastocytosis: the puzzling clinical spectrum and challenging diagnostic aspects of an enigmatic disease.
      ,
      • Valent P.
      • Akin C.
      • Metcalfe D.D.
      Mastocytosis 2016: updated WHO classification and novel emerging treatment concepts.
      (see Table 1). The incidence and prevalence of mastocytosis are unknown, but evidence suggests that it is a rare condition. In recent studies, the prevalence of ISM is estimated to be 9.6 to 13 in 100,000 and the incidence for all subtypes of SM is predicted to be 0.89 per 100,000 per year.
      • van Doormaal J.J.
      • Arends S.
      • Brunekreeft K.L.
      • et al.
      Prevalence of indolent systemic mastocytosis in a Dutch region.
      ,
      • Cohen S.S.
      • Skovbo S.
      • Vestergaard H.
      • et al.
      Epidemiology of systemic mastocytosis in Denmark.
      WHO classification of mastocytosis 2016a
      • Cutaneous mastocytosis (CM)
        • Maculopapular CM (MPCM) = Urticaria pigmentosa (UP)
        • Diffuse CM
        • Mastocytoma of skin
      • Systemic mastocytosis (SM)
        • Indolent SM
        • Smouldering SM
        • SM with associated hematological neoplasm (AHN)b
        • Aggressive SM
        • Mast-cell leukemia
      aAdapted from
      • Gulen T.
      • Hagglund H.
      • Dahlen B.
      • et al.
      Mastocytosis: the puzzling clinical spectrum and challenging diagnostic aspects of an enigmatic disease.
      ,
      • Valent P.
      • Akin C.
      • Metcalfe D.D.
      Mastocytosis 2016: updated WHO classification and novel emerging treatment concepts.
      .
      bThe previous term SM with clonal hematologic non–mast cell-lineage disease.
      The clinical picture of SM is protean, ranging from asymptomatic disease to a highly aggressive course with multisystem involvement. In patients with ISM, symptoms may be acute or chronic and result from the local or remote effects of excess mediator release from MCs, such as histamine, proteases, leukotrienes, and prostaglandins. Exogenous and endogenous triggers include physical exertion, cold, heat, insect venoms, consumption of alcohol, infections, nonsteroidal anti-inflammatory drugs (NSAIDs), and emotional stress. Specific triggers vary greatly among patients. Individual patients often present a variable and changing pattern of symptoms. These so-called MC mediator-release symptoms and signs include flushing, pruritus, palpitations, dizziness, hypotension, syncope, breathing difficulties, abdominal pain, nausea, vomiting, diarrhea, headache, sweating, lethargy, fatigue, impaired concentration, irritability, anxiety, depression, arthralgia, myalgia, and osteoporosis.
      • Gulen T.
      • Hagglund H.
      • Dahlen B.
      • et al.
      Mastocytosis: the puzzling clinical spectrum and challenging diagnostic aspects of an enigmatic disease.
      Not all patients experience all these manifestations; however, a history of flushing is a cardinal symptom. In addition, some subjects may experience isolated symptoms, whereas others develop a constellation of signs and symptoms resembling an anaphylaxis, which can be life threatening (ie, anaphylactic shock).
      • Gulen T.
      • Hagglund H.
      • Dahlen B.
      • et al.
      High prevalence of anaphylaxis in patients with systemic mastocytosis - a single-centre experience.
      ,
      • Brockow K.
      • Jofer C.
      • Behrendt H.
      • et al.
      Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients.
      Typically, patients suddenly feel very warm and then experience palpitations, dizziness, and a decrease in blood pressure due to systemic vasodilatation that often leads to syncope.
      • Gulen T.
      • Hagglund H.
      • Dahlen S.E.
      • et al.
      Flushing, fatigue, and recurrent anaphylaxis: a delayed diagnosis of mastocytosis.
      Acute attacks may be brief or prolonged, but duration is usually 15 to 30 minutes.
      • Gulen T.
      • Hagglund H.
      • Dahlen S.E.
      • et al.
      Flushing, fatigue, and recurrent anaphylaxis: a delayed diagnosis of mastocytosis.
      Patients often experience severe fatigue lasting around 24 hours following the spells.
      • Gulen T.
      • Hagglund H.
      • Dahlen S.E.
      • et al.
      Flushing, fatigue, and recurrent anaphylaxis: a delayed diagnosis of mastocytosis.
      There are also subjects with advanced SM, including aggressive SM, SM with associated hematologic neoplasm, and MC leukemia. Interestingly, the occurrence of anaphylaxis due to the excessive release of MC mediators in these patients is less common compared with that in patients with ISM.

      Monoclonal Mast Cell Activation Syndrome

      Recently, a novel variant of clonal MCAD has been introduced, the so-called monoclonal mast cell activation syndrome (MMAS).
      • Akin C.
      • Scott L.M.
      • Kocabas C.N.
      • et al.
      Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with "idiopathic" anaphylaxis.
      ,
      • Sonneck K.
      • Florian S.
      • Mullauer L.
      • et al.
      Diagnostic and subdiagnostic accumulation of mast cells in the bone marrow of patients with anaphylaxis: Monoclonal mast cell activation syndrome.
      These patients are also mainly characterized by recurring episodes of anaphylaxis with hypotension and syncope and have clonal MCs expressing the D816V KIT mutation and/or CD25+ aberrant surface markers. However, they do not fulfill the WHO criteria for SM diagnosis and lack typical skin changes of mastocytosis (Table 1).
      • Akin C.
      • Scott L.M.
      • Kocabas C.N.
      • et al.
      Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with "idiopathic" anaphylaxis.
      ,
      • Sonneck K.
      • Florian S.
      • Mullauer L.
      • et al.
      Diagnostic and subdiagnostic accumulation of mast cells in the bone marrow of patients with anaphylaxis: Monoclonal mast cell activation syndrome.

      Why is the risk of severe anaphylaxis increased in mast cell disorders?

      The likelihood of MCs to secrete mediators, also known as “releasability” in the context of systemic MC activation and anaphylaxis, depends on several factors including the underlying primary disease.
      • Valent P.
      • Akin C.
      • Bonadonna P.
      • et al.
      Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome.
      ,
      • Gülen T.
      • Akin C.
      • Bonadonna P.
      • et al.
      Selecting the right criteria and proper classification to diagnose mast cell activation syndromes: a critical review.
      Greater severity correlates with the higher burden or number of involved MCs, and the cellular activation level, for example, “hyperactivated” state.
      • Valent P.
      • Akin C.
      • Bonadonna P.
      • et al.
      Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome.
      ,
      • Gülen T.
      • Akin C.
      • Bonadonna P.
      • et al.
      Selecting the right criteria and proper classification to diagnose mast cell activation syndromes: a critical review.
      These factors together result in an increased releasability of MC mediators. There are some additional factors, including level of expression of activated receptors and/or signaling molecules on MCs, genetic predisposition (eg, genetic polymorphisms in IL-10 or IL-13), copy number of the tryptase gene, route of allergen exposure (eg, parenteral route) and type of triggering allergen (eg, insect venom), level of allergen-specific IgE, triggering cofactors, hormonal influences, and the presence of comorbid conditions
      • Gülen T.
      • Akin C.
      • Bonadonna P.
      • et al.
      Selecting the right criteria and proper classification to diagnose mast cell activation syndromes: a critical review.
      • Metcalfe D.D.
      • Peavy R.D.
      • Gilfillan A.M.
      Mechanisms of mast cell signaling in anaphylaxis.
      • Gilfillan A.M.
      • Peavy R.D.
      • Metcalfe D.D.
      Amplification mechanisms for the enhancement of antigen-mediated mast cell activation.
      (Box 2). Such activation processes culminate in degranulation and release of preformed and newly synthesized membrane lipid mediators, such as histamine, tryptase, prostaglandins, and proinflammatory cytokines. Measurement of acute serum total tryptase is the current gold standard laboratory test to confirm systemic MC activation.
      Potential factors associated to severe mast cell activation
      • Increased number of mast cells involved in the reaction
      • Increased releasability of mast cells
      • Hyperreactive state of mast cells
      • Increased copy number of tryptase gene (ie, hereditary alpha-tryptasemia)
      • Presence of cofactors
      • Type of allergen
      • Route of allergen
      • Presence of comorbidities (eg, cardiovascular)
      • Gender (male)
      • Increased age
      Subjects with mastocytosis, for instance, have a high risk of developing severe, life-threatening anaphylaxis; this may depend on hyperreleasability of MCs in these subjects due to their inherent state of hyperreactivity, often associated with occult or overt IgE-dependent allergies.
      • Valent P.
      • Akin C.
      • Bonadonna P.
      • et al.
      Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome.
      ,
      • Gülen T.
      • Akin C.
      • Bonadonna P.
      • et al.
      Selecting the right criteria and proper classification to diagnose mast cell activation syndromes: a critical review.
      Chronically activated KIT receptor in mastocytosis may be responsible for the hyperreactivity in MCs. Indeed, in almost all subjects with SM, MCs exhibit the KIT D816V mutation, and the KIT ligand stem cell factor augments IgE-dependent mediator release in normal MCs.
      • Gulen T.
      • Hagglund H.
      • Dahlen S.E.
      • et al.
      Flushing, fatigue, and recurrent anaphylaxis: a delayed diagnosis of mastocytosis.
      However, not all patients with SM bearing the KIT D816V mutation develop anaphylaxis. Therefore, additional genetic polymorphisms or mutations in MC signaling components, other than the activating KIT D816V mutation, may contribute to MC dysregulation and the predisposition for anaphylaxis.
      • Valent P.
      • Akin C.
      • Arock M.
      Diagnosis and treatment of anaphylaxis in patients with mastocytosis.

      Hereditary Alpha-Tryptasemia

      Hereditary alpha-tryptasemia (HαT) is another modifying factor that may influence the prevalence and severity of anaphylaxis. HαT is a recently identified autosomal dominant genetic trait that is characterized by excess copies of alpha-tryptase gene, TPSAB1.
      • Lyons J.J.
      • Sun G.
      • Stone K.D.
      • et al.
      Mendelian inheritance of elevated serum tryptase associated with atopy and connective tissue abnormalities.
      ,
      • Lyons J.J.
      • Yu X.
      • Hughes J.D.
      • et al.
      Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number.
      Individuals with HαT may have slightly increased numbers of MCs in bone marrow and GI biopsies, and serum baseline tryptase (sBT) levels are typically greater than 8 ng/mL (often ≥10 ng/mL).
      • Lyons J.J.
      • Yu X.
      • Hughes J.D.
      • et al.
      Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number.
      However, they generally do not have increased urinary secretion of other MC mediators, such as prostaglandins and histamine metabolites. HαT is found in approximately 6% of the general population, and there is no consistent clinical phenotype associated with HαT.
      • Robey R.C.
      • Wilcock A.
      • Bonin H.
      • et al.
      Hereditary alpha-tryptasemia: UK prevalence and variability in disease expression.
      ,
      • Chollet M.B.
      • Akin C.
      Hereditary alpha tryptasemia is not associated with specific clinical phenotypes.
      The risk for severe spontaneous and/or insect venom-triggered anaphylaxis in HαT subjects was reported to be increased.
      • O'Connell M.P.
      • Lyons J.J.
      Hymenoptera venom-induced anaphylaxis and hereditary alpha-tryptasemia.
      • Lyons J.J.
      • Chovanec J.
      • O'Connell M.P.
      • et al.
      Heritable risk for severe anaphylaxis associated with increased α-tryptase-encoding germline copy number at TPSAB1.
      • Greiner G.
      • Sprinzl B.
      • Górska A.
      • et al.
      Hereditary alpha tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis.
      It is also reported that increased germline copies of α-tryptase are associated with increased severity of venom anaphylaxis and idiopathic anaphylaxis (IA) in SM.
      • Greiner G.
      • Sprinzl B.
      • Górska A.
      • et al.
      Hereditary alpha tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis.
      Thus, HαT may confer an increased risk for SA, which is independent of the presence of concomitant CMD. However, to date, no studies have shown that MCs in patients with HαT are hyperreactive. In addition, the prevalence of HαT among patients with allergies is the same as that among unselected controls.
      • Robey R.C.
      • Wilcock A.
      • Bonin H.
      • et al.
      Hereditary alpha-tryptasemia: UK prevalence and variability in disease expression.
      Therefore, these findings related to HαT need to be confirmed in larger cohorts.

      Characteristic of anaphylaxis in patients with clonal mast cell disorders

      Distinct features of SA in subjects with SM are the profile of eliciting triggers as well as the clinical course of reactions.
      The cause of anaphylaxis in SM may vary; however, Hymenoptera venom is the most common elicitor.
      • Gulen T.
      • Hagglund H.
      • Dahlen B.
      • et al.
      High prevalence of anaphylaxis in patients with systemic mastocytosis - a single-centre experience.
      ,
      • Gulen T.
      • Ljung C.
      • Nilsson G.
      • et al.
      Risk factor analysis of anaphylactic reactions in patients with systemic mastocytosis.
      ,
      • Alvarez-Twose I.
      • Gonzalez de Olano D.
      • Sanchez-Munoz L.
      • et al.
      Clinical, biological, and molecular characteristics of clonal mast cell disorders presenting with systemic mast cell activation symptoms.
      There is a correlation between elevated sBT levels and the severity of systemic reactions to Hymenoptera stings.
      • Rueff F.
      • Przybilla B.
      • Bilo M.B.
      • 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.
      In a study analyzing 226 patients presenting with anaphylaxis to an emergency care setting, SM was diagnosed in 7.7% of adults and stings from flying insects were the triggers in half of these subjects.
      • Oropeza A.R.
      • Bindslev-Jensen C.
      • Broesby-Olsen S.
      • et al.
      Patterns of anaphylaxis after diagnostic workup: a follow-up study of 226 patients with suspected anaphylaxis.
      Another study reported a 28% overall prevalence of venom-induced anaphylaxis (VIA) among 122 patients with SM, which is clearly higher than in the general population.
      • Gulen T.
      • Ljung C.
      • Nilsson G.
      • et al.
      Risk factor analysis of anaphylactic reactions in patients with systemic mastocytosis.
      Interestingly, VIA may be the presenting symptom that may lead to the diagnosis of SM. In this regard, one large study reported that approximately 10% of 379 subjects with systemic reactions to Hymenoptera sting had elevated sBT levels (≥11.4 ng/mL), and most of these subjects had SM or MMAS diagnosed by bone marrow biopsies.
      • Bonadonna P.
      • Perbellini O.
      • Passalacqua G.
      • et al.
      Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels.
      Many such patients have evidence of venom-specific IgE in blood, although specific IgE levels may be lower compared with the nonmastocytosis venom-allergic population
      • Jarkvist J.
      • Salehi C.
      • Akin C.
      • et al.
      Venom immunotherapy in patients with clonal mast cell disorders: IgG4 correlates with protection.
      ; this could possibly be due to the binding of IgE onto the increased numbers of MCs, making it less available to be detected in the serum. Notably also, skin prick test reactions to venom extract in SA may be diminished in size or even absent.
      • Gulen T.
      • Moller Westerberg C.
      • Lyberg K.
      • et al.
      Assessment of in vivo mast cell reactivity in patients with systemic mastocytosis.
      Drug- or food-induced reactions were also reported as an elicitor of anaphylaxis in SM
      • Brockow K.
      • Jofer C.
      • Behrendt H.
      • et al.
      Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients.
      ,
      • Gonzalez de Olano D.
      • de la Hoz Caballer B.
      • Nunez Lopez R.
      • 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).
      ; however, most of those reactions remain patient reported and unconfirmed. Therefore, interpretations of these data should be made with caution due to the lack of reliable confirmatory in vitro tests and the absence of provocation tests. There are occasional case reports of patients with allergy to foods or preservatives.
      • Cifuentes L.
      • Ring J.
      • Brockow K.
      Clonal mast cell activation syndrome with anaphylaxis to sulfites.
      Another case report presented a patient with more than 10 SA episodes after eating meat, where a provocation test with pork resulted in delayed SA with only low levels of specific IgE to meats and galactose-alpha-1,3-galactose.
      • Roenneberg S.
      • Bohner A.
      • Brockow K.
      • et al.
      alpha-Gal-a new clue for anaphylaxis in mastocytosis.
      Further diagnostic workup confirmed an underlying ISM.
      • Roenneberg S.
      • Bohner A.
      • Brockow K.
      • et al.
      alpha-Gal-a new clue for anaphylaxis in mastocytosis.
      Most recently, a large, systematic study investigating food hypersensitivity and food-induced anaphylaxis (FIA) in SM subjects found that the prevalence of FIA in SM was at least 10-fold less compared with the prevalence of VIA in SM.
      • Jarkvist J.
      • Brockow K.
      • Gülen T.
      Low frequency of IgE-mediated food hypersensitivity in mastocytosis.
      Thus cumulative clinical experience suggests that the incidence of IgE-mediated food allergy is not, or not fundamentally, increased in subjects with SM compared with that in the general population.
      • Jarkvist J.
      • Brockow K.
      • Gülen T.
      Low frequency of IgE-mediated food hypersensitivity in mastocytosis.
      Some patients with SM complain about flushing and GI symptoms triggered by histamine-rich diets, spicy foods, and alcohol; however, these symptoms rarely progress to anaphylaxis.
      • Jarkvist J.
      • Brockow K.
      • Gülen T.
      Low frequency of IgE-mediated food hypersensitivity in mastocytosis.
      Likewise, data on patients with drug hypersensitivity and MC disorders are scarce and literature is largely limited to case reports.
      • Bonadonna P.
      • Pagani M.
      • Aberer W.
      • et al.
      Drug hypersensitivity in clonal mast cell disorders: ENDA/EAACI position paper.
      Remarkably, most of these cases are related to general anesthesia and radiocontrast media exposure.
      • Weingarten T.N.
      • Volcheck G.W.
      • Sprung J.
      Anaphylactoid reaction to intravenous contrast in patient with systemic mastocytosis.
      ,
      • Renauld V.
      • Goudet V.
      • Mouton-Faivre C.
      • et al.
      Case report: perioperative immediate hypersensitivity involves not only allergy but also mastocytosis.
      Experience suggests that some patients with SM may be at risk for severe non-IgE-mediated reactions, such as those experienced with perioperative muscle relaxants. Such risk is probably lower in patients who have tolerated previous general anesthesia and/or who have no history of anaphylaxis during anesthesia. At present, available data in the literature are scant on this topic, and it is not possible to provide clear recommendations. Some experts suggest premedicating with antihistamines and corticosteroids before anesthesia and recommend perioperative drugs with lower intrinsic MC activation properties. Furthermore, unlike VIA, drug-induced anaphylaxis (DIA) is rarely associated with undetected MC disorder in the literature. In this regard, a study investigating patients with NSAID hypersensitivity and its correlation to occult SM failed to show elevated sBT levels.
      • Seitz C.S.
      • Brockow K.
      • Hain J.
      • et al.
      Non-steroidal anti-inflammatory drug hypersensitivity: association with elevated basal serum tryptase?.
      Thus, it is not known whether the incidence of DIA is increased in SM because there are currently no systematic studies.
      By contrast, patients with IA, that is, unexplained anaphylaxis, are more likely to have SM.
      • Gulen T.
      • Hagglund H.
      • Dahlen B.
      • et al.
      High prevalence of anaphylaxis in patients with systemic mastocytosis - a single-centre experience.
      ,
      • Gonzalez de Olano D.
      • de la Hoz Caballer B.
      • Nunez Lopez R.
      • 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).
      Indeed, there is an intriguing relationship between IA and MCAD. Because CMD can be potentially misdiagnosed as IA, it is, therefore, essential to distinguish it from true IA.
      • Akin C.
      • Scott L.M.
      • Kocabas C.N.
      • et al.
      Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with "idiopathic" anaphylaxis.
      ,
      • Gulen T.
      • Hagglund H.
      • Sander B.
      • et al.
      The presence of mast cell clonality in patients with unexplained anaphylaxis.
      Akin and colleagues
      • Akin C.
      • Scott L.M.
      • Kocabas C.N.
      • et al.
      Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with "idiopathic" anaphylaxis.
      reported the presence of a clonal MC population in 5 of 12 patients with IA in whom there were no features of urticaria pigmentosa or histologic evidence for SM on bone marrow biopsies.
      • Akin C.
      • Scott L.M.
      • Kocabas C.N.
      • et al.
      Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with "idiopathic" anaphylaxis.
      Similarly, Gulen and colleagues
      • Gulen T.
      • Hagglund H.
      • Sander B.
      • et al.
      The presence of mast cell clonality in patients with unexplained anaphylaxis.
      performed bone marrow examinations in 30 cases of unexplained SA without signs of CM and reported that 47% of these patients were subsequently diagnosed with CMD, both clonal and/or aberrant MC populations. Finally, a recent study investigated 56 subjects with more than 3 episodes/y of unexplained SA. Bone marrow (BM) examination found evidence of MC clonal disease in 14% (8 of 56).
      • Carter M.C.
      • Desai A.
      • Komarow H.D.
      • et al.
      A distinct biomolecular profile identifies monoclonal mast cell disorders in patients with idiopathic anaphylaxis.
      The reasons for the discrepancies among these studies may be the differences in diagnostic criteria for IA and referral patterns.
      Another suggestive feature of SA in patients with SM is the distinct clinical pattern and course of episodes. Patients with SM with SA frequently present with severe cardiovascular signs and symptoms including hypotensive syncope,
      • Gulen T.
      • Hagglund H.
      • Dahlen B.
      • et al.
      High prevalence of anaphylaxis in patients with systemic mastocytosis - a single-centre experience.
      ,
      • Brockow K.
      • Jofer C.
      • Behrendt H.
      • et al.
      Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients.
      ,
      • Alvarez-Twose I.
      • Gonzalez de Olano D.
      • Sanchez-Munoz L.
      • et al.
      Clinical, biological, and molecular characteristics of clonal mast cell disorders presenting with systemic mast cell activation symptoms.
      whereas respiratory symptoms, urticaria, and angioedema are rare.
      • Alvarez-Twose I.
      • Gonzalez de Olano D.
      • Sanchez-Munoz L.
      • et al.
      Clinical, biological, and molecular characteristics of clonal mast cell disorders presenting with systemic mast cell activation symptoms.
      For instance, the occurrence of syncope/loss of conciseness has been reported to be 72% during SA among patients with SM regardless of triggers
      • Gulen T.
      • Hagglund H.
      • Dahlen B.
      • et al.
      High prevalence of anaphylaxis in patients with systemic mastocytosis - a single-centre experience.
      ; this is also confirmed in SM with VIA.
      • Jarkvist J.
      • Salehi C.
      • Akin C.
      • et al.
      Venom immunotherapy in patients with clonal mast cell disorders: IgG4 correlates with protection.
      These observations led to the development of predictive models to distinguish patients presenting with SA and underlying CMD, specifically SM and MMAS. Because the diagnosis of SM requires an extracutaneous biopsy, it may be challenging for clinicians to decide whether to pursue further evaluation in subjects presenting with SA but no other features of SM. In this regard, the Spanish Network on Mastocytosis (REMA) proposed a scoring tool to predict high-risk patients, which is based on a combined clinical (ie, male gender and clinical symptoms of syncopal episodes in the absence of urticaria/angioedema during SA) and laboratory (elevated sBT levels of ≥25 ng/mL) criteria.
      • Alvarez-Twose I.
      • Gonzalez de Olano D.
      • Sanchez-Munoz L.
      • et al.
      Clinical, biological, and molecular characteristics of clonal mast cell disorders presenting with systemic mast cell activation symptoms.
      Thus, the REMA score has been used to screen patients presenting with SA but lack typical signs of CM and showed a sensitivity of 92% and specificity of 81%, regardless of the trigger.
      • Alvarez-Twose I.
      • Gonzalez de Olano D.
      • Sanchez-Munoz L.
      • et al.
      Clinical, biological, and molecular characteristics of clonal mast cell disorders presenting with systemic mast cell activation symptoms.
      A modification of the “REMA score” subsequently has been proposed as the “Karolinska score,” using a reduced sBT level of ≥20 ng/mL.
      • Gulen T.
      • Hagglund H.
      • Sander B.
      • et al.
      The presence of mast cell clonality in patients with unexplained anaphylaxis.
      This modified version resulted in a better sensitivity (93%) and specificity (94%), when retrospectively applied in patients with IA.
      • Gulen T.
      • Hagglund H.
      • Sander B.
      • et al.
      The presence of mast cell clonality in patients with unexplained anaphylaxis.
      When available, these tools should be used together with peripheral blood KIT D816V mutation analysis, because it is independently a strong indicator of the underlying SM.
      • Kristensen T.
      • Vestergaard H.
      • Bindslev-Jensen C.
      • et al.
      Sensitive KIT D816V mutation analysis of blood as a diagnostic test in mastocytosis.
      Finally, further modification of previous tools was proposed—the so-called National Institute of Health Idiopathic Clonal Anaphylaxis Score—by using clinical symptoms, gender, a baseline tryptase cutoff of 11.4 ng/mL, and allele-specific polymerase chain reaction testing to detect the presence or absence of KIT D816V mutation in peripheral blood.
      • Carter M.C.
      • Desai A.
      • Komarow H.D.
      • et al.
      A distinct biomolecular profile identifies monoclonal mast cell disorders in patients with idiopathic anaphylaxis.
      However, this scoring tool has not been yet validated.

      Mast cell activation syndromes

      MC activation syndrome (MCAS) may be diagnosed in some patients when the symptoms are systemic and MCAS criteria are fulfilled
      • Valent P.
      • Akin C.
      • Bonadonna P.
      • et al.
      Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome.
      ,
      • Gülen T.
      • Akin C.
      • Bonadonna P.
      • et al.
      Selecting the right criteria and proper classification to diagnose mast cell activation syndromes: a critical review.
      ,
      • Akin C.
      • Valent P.
      • Metcalfe D.D.
      Mast cell activation syndrome: proposed diagnostic criteria.
      ,
      • Valent P.
      • Akin C.
      • Arock M.
      • et al.
      Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal.
      (see Table 1). MCAS can be defined as a disorder of MC activation with various causes all resulting in severe, recurrent, and episodic symptoms due to systemic MC mediator release.
      • Valent P.
      • Akin C.
      • Bonadonna P.
      • et al.
      Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome.
      ,
      • Gülen T.
      • Akin C.
      • Bonadonna P.
      • et al.
      Selecting the right criteria and proper classification to diagnose mast cell activation syndromes: a critical review.
      ,
      • Akin C.
      • Valent P.
      • Metcalfe D.D.
      Mast cell activation syndrome: proposed diagnostic criteria.
      ,
      • Valent P.
      • Akin C.
      • Arock M.
      • et al.
      Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal.
      Patients with MCAS often present with symptoms of anaphylaxis. However, it is noteworthy that neither all anaphylaxis fulfill diagnostic criteria of MCAS nor do all MCAS episodes reach the severity of anaphylaxis. It is also worth mentioning that MC activation can manifest as a less severe and/or chronic condition, therefore MCAS cannot be diagnosed in these patients. Thus, not all mediator-related and clinically relevant symptoms can be classified as MCAS.
      • Gülen T.
      • Akin C.
      • Bonadonna P.
      • et al.
      Selecting the right criteria and proper classification to diagnose mast cell activation syndromes: a critical review.
      Three sets of criteria are required for an MCAS diagnosis: (1) typical episodic symptoms consistent with MC activation, (2) objective laboratory evidence of MC involvement with a substantial transient increase in validated MC mediators in the serum or in the urine (preferably, an event-related increase in serum tryptase levels according to the formula ≥ 1.2 × sBT + 2 ng/mL within 4 hours of an acute episode), and (3) control of symptoms with MC-directed therapies.
      • Valent P.
      • Akin C.
      • Bonadonna P.
      • et al.
      Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome.
      ,
      • Gülen T.
      • Akin C.
      • Bonadonna P.
      • et al.
      Selecting the right criteria and proper classification to diagnose mast cell activation syndromes: a critical review.
      ,
      • Valent P.
      • Akin C.
      • Arock M.
      • et al.
      Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal.
      Once a diagnosis of MCAS has been confirmed, further classification is necessary. MCAS has been classified into 3 variants.
      • Valent P.
      • Akin C.
      • Bonadonna P.
      • et al.
      Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome.
      ,
      • Gülen T.
      • Akin C.
      • Bonadonna P.
      • et al.
      Selecting the right criteria and proper classification to diagnose mast cell activation syndromes: a critical review.
      Primary MCAS is defined by the presence of clonal MCs and includes MMAS and mastocytosis (systemic and/or cutaneous) (Table 2). Diagnosis of primary (clonal) MCAS can only be made after an extracutaneous biopsy, most often after a bone marrow biopsy.
      • Gulen T.
      • Hagglund H.
      • Dahlen B.
      • et al.
      Mastocytosis: the puzzling clinical spectrum and challenging diagnostic aspects of an enigmatic disease.
      ,
      • Valent P.
      • Akin C.
      • Metcalfe D.D.
      Mastocytosis 2016: updated WHO classification and novel emerging treatment concepts.
      Clonal MCAS can present with IA.
      • Akin C.
      • Scott L.M.
      • Kocabas C.N.
      • et al.
      Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with "idiopathic" anaphylaxis.
      ,
      • Gulen T.
      • Hagglund H.
      • Sander B.
      • et al.
      The presence of mast cell clonality in patients with unexplained anaphylaxis.
      ,
      • Carter M.C.
      • Desai A.
      • Komarow H.D.
      • et al.
      A distinct biomolecular profile identifies monoclonal mast cell disorders in patients with idiopathic anaphylaxis.
      Secondary MCAS results in symptoms of MC activation through IgE- and non-IgE-mediated processes, such as food-, drug-, or Hymenoptera venom-induced SA. This variant has no evidence of a clonal MC population. Finally, idiopathic MCAS results in MC activation symptoms without a clear precipitating cause. Patients with IA are the epitome of idiopathic MCAS; therefore, it is essential to evaluate whether the patient meets criteria for IA. However, idiopathic MCAS is a broader entity and may also include patients whose episodes may not fulfill the clinical criteria of IA, such as patients presenting with concomitant skin and GI symptoms causing event-related elevation of serum tryptase.
      Table 2Classification of mast cell activation syndromes
      Data from Refs.
      • Valent P.
      • Akin C.
      • Bonadonna P.
      • et al.
      Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome.
      ,
      • Gülen T.
      • Akin C.
      • Bonadonna P.
      • et al.
      Selecting the right criteria and proper classification to diagnose mast cell activation syndromes: a critical review.
      Variant of MCASClinical and Laboratory Findings
      Primary (clonal)
      • Clonal mast cells found
        • a.
          Established SM: criteria to diagnose SM are fulfilled
        • b.
          Established CM: criteria for CM are fulfilled but the criteria to diagnose SM are not fulfilled
        • c.
          Neither CM nor SM can be diagnosed, but one or both of the following minor SM criteria documenting mast cell clonality found:
          • i.
            KIT D816V or
          • ii.
            CD25 expression in mast cells
      SecondaryAn underlying allergic, atopic, inflammatory, or neoplastic disease is found but no monoclonal mast cells are detectable (KIT mutation and/or CD25 expression in mast cells not found)
      IdiopathicNo underlying allergy or atopy and no monoclonal (KIT-mutated and/or CD25+) mast cells are detectable
      Table 3 illustrates features of anaphylaxis in various MCADs and HαT.
      Table 3Features of anaphylaxis in various mast cell activation disorders and hereditary alpha-tryptasemia
      SMCMMCASHαT
      Risk of anaphylaxis increased?++/−++ in a subgroup
      Clinical featuresHypotension, flushing, abdominal cramping, less urticarial, and angioedemaVariableNot all episodes may reach the severity of anaphylaxis. Symptoms may also include urticaria and angioedema; however, it should always involve ≥2 organsVariable. HαT by itself does not confer a particular clinical phenotype but is thought to amplify symptoms and severity of anaphylaxis
      Markers of clonality (KIT D816V, CD25 on MCs)++/−+ in primary MCAS, whereas − in secondary and idiopathic MCASNegative in pure HαT; however, SM is detected more frequently in HαT and patients may have both conditions
      Baseline tryptase>20 ng/mL in most patientsMay be normal or elevatedNormal or elevated>8 ng/mL
      DiagnosisBone marrow biopsy and checking for WHO criteriaInspection of skin, Darier sign, skin biopsyConsensus criteria (see text)Genetic testing for TPSAB1 copy number

      Therapeutic options

      Acute episodes of SA in patients with MC disorders should be treated in the same manner as other forms of anaphylaxis.
      • Simons F.E.
      • Ardusso L.R.
      • Bilo M.B.
      • et al.
      World allergy organization guidelines for the assessment and management of anaphylaxis.
      ,
      • Muraro A.
      • Roberts G.
      • Worm M.
      • et al.
      Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology.
      ,
      • Lieberman P.L.
      Recognition and first-line treatment of anaphylaxis.
      Roberts and colleagues
      • Roberts 2nd, L.J.
      • Turk J.W.
      • Oates J.A.
      Shock syndrome associated with mastocytosis: pharmacologic reversal of the acute episode and therapeutic prevention of recurrent attacks.
      ,
      • Turk J.
      • Oates J.A.
      • Roberts 2nd, L.J.
      Intervention with epinephrine in hypotension associated with mastocytosis.
      stressed the unique role of epinephrine in the treatment of SA in a patient with SM who was refractory to vasopressor therapy with dopamine, yet quickly improved with epinephrine. Intramuscular (IM) epinephrine is the drug of choice. Evidence suggests that treatment of systemic reactions with epinephrine prevents progression to more severe symptoms.
      • Lieberman P.L.
      Recognition and first-line treatment of anaphylaxis.
      Unfortunately, epinephrine is still underutilized, whereas corticosteroids are widely used as first-line therapy despite the lack of evidence.
      • Clark S.
      • Camargo Jr., C.A.
      Emergency treatment and prevention of insect-sting anaphylaxis.
      In refractory cases of severe hypotension not responding to repeated doses of IM epinephrine, or hypotension followed by cardiac arrest, intravenous (IV) epinephrine should be given with continuous monitoring of cardiac response, blood pressure, and oxygen saturation. Supplemental high-flow oxygen and IV fluid (eg, normal saline) replacement should be administered. When cardiovascular status and respiratory function stabilize, second-line medications such as histamine receptor type-1 (HR1) and type-2 (HR2) blockers and corticosteroids are usually recommended.
      • Muraro A.
      • Roberts G.
      • Worm M.
      • et al.
      Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology.
      However, the value of corticosteroids in the acute management of anaphylaxis is unclear because there is no substantial evidence to support their proposed effect on the prevention of protracted or biphasic reactions.
      • Campbell D.E.
      Anaphylaxis management: time to re-evaluate the role of corticosteroids.
      With regard to the long-term management and prevention of SA, measures aim to reduce the severity and/or frequency of the acute episodes. Prevention is the most important aspect, therefore all patients with mastocytosis who have a history of anaphylaxis should be prescribed self-injectable epinephrine after receiving adequate information and training on the appropriate use. Information and education should also be extended to the patient’s family and caregivers, and an action plan for the management of acute episodes should be implemented.
      Although avoidance is the mainstay of the prevention of SA, there is a wide individual variation among patients with mastocytosis. Hence, the general advice to avoid all the literature-reported potential triggers for MC degranulation is not recommended; instead, a tailored management strategy is necessary.
      • Gulen T.
      • Akin C.
      Pharmacotherapy of mast cell disorders.
      When possible, patients should undergo a thorough allergy workup including allergy tests for several known/potential triggers to assess for potential culprit agents. In addition, an allergist evaluation can be used as guidance to map out patients’ individual trigger profile to avoid relevant food, medication, and inhalational triggers of MC activation. For instance, eliminations of histamine-rich diets or avoidance of certain drugs including NSAIDs is not routinely recommended. In contrast, Hymenoptera stings seem to be the most frequent cause of anaphylaxis in adult patients with mastocytosis.
      • Gulen T.
      • Hagglund H.
      • Dahlen B.
      • et al.
      High prevalence of anaphylaxis in patients with systemic mastocytosis - a single-centre experience.
      Thus, those with sting anaphylaxis who are sensitized to Hymenoptera venom should be recommended lifelong venom immunotherapy, which reduces recurrent anaphylaxis risk with stings.
      • Jarkvist J.
      • Salehi C.
      • Akin C.
      • et al.
      Venom immunotherapy in patients with clonal mast cell disorders: IgG4 correlates with protection.
      At present, there is no consensus among experts whether to prescribe epinephrine to all patients diagnosed with mastocytosis or to prescribe it only to those with a history of anaphylaxis or who are at increased risk for anaphylaxis. This issue has been discussed in a recent study, wherein a risk assessment tool to predict occurrence of anaphylaxis in patients with mastocytosis was developed.
      • Gulen T.
      • Ljung C.
      • Nilsson G.
      • et al.
      Risk factor analysis of anaphylactic reactions in patients with systemic mastocytosis.
      This tool may facilitate the determination of “correct” patients with mastocytosis who need epinephrine autoinjectors.
      There are currently no randomized studies to show which prophylactic therapy options are superior in mastocytosis. A stepwise approach should therefore be considered in all patients
      • Gulen T.
      • Akin C.
      Pharmacotherapy of mast cell disorders.
      (Table 4). The first step includes HR1 blockers. Doses can be adjusted individually, and doses up to 4 times higher than the recommended doses can be used similar to those in patients with chronic urticaria. In the same manner, HR2 blockers, antileukotrienes, oral cromolyn, and corticosteroids can be additionally given in unresponsive patients. If the combination therapies are ineffective, omalizumab, which is a humanized monoclonal antibody that specifically binds to free IgE, can be used. Omalizumab has been shown to diminish the frequency of anaphylactic episodes in anecdotal reports and case series with varying success.
      • Gulen T.
      • Hagglund H.
      • Sander B.
      • et al.
      The presence of mast cell clonality in patients with unexplained anaphylaxis.
      ,
      • Carter M.C.
      • Robyn J.A.
      • Bressler P.B.
      • et al.
      Omalizumab for the treatment of unprovoked anaphylaxis in patients with systemic mastocytosis.
      ,
      • Broesby-Olsen S.
      • Vestergaard H.
      • Mortz C.G.
      • et al.
      Omalizumab prevents anaphylaxis and improves symptoms in systemic mastocytosis: efficacy and safety observations.
      Nevertheless, there are presently no randomized, placebo-controlled studies to recommend omalizumab in routine use.
      Table 4Prophylactic therapy in patients with mast cell activation disorders
      DrugIndicationProposed Mechanism of Action
      Histamine receptor type-1 blockerAll patientsBlocks histamine receptor type-1
      Histamine receptor type-2 blockerPatients with gastrointestinal symptoms or those not responding to histamine receptor type-1 blockerBlocks histamine receptor type-2
      AntileukotrienesAdd-on treatment in patients with persistent dermatologic complaints who do not respond adequately to histamine receptor type-1 blockerBlocks leukotriene receptor
      Cromolyn sodiumPatients with persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting, diarrhea) and resistance to histamine receptor type-1 and type 2 blockersEffects on various cell types including MCs; may block IgE-dependent activation of MCs
      KetotifenIn patients with idiopathic anaphylaxis and resistance to histamine receptor-type 1 blockersInhibits activation of MCs, inhibits histamine binding to histamine receptor type 1
      AspirinPatients with severe, recurrent anaphylaxisSuppresses the generation of prostaglandin D2 in human MCs
      GlucocorticosteroidsPreventive maintenance therapy at low doses for recurrent anaphylaxis not responsive to histamine receptor blockersBlocks mediator production and cytokine synthesis as well as mediator secretion in MCs
      Allergen immunotherapyIn patients with mastocytosis in whom venom allergy is detected, lifelong immune therapy is generally recommendedEffects on various cell types including MCs, and aids development of venom-specific immune tolerance
      OmalizumabPatients with severe, recurrent anaphylaxisIgE depletion and hyposensitization of MCs through downregulation of nonspecific IgE receptors
      Interferon-alphaGenerally recommended in patients with aggressive SM but has also been shown to control severe MC activation episodesSuppresses mast cell function, including histamine release
      CladribinePatients with aggressive variant of SM and severe, life-threatening anaphylaxisCauses apoptosis in MCs independent of the presence of the common D816V KIT mutation
      MidoaustrinPatients with aggressive variant of SM and in certain cases, indolent SM with severe, life-threatening anaphylaxisBlocks KIT D816V activation and MC proliferation in SM and also inhibits IgE-dependent activation and mediator secretion in MCs
      AvapritinibPatients with aggressive variant of SM and in certain cases, indolent SM with severe, life-threatening anaphylaxisSelectively inhibits KIT exon 17 mutants, including KIT D816V
      Although it is generally assigned for patients with aggressive SM, in rare, refractory cases, cytoreductive or immunomodulatory therapy including interferon-alpha 2b
      • Kluin-Nelemans H.C.
      • Jansen J.H.
      • Breukelman H.
      • et al.
      Response to interferon alfa-2b in a patient with systemic mastocytosis.
      and cladribine (2-CDA)
      • Wimazal F.
      • Geissler P.
      • Shnawa P.
      • et al.
      Severe life-threatening or disabling anaphylaxis in patients with systemic mastocytosis: a single-center experience.
      was historically reported to be beneficial in controlling mediator-related symptoms. Current first-line cytoreductive therapy options include tyrosine kinase inhibitors (TKIs) targeting the MC growth receptor KIT. A recent study provided initial evidence that midostaurin, in addition to reversed organ damage and decreased splenomegaly and bone marrow MC burden in patients with advanced SM,
      • Gotlib J.
      • Kluin-Nelemans H.C.
      • George T.I.
      • et al.
      Efficacy and safety of midostaurin in advanced systemic mastocytosis.
      was found to improve mediator-related symptoms and quality of life, suggesting that the drug may also be useful in patients with ISM suffering from severe mediator-related symptoms resistant to conventional therapies.
      • Valent P.
      • Akin C.
      • Hartmann K.
      • et al.
      Midostaurin: a magic bullet that blocks mast cell expansion and activation.
      ,
      • Hartmann K.
      • Gotlib J.
      • Akin C.
      • et al.
      Midostaurin improves quality of life and mediator-related symptoms in advanced systemic mastocytosis.
      Avapritinib is another novel TKI that selectively inhibits KIT D816V.
      • Gilreath J.A.
      • Tchertanov L.
      • Deininger M.W.
      Novel approaches to treating advanced systemic mastocytosis.
      Both midostaurin and avapritinib are currently approved for treatment of advanced SM. A recent phase 2 study reported symptom reduction and MC cytoreduction with avapritinib in patients with ISM.
      • Akin C.
      • Elberink H.O.
      • Gotlib J.
      • et al.
      PIONEER: a randomized, double-blind, placebo-controlled, phase 2 study of avapritinib in patients with indolent or smoldering systemic mastocytosis (SM) with symptoms inadequately controlled by standard therapy.
      Additionally, prompt resolution of recurrent anaphylaxis with the addition of avapritinib was described in a patient with SM-AHN.
      • Kudlaty E.
      • Perez M.
      • Stein B.L.
      • et al.
      Systemic mastocytosis with an associated hematologic neoplasm complicated by recurrent anaphylaxis: prompt resolution of anaphylaxis with the addition of avapritinib.
      However, the effects of TKIs on anaphylaxis remain to be explored.

      Summary

      Anaphylaxis is an important feature of patients with MC disorders. Hence, the presence of underlying CMD should be strongly suspected in patients with VIA as well as patients with recurrent IA; in particular, when these episodes present with severe hypotensive syncope. A bone marrow examination should be considered if the sBT level is elevated (≥11.4 ng/mL) and/or if the peripheral blood KIT D816V mutation is present.
      Appropriate treatment with IM epinephrine remains underutilized in most cases, despite increased awareness and recognition of anaphylaxis. Expanding knowledge on the presentation and triggers of anaphylaxis among patients with mastocytosis, their relatives, and health care providers will improve its recognition and management and increase patient safety. Moreover, a better understanding of the pathogenesis of SA by exploring the intrinsic changes in MCs of patients will provide important insight into its long-term management. Further research may lead to identification of novel biomarkers
      • Gülen T.
      • Teufelberger A.
      • Ekoff M.
      • et al.
      Distinct plasma biomarkers confirm the diagnosis of mastocytosis and identify increased risk of anaphylaxis.
      to distinguish patients with SA as well as development of new drugs targeting intracellular MC activation mechanisms and mediators.

      Clinics care points

      • The presence of recurrent hypotensive episodes and/or syncope without urticaria and/or angioedema and/or respiratory symptoms during anaphylaxis increases the odds of underlying CMD.
      • Patients with Hymenoptera VIA and elevated baseline serum tryptase level should be investigated for the presence of mastocytosis; particularly if peripheral blood KIT D816V mutation is present.
      • HαT is a genetic trait and may confer an increased risk for SA, which is independent of the presence of concomitant CMD.
      • MCAS may be diagnosed when the symptoms due to MC mediator release are severe, recurrent, and systemic, and MCAS criteria are fulfilled. An event-related increase in sBT is critical to diagnosis.

      Funding

      This study was supported by grants from the Konsul TH C Bergh Foundation, Sweden, and through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, Stockholm, Sweden.

      Disclosure

      T. Gülen has received lecture fees from Thermo Fisher. C. Akin has received consultancy fees from Blueprint Medicines and Novartis and has a patent for LAD2 cells.

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