Introduction

Anaphylaxis is an acute and life-threatening multisystem syndrome caused by sudden release of mast cell mediators into systemic circulation [1, 2]. Signs and symptoms can include cutaneous (erythema, pruritus, urticaria, and/or angioedema); respiratory (wheezing, coughing, bronchospasm, laryngeal edema); cardiac (arrhythmias, dizziness, palpitations), gastrointestinal (hyperperistalsis, nausea, vomiting); and neurologic (headache, feeling of impending doom, and unconsciousness) findings [3]. The prevalence of anaphylaxis is estimated to be as high as 2% in the USA based on stringent clinical diagnostic criteria [4]. The prevalence appears to be rising in developed countries [5,6,7]. Factors affecting the incidence are geographic location, sex, atopy, and socioeconomic status, although a precise definition of risk factors have been lacking [8]. Overall, anaphylaxis is under-recognized [9], under-reported [10], and under treated [9].

Anaphylaxis may be “allergic” or IgE-dependent, “immunologic” or IgG-mediated, or immune complex/complement-mediated or non-immunologic [11]. IgE is unequivocally involved in conferring immunological specificity to effector cells [12, 4, 13]. It binds to the high-affinity receptor FcεRI on mast cells. In anaphylaxis, there is cross-linking of FcεRI-bound IgE, which induces activation of mast cells and causes release of mediators, such as histamine, tryptase, chymase, and heparin [3], as well as de novo synthesis of many inflammatory mediators, such as leukotrienes, prostaglandins, and cytokines [13]. H1 and H2 receptors are directly activated by histamine. H1 receptors mediate itching, rhinorrhea, tachycardia, and bronchospasm, whereas both H1 and H2 receptors mediate HA, flushing and hypotension [14].

Anaphylaxis can also occur in a mechanism independent of IgE. It is known that some patients can experience anaphylaxis despite having low or undetectable levels of circulating allergen-specific IgE [15]. Conversely, allergen-specific IgE can be found in many people who do not develop clinical symptoms even when exposed [16]. Therefore, presence of specific IgE alone does not predict anaphylaxis. This suggests that abnormalities in activation pathways or numbers of effector cells (mast cells) may also contribute to the susceptibility and severity of anaphylaxis.

Role of Mast Cell in Anaphylaxis

Mast cells are widely accepted as the most important player in IgE-dependent anaphylaxis [12]. They express high-affinity IgE receptor (FcεRI), though differences in their degranulation may influence clinical outcome with or without the presence of IgE [17, 18]. The key role that mast cells play in anaphylaxis is illustrated by the high occurrence of anaphylaxis in patients with mastocytosis, defined as a heterogeneous grouping of neoplasms with clonal expansion of mast cells in one or more organ systems, typically including the skin and hematopoietic system [19•]. Estimated prevalence of mastocytosis in Middle Europe is 0.005–0.01% or 0.5–1 per 10,000 [20]. The lifetime prevalence of anaphylaxis has been reported to be approximately 30%, and the incidence at least six times greater in patients with mastocytosis compared to general population [21]; anaphylaxis is also more severe in those with mastocytosis compared to those without [22•].

Mastocytosis and related diagnostic criteria have been refined and updated by the consensus group and the World Health Organization (WHO) [23••]. Mastocytosis can be divided into sub-variants of cutaneous mastocytosis (CM), in which no systemic involvement is found, systemic variants (SM), and localized MC tumor. In systemic mastocytosis (SM), neoplastic MCs infiltrate organs, including the bone marrow, spleen, liver, and gastrointestinal system. Bone marrow is involved in virtually all patients with SM [24]. Skin involvement in CM is usually found in patients with indolent SM (ISM), is less frequently detected in aggressive SM (ASM), and is rarely seen in MC leukemia (MCL). The diagnosis of systemic mastocytosis requires a tissue (most often bone marrow) biopsy. WHO diagnostic criteria for systemic mastocytosis are shown in Table 1. A limited histopathologic variant presenting with mast cell activation symptoms/anaphylaxis and 1 or 2 clonality criteria (KIT D816V mutation and/or CD25 expression on mast cells) has been termed monoclonal mast cell activation syndrome [25].

Table 1 World Health Organization’s updated classification of mastocytosis in 2016
Full size table

KIT Mutations

Mast cells are hematopoietic stem cells-derived tissue resident-granulated cells found close to blood vessels, nerves, and mucosal surfaces. The major growth and differentiation factor for the mast cell lineage is stem cell factor, which binds KIT, a transmembrane receptor with intrinsic tyrosine kinase activity [26]. The c-KIT proto-oncogene is necessary for the development and survival of mast cells through the Stat5-P13Akt signaling pathway [27, 28]. Upon binding its ligand, stem cell factor, KIT induces autophosphorylation and downstream signal transduction, which leads to differentiation, proliferation, and antiapoptotic effects in mast cells [29, 30].

The pathophysiology of mastocytosis is driven by an activating KIT mutation in neoplastic mast cells [31], which is present in more than 95% of patients with systemic mastocytosis [32]. In adults with SM, KIT mutations primary affect exon 17 encoding for phosphotransferase domain, usually D816V [33]. Other less frequent mutations affect exons 2, 8, 9, and 10 encoding for the extracellular or transmembrane domains, or exons 13, 14, and 17 encoding for kinase domain. These atypical mutations have been described in childhood onset cutaneous mastocytosis (extracellular forms) or advanced systemic disease (atypical exon 816 mutations). The majority of mastocytosis mutations are sporadic somatic mutations that affect the mast cell progenitors and are not present in germ cells. In cases of rare familial mastocytosis (representing < 1% of all cases), these patients usually do not have KIT mutations or have rare mutations, such as K509I, N835I, N835K, A533D, M835K, S841I, or K839E [34].

The degree of KIT D816V mutation status in SM can be highly variable given the differing degrees of mast cell infiltration in affected organs. One review illustrated that the rate of KIT mutation varied among skin, bone marrow, and blood, from 81 to 95% [32].

Anaphylaxis and Mastocytosis

There are many risk factors for anaphylaxis in those with mastocytosis. In children, risk is proportional to the extent and density of skin lesions and serum tryptase level [35]. Adults with mastocytosis are at greater risk for anaphylaxis than children with a prevalence between 22 and 49% [35,36,37]. Prevalence is higher in males and those with higher IgE [36]. Similar to children, those with higher baseline serum tryptase level are also at higher risk for anaphylaxis [35].

Idiopathic anaphylaxis (IA) is a form of anaphylaxis with unknown etiology but similar symptoms to other forms of anaphylaxis [38]. While the causes of the majority of cases of anaphylaxis can be identified, over 8% of anaphylaxis events are idiopathic [39]. IA is increased in patients with mastocytosis [37, 36], with 14–42% of patients having clonal mast cell disorder in different series (mastocytosis or monoclonal mast cell activation syndrome) [40•, 41]. A sensitive peripheral blood allele-specific quantitative PCR was able to identify the presence of KIT D816V mutation and predicted bone marrow disease in patients with IA and a clonal disorder with a 100% positive predictive value [41]. There was no evidence of a hyper-responsive mast cell phenotype in patients with IA in patients without clonal mast cell disorder [41].

Hymenoptera venom allergy has a strong association with clonal mast cell disease; in patients with mastocytosis and anaphylaxis, 19–30% reported hymenoptera stings as a culprit [35, 42]. On the other hand, several studies reported elevated baseline tryptase levels in patients with hymenoptera venom allergy correlating with severity of the reaction [43, 44]. One study from Italy found that as many as 12% of patients with systemic reactions to venoms have elevated baseline tryptase levels (> 11.4 ng/ml), and the majority of these patients had clonal mast cell disease [45]. Another study confirmed elevated basal tryptase levels in 12.0% of the hymenoptera allergic patients and elevation of tryptase was most significantly correlated with the severity of anaphylaxis (P < 0.001) [46]. Up to 15% of patients with mastocytosis and systemic reactions to hymenoptera venom may be negative to skin prick and specific IgE, which is more frequent than the general public [47•]. Venom immunotherapy (VIT) is recommended for patients with SM with IgE-mediated allergy, and is considered safe and effective [48,49,50]. Omalizumab has been used successfully to help tolerate desensitization for VIT [51,52,53].

Perioperative periods are also a potent risk factor for anaphylaxis. Mast cell disease was identified in 4% of patients with perioperative anaphylaxis [54]. Conversely, 0–2% of patients with mastocytosis experienced anaphylaxis while undergoing procedures requiring general anesthesia [55•].

Procedures that occur under anesthesia can increase release of mast cell mediators, which are likely multifactorial from stress, tissue manipulation, and medications including neuromuscular blockers, analgesics (opioids and NSAID), and hypnotics [56,57,58,59]. These procedures, therefore, are considered higher risk in patients with mastocytosis based on reports of severe reactions, including death [60,61,62,63,64]. Reactions are more likely to occur in patients who have had anaphylaxis before or are undergoing a procedure under general anesthesia [61]. Most agree that patients with prior episodes of anaphylaxis should be pretreated with medications [65, 61, 58], and some authors focus on treating anxiety, which could cause worsening mast cell mediator release [61]. To date, there is no placebo controlled trials to examine the effects of pre-treating all patients.

Food allergies are much less frequently reported as the presenting symptoms of mastocytosis [66, 35]. The rate of food allergy does not appear to differ greatly in patients with mastocytosis compared to the general population [36]. Allergy to mammalian meat is a recently identified etiology of anaphylaxis triggered by exposure to a mammalian oligosaccharide, galactose-α-1,3-galactose (α-gal) [67], after sensitization from a tick bite [68], and has been reported as a cause of anaphylaxis in mastocytosis [69, 70].

Unlike traditional food allergies, anaphylaxis to mammalian meat may occur in a delayed fashion, up to 6 h after consumption [67]. It has been suggested that a screening tryptase should be obtained in those with severe α-gal anaphylaxis [71].

Several physical anaphylaxis conditions exist, including temperature and exercise-induced forms. Exercise-induced anaphylaxis is characterized by symptoms of anaphylaxis at the beginning, during, or after exercise [72]. It should be suspected based on history, and its diagnosis can be confirmed with a positive exercise challenge, but negative exercise challenge does not exclude this disorder [73]. The condition is thought to be related to release of mediators by mast cells as with most IgE-related anaphylaxis. However, the mechanism is less clear than in general anaphylaxis. Our personal experience suggests that there is likely an overlap in EIAn and clonal mast cell disorders; however, their precise relationship is not well-documented.

Most frequent symptoms of anaphylaxis in patients with mastocytosis are cardiovascular, with skin lesions being surprisingly infrequent [74, 35, 37]. A scoring system based on gender, tryptase levels, and symptoms of anaphylaxis was proposed to predict patients with a high likelihood of having mastocytosis [75].

Diagnostic and Therapeutic Considerations

To screen for systemic mastocytosis, an algorithm was developed based on clinical signs and symptoms, and tryptase levels that is capable of predicting the existence of clonality with a sensitivity of 92% and a specificity of 81%. A score ≥ 2 suggests that ISM should be ruled out [76]. Patients with idiopathic anaphylaxis and venom-induced anaphylaxis with normal tryptase levels at baseline need evaluation for the KIT D816V mutation in peripheral blood. If results are positive, a bone marrow biopsy is warranted [77].

Once mastocytosis is diagnosed, the goal of treatment is either symptomatic management or cytoreductive therapy. Current treatments for symptomatic management are with antihistamines (H1 and H2 receptor blockers), antileukotrienes, and mast cell stabilizers. Data have shown that antihistamines can increase quality of life in patients with mastocytosis [78]. H1 and H2 receptor antagonists are helpful for dermatologic and GI symptoms of mastocytosis [79]. Patients with predominantly GI complaints, such as abdominal cramping, vomiting, or diarrhea, may benefit from cromolyn [80]. Leukotriene inhibitors, such as montelukast, have limited data but are frequently used as an adjunctive therapy. It has been shown to be effective for patients with dermatologic complaints [81, 82]. In terms of cytoreductive therapy, patients were typically treated with cladribine or interferon-alpha until midostaurin was approved. Although chemotherapy, such as cladribine, can induce a response of 50% in patients with SM, ASM, or MCL, and can also drastically reduce anaphylactic episodes, it can have significant toxicities including lymphopenias and opportunistic infections [83]. Therefore, targeted therapies to reduce mast cell burden and activation have been investigated.

The most studied targeted drugs specific to mast cell proliferation are KIT tyrosine kinase inhibitors [84]. Midostaurin, a tyrosine kinase inhibitor, is the only FDA-approved therapy for patients with advanced subtypes of mastocytosis [85]. Unlike previous tyrosine kinase inhibitors such as imatinib, midostaurin inhibits not only the wild-type form of its targets but also their mutant forms, including D816V mutant [26]. It is shown to reduce organ damage and disease progression [86••], and is found to have durable effect and is safe at 10 year follow-up [87]. In addition, midostaurin also seems to reduce symptoms in patients with severely symptomatic indolent mastocytosis [88]. BLU-285 compound or avapritinib is another novel tyrosine kinase inhibitor that selectively inhibits KIT exon 17 mutants, including KIT D816V. It also inhibits STAT3 and AKT phosphorylation in vitro in human MC line [89]. It seems to be well-tolerated and demonstrated significant clinical and biologic activities in all advanced SM subtypes, including in those who did not respond to midostaurin [90]. The effects of tyrosine kinase inhibitors on anaphylaxis in clonal mast cell disease remain to be explored.

Omalizumab (anti-IgE antibody) seems not only to be a promising treatment for patients with chronic urticaria and allergic asthma but also reduces anaphylaxis in clonal and non-clonal mast cell disorders [91, 92]. Mechanisms of omalizumab action in these patients remain to be elucidated [93••, 51].

Conclusions

Mast cells play an important role in IgE-dependent anaphylaxis, which is a life-threatening condition. Those with mastocytosis, a group of neoplasms with clonal expansion of mast cells, are at a particularly elevated risk of anaphylaxis. Mastocytosis is driven by an activating KIT mutation in mast cells, which is present in majority of people with the disorder. This group of individuals is more prone to experience anaphylaxis in many situations, such as during peri-operative periods, with bee stings, foods, and medications, as well as physical factors, such as temperature and exercise. The identification of KIT mutation is instrumental in guiding therapies. Many symptoms of mastocytosis can be controlled with anti-histamines, and most novel-targeted therapies currently involve KIT tyrosine kinase inhibitors.