Mast cell activation syndrome: Proposed diagnostic criteria

The term mast cell activation syndrome (MCAS) is finding increasing use as a diagnosis for subjects who present with signs and symptoms involving the dermis, gastrointestinal track, and cardiovascular system frequently accompanied by neurologic complaints. Such patients often have undergone multiple extensive medical evaluations by different physicians in varied disciplines without a definitive medical diagnosis until the diagnosis of MCAS is applied. However, MCAS as a distinct clinical entity has not been generally accepted, nor do there exist definitive criteria for diagnosis. Based on current understanding of this disease "syndrome" and on what we do know about mast cell activation and resulting pathology, we will explore and propose criteria for its diagnosis. The proposed criteria will be discussed in the context of other disorders involving mast cells or with similar presentations and as a basis for further scientific study and validation.     

Novel insights into mechanisms of food allergy and allergic airway inflammation using experimental mouse models

Over the last decades, considerable efforts have been undertaken in the development of animal models mimicking the pathogenesis of allergic diseases occurring in humans. The mouse has rapidly emerged as the animal model of choice, due to considerations of handling and costs and, importantly, due to the availability of a large and increasing arsenal of genetically modified mouse strains and molecular tools facilitating the analysis of complex disease models. Here, we review latest developments in allergy research that have arisen from in vivo experimentation in the mouse, with a focus on models of food allergy and allergic asthma, which constitute major health problems with increasing incidence in industrialized countries. We highlight recent novel findings and controversies in the field, most of which were obtained through the use of gene‐deficient or germ‐free mice, and discuss new potential therapeutic approaches that have emerged from animal studies and that aim at attenuating allergic reactions in human patients.     

The protein tyrosine kinase Tec regulates mast cell function

Mast cells play crucial roles in a variety of normal and pathophysiological processes and their activation has to be tightly controlled. Here, we demonstrate that the protein tyrosine kinase Tec is a crucial regulator of murine mast cell function. Tec was activated upon FcεRI stimulation of BM‐derived mast cells (BMMC). The release of histamine in the absence of Tec was normal in vitro and in vivo; however, leukotriene C₄ levels were reduced in Tec^?/? BMMC. Furthermore, the production of IL‐4 was severely impaired, and GM‐CSF, TNF‐α and IL‐13 levels were also diminished. Finally, a comparison of WT, Tec^?/?, Btk^?/? and Tec^?/?Btk^?/? BMMC revealed a negative role for Btk in the regulation of IL‐4 production, while for the efficient production of TNF‐α, IL‐13 and GM‐CSF, both Tec and Btk were required. Our results demonstrate a crucial role for Tec in mast cells, which is partially different to the function of the well‐characterized family member Btk.     

Validation of international consensus equation for acute serum total tryptase in mast cell activation: A perioperative perspective

There is no standardized method for assessing serum total mast cell tryptase (MCT) in anaphylaxis. The consensus equation (peak MCT should be>1.2× baseline tryptase+2 mg/L) has been proposed to interpret acute MCT in mast cell activation syndrome (MCAS). To validate consensus equation in a perioperative setting analyses of cases of suspected perioperative anaphylaxis during general anaesthesia (GA) were performed. Anaphylaxis was defined as per World Allergy Organisation (WAO) criteria. Timed serial MCT measurements were mapped against the consensus equation and receiver operating characteristic (ROC) curves produced. A total of 82 patients (60 females, mean age 56.5 years±SD17.2) underwent investigation. Sixty (73%) patients fulfilled WAO criteria for anaphylaxis, and 22 patients did not. Aetiology included 59% IgE‐mediated anaphylaxis, 2% non‐IgE‐mediated anaphylaxis, 12% anaphylaxis of unknown cause and 27% deemed non‐anaphylaxis. IgE‐mediated anaphylaxis included the following: NMBA (35%), antibiotics (46%), chlorhexidine (8%), patent blue dye (8%) and others (8%). An acute MCT with a comparable baseline was available in 71 of 82 (87%) patients (60 anaphylaxis and 11 controls). The median interquartile range (IQR) time from reaction to peak MCT was 1.34 (0.82‐2.51) hours. Analyses confirmed that a rise in acute MCT greater than that defined by the equation had a sensitivity, specificity, positive predictive value (PPV) and negative (N) PV of 78%, 91%, 98% and 44%, respectively. The magnitude of increase in acute MCT above the threshold predicted by consensus equation was higher in the anaphylaxis group compared to controls (P=.0001). This equation has a high specificity, PPV with a moderate NPV and sensitivity in perioperative anaphylaxis.     

The history of mast cell and basophil research – some lessons learnt from the last century

This year (2013) marks the 50th anniversary of death of Otto Carl Willy Prausnitz (1876–1963) and Heinz Küstner (1897–1963). The two physicians, when working at the Hygiene Institute at the University of Breslau, Germany (Prausnitz was the Head of the Institute), described in 1921 what is still called today the Prausnitz–Küstner or PK reaction showing that allergy could be transferred from the allergic person by transferring serum to a healthy person. Their discovery ended the belief that an anaphylactic/allergic reaction was caused by poisons, but to the contrary showed that the presence of the hypersensitivity factor could be transferred to other people. We know now that this factor is immunoglobulin E (IgE), sensitizing mast cells and basophils to respond to an allergic stimulus. We take this occasion to retrace some of the important discoveries and lessons learnt from the last century relating to the function of these two cell types as effectors of the IgE system and the mediators they produce.     

Cutaneous manifestations in Hymenoptera and Diptera anaphylaxis: relationship with basal serum tryptase

Objectives To compare the clinical presentation of systemic anaphylaxis to Hymenoptera and Diptera with regard to basal serum tryptase (BT) and to evaluate mastocytosis in patients with elevated tryptase.
Patients and Methods The medical records of 140 patients with a history of a systemic reaction to venom were retrospectively reviewed. Symptoms and severity of anaphylaxis and BT were recorded. Most patients with elevated tryptase were screened for mastocytosis: a dermatological examination with a skin biopsy was performed in 19 cases and a bone marrow biopsy in 14 cases.
Results Tryptase was elevated in 23 patients. These patients reported fewer usual skin reactions (urticaria in 26.1% of cases with raised tryptase vs. 76.1% of cases with normal tryptase), more flushing (52.2% vs. 4.3%) and frequently did not present skin reaction (26.1% vs. 9.4%). They presented a more severe reaction (mean grade of severity: 3.48 vs. 2.69). Mastocytosis was diagnosed in seven patients with elevated tryptase: indolent systemic mastocytosis in six cases and cutaneous mastocytosis without systemic involvement in one case. In five cases, mastocytosis was previously undiagnosed. Lesions of cutaneous mastocytosis, diagnosed in five patients, consisted of urticaria pigmentosa in all cases and were often inconspicuous.
Conclusion These results demonstrate particular clinical features of the allergic reaction in patients with elevated BT and the higher frequency of mastocytosis in this population. In patients with a severe anaphylactic reaction without urticaria, but with flushing, tryptase should be assayed and an underlying mastocytosis should be considered.     

Analysis of the lineage relationship between mast cells and basophils using the c-kit D816V mutation as a biologic signature

BACKGROUND: Mast cells and basophils share similar morphologic and functional properties; however, it is not known whether they are derived from a bilineage (basophil/mast cell)-restricted progenitor. OBJECTIVE: To assess whether basophils and mast cells are derived from common committed progenitors using the c-kit D816V mutation as a biologic signature. METHODS: The D816V c-kit mutation found in mast cells of patients with systemic mastocytosis is used as a trackable genetic marker to assess the lineage relationship between mast cells and basophils. Blood and bone marrow aspirates were collected from 33 consecutive patients with mastocytosis with different disease severity. Peripheral blood basophils, monocytes and neutrophils were sorted by immunomagnetic beads. Presence of the D816V c-kit mutation was analyzed by restriction fragment length polymorphism in the genomic DNA and mRNA from sorted cells in all patients and in the genomic DNA of individual basophils of 1 patient. RESULTS: The c-kit D816V mutation was detectable in basophils of 5 patients (15%). All 5 patients had the c-kit mutation also detectable in monocytes and thus had multilineage involvement. Single cell analysis of the genomic DNA in 1 patient showed a similar degree of clonal expansion in basophils, monocytes, and neutrophils. Mutated c-kit was expressed at the mRNA level in all 5 patients. There was no difference in surface Kit expression levels in basophils. CONCLUSION: Basophils carrying the D816V c-kit mutation in mastocytosis were detected only in the context of a multilineage involvement. These results argue against the presence of a bilineage-restricted committed progenitor for mast cells and basophils.     

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)

BACKGROUND: Mast cells (MCs) play a key role in allergic diseases through the release of inflammatory mediators, which are responsible of allergic symptoms. Mastocytosis is characterized by an abnormal proliferation and accumulation of mast cells, in which mediators are released intermittingly or continuously. Despite these clinical similarities, few studies have addressed the presence of allergic symptoms in mastocytosis patients, including anaphylaxis. OBJECTIVE: A prospective evaluation was carried out to study the prevalence of allergic diseases in patients with mastocytosis and their impact on the natural history of mastocytosis. METHODS: A questionnaire was given to 210 patients with mastocytosis to evaluate the history of asthma, rhinitis, conjunctivitis, atopic dermatitis, urticaria and anaphylaxis. Patients underwent total IgE, Phadiatop infant (aeroallergens and food allergens), specific IgE to latex and to Anisakis simplex determinations. Skin tests were done to 72 patients. RESULTS: The prevalence of allergy, as defined by clinical symptoms associated to specific IgE, was 23.9%. Total IgE level was significantly higher in patients with allergy as compared with patients without allergy (median 58 vs. 16.5 kU/L, P<0.0001). Anaphylactic symptoms were present in 36 patients (22%), in nine the allergen was identified. Males had more allergy and anaphylactic symptoms than females (61.5% vs. 38.5% and 72% vs. 28%, respectively). CONCLUSIONS: Allergic diseases coexist in patients with mastocytosis with similar frequency as compared with the general population. Anaphylactic symptoms are more prevalent in males with mastocytosis and in patients with elevated IgE. CAPSULE SUMMARY: The prevalence of allergy in mastocytosis is similar to the general population. Anaphylactic symptoms are more prevalent in males and in patients with elevated IgE. The coexistence of atopy does not influence mastocytosis-associated symptoms.     

Drug hypersensitivity in clonal mast cell disorders: ENDA/EAACI position paper

Mastocytosis is a clonal disorder characterized by the proliferation and accumulation of mast cells (MC) in different tissues, with a preferential localization in skin and bone marrow (BM). The excess of MC in mastocytosis as well as the increased releasability of MC may lead to a higher frequency and severity of immediate hypersensitivity reactions. Mastocytosis in adults is associated with a history of anaphylaxis in 22–49%. Fatal anaphylaxis has been described particularly following hymenoptera stings, but also occasionally after the intake of drugs such as nonsteroidal anti‐inflammatory drugs, opioids and drugs in the perioperative setting. However, data on the frequency of drug hypersensitivity in mastocytosis and vice versa are scarce and evidence for an association appears to be limited. Nevertheless, clonal MC disorders should be ruled out in cases of severe anaphylaxis: basal serum tryptase determination, physical examination for cutaneous mastocytosis lesions, and clinical characteristics of anaphylactic reaction might be useful for differential diagnosis. In this position paper, the ENDA group performed a literature search on immediate drug hypersensitivity reactions in clonal MC disorders using MEDLINE, EMBASE, and Cochrane Library, reviewed and evaluated the literature in five languages using the GRADE system for quality of evidence and strength of recommendation.     

A novel mast cell‐dependent allergic peritonitis model

Typical murine models of allergic inflammation are induced by the combination of ovalbumin and aluminum hydroxide. However, accumulating evidence indicates that, in models of asthma and atopic dermatitis, allergic inflammation can be generated in the absence of aluminum hydroxide. Moreover, co‐administration of Staphylococcus aureus enterotoxin B with ovalbumin can enhance inflammation. The objective of this study was to establish a rapid and mast cell‐dependent murine model of allergic inflammation by inducing allergic peritonitis using ovalbumin and S. aureus enterotoxin B. Allergic peritonitis was induced in C57BL/6 mice by subcutaneous sensitization and intraperitoneal challenge with ovalbumin and S. aureus enterotoxin B. Disease characteristics were assessed by flow cytometry, enzyme‐linked immunosorbent assay (ELISA), trypan blue exclusion and colorimetric assays. The time–course of the allergic peritonitis revealed a peak of peritoneal inflammation 48 h after challenge, as assessed by total cells and eosinophil counts. The decrease of cell numbers started 96 h post‐challenge, with complete clearance within 168 h. Moreover, significantly higher levels of tryptase and increased vascular permeability were found 30 min following challenge. Allergic inflammation induction by ovalbumin and S. aureus enterotoxin B was impaired in mast cell‐deficient mice and partially restored by mice reconstitution with bone marrow‐derived mast cells, indicating the mast cell role in this model. We present a novel model of allergic peritonitis that is mast cell‐dependent, simple and robust. Moreover, the use of S. aureus enterotoxin B better resembles human allergic inflammation, which is known to be characterized by the colonization of S. aureus.