Definition of standards for allergology specialty/subspecialty training in mast cell disorders, in Europe: a EAACI position paper

Definition of standards for allergology specialty/subspecialty training in mast cell disorders, in Europe: a EAACI position paper | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 29 January 2026 V1 Latest version Share on Definition of standards for allergology specialty/subspecialty training in mast cell disorders, in Europe: a EAACI position paper Authors : Tiago Rama 0000-0003-0134-617X , Theo Gulen , Knut Brockow 0000-0002-2775-3681 , Patrizia Bonadonna , Vito Sabato 0000-0002-1321-314X [email protected] , C. Grattan , Sigurd Broesby-Olsen 0000-0002-1558-8471 , Sabine Altrichter 0000-0001-9955-385X , Frank Siebenhaar 0000-0003-4532-1644 , Jolanta Walusiak-Skorupa , and David González-de-Olano 0000-0001-6653-4900 Authors Info & Affiliations https://doi.org/10.22541/au.176967556.62286692/v1 242 views 120 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Mast cell disorders (MCD), including mastocytosis and mast cell (MC) activation syndrome (MCAS), encompass a heterogeneous spectrum of diseases often presenting with debilitating manifestations. Variable clinical manifestations, ranging from otherwise asymptomatic cutaneous forms to recurrent anaphylaxis, pose significant challenges for timely diagnosis and effective management. Despite increasing recognition of MCD in Europe, diagnosis is frequently delayed, and therapeutic approaches remain inconsistent, potentially due to gaps and disparities in training. An European Academy of Allergy and Clinical Immunology (EAACI) Task Force (TF) was created to address this need. Through iterative consensus, the TF members formulated ten expert-based recommendations outlining the minimum competencies that allergology and clinical immunology trainees should acquire regarding MCD. These include fundamental knowledge of MC biology, pathogenesis of clonality, recognition of systemic manifestations, diagnostic methodologies, pharmacological and preventive strategies, management of comorbid Hymenoptera venom allergy, pediatric aspects, communication skills, and how to acquire and consolidate expertise. This position paper underscores the need for harmonized competency-based training standards on MCD for Allergists and Clinical Immunologists across Europe. We advocate for the incorporation of these recommendations into national postgraduate curricula, aiming to foster earlier recognition, improve management, and ultimately enhance long-term outcomes for MCD patients. Introduction Mast cell (MC) disorders (MCD), including mastocytosis and mast cell activation syndrome (MCAS), comprise a group of complex and often debilitating conditions that require specialized knowledge and management (1). These disorders manifest across a broad clinical spectrum, ranging from pauci-symptomatic cases (i.e., otherwise asymptomatic cutaneous mastocytosis) through overtly symptomatic cases to recurrent episodes of anaphylaxis, presenting significant challenges in both diagnosis and treatment (2). Also, patients with advanced forms may present with signs of organ dysfunction, which may compromise life expectancy, if left untreated, but these are out of scope for this position paper. Despite a steady increase in the reported incidence of mast cell disorders in Europe, delays in diagnosis remain frequent, compromising patients’ well-being and quality of life (3) and overall prognosis (4). Recent data suggest that overall, 3.5-5% of patients presenting with anaphylaxis (5-7), and around 22% of patients presenting with Hymenoptera venom allergy requiring VIT may actually show underlying MC clonality (8). Up to two-thirds of patients with systemic mastocytosis without skin lesions in large patient series present with anaphylaxis (9, 10). A widespread belief that all patients with mastocytosis face an alarming and unpredictable risk for anaphylaxis frequently leads to an empirically-based and unnecessary avoidance of several drugs (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs), opiates/opioids, neuromuscular blocking agents (NMBAs), radiocontrast media (RCM), quinolones, vancomycin and other antibiotics (11-16)), vaccines and the so called histamine-releasing foods (e.g., tomatoes, shellfish, peanuts) (17, 18). Avoidance of such stimuli is frequently unnecessary as the associated risk of MC activation is often low and similar to the risk in the general population (11, 19-22), and may lead to unnecessary anxiety among patients and caretakers. Thus, allergists and clinical immunologists need to be fully aware of the spectrum of MCD and of how to diagnose and manage it. The variability in clinical presentations and the need for precise diagnostic approaches underscore the key role of healthcare professionals specializing in Allergology and Clinical Immunology. These specialists are best positioned to address the consequences of mast cell activation. However, disparities in education and training standards across European countries have underscored a need for harmonized guidelines. Variations in healthcare systems and differing levels of awareness among practitioners compound these challenges, emphasizing the need to establish unified and comprehensive training frameworks. This European Academy of Allergy and Clinical Immunology (EAACI) task force (TF) aims to provide expert-based recommendations for the minimum requirements and standards for mast cell disorder training for allergologists and clinical immunologists across Europe. Definitions Mastocytosis encompasses a spectrum of heterogeneous clinical presentations characterized by clonal and phenotypically aberrant MC accumulation in different tissues and organs, such as the skin, bone marrow, and the gastrointestinal (GI) tract, that frequently presents with manifestations of MC activation (23, 24). The diagnosis of mastocytosis is established in the presence of diagnostic criteria for cutaneous and, or systemic mastocytosis (SM) (25). Patients without cutaneous mastocytosis that are shown to present with clonal MC (i.e., that express CD25 or in whom a KIT mutation is detected) and that do not meet criteria for SM are diagnosed with monoclonal mast cell activation syndrome (MMAS) (23, 24). Notably, patients presenting with a single episode of anaphylaxis due to any cause, but most frequently due to Hymenoptera venom allergy (HVA), may fall within this category (26, 27). MCAS is a distinct entity within the broader spectrum of mast cell activation disorders and is characterized by recurrent, severe, systemic symptoms of MC activation. MCAS is diagnosed when all three diagnostic criteria (i.e., clinical, laboratory and therapeutic response criteria) are met (28, 29). The clinical criterion refers to at least 2, severe episodes of manifestations with involvement of at least two organ systems simultaneously, usually fulfilling anaphylaxis criteria. The laboratory criterion involves the elevation of a validated mast cell mediator during symptomatic episodes, such as serum tryptase, urinary metabolites of histamine, or prostaglandin D2. Event-related elevation of serum tryptase levels, as determined by the formula≥20% + 2 ng/mL compared to baseline levels, appears to be the most specific marker of mast cell activation (28, 29). Despite tryptase being highly specific for mast cell activation, studies indicate that its elevation during anaphylaxis has a low negative predictive value (30) Other validated markers e.g., urinary histamine, prostaglandin and leukotriene metabolites are not widely available; however when measured on spot samples within the first 4 hours of the event, acute elevation of 30% and above compared to baseline levels has been suggested to be significant (31, 32). Non-validated biomarkers indicative of MC activation have been proposed, including heparin, chromogranin A, serotonin, and substance P, but these are not recommended to confirm mast cell activation (28). The therapeutic response criterion requires a decrease in the severity and frequency of MC activation episodes with anti-mediator therapies, mast cell-stabilizing drugs, or both. MCAS are subcategorized according to an endotypical classification into primary (i.e., clonal), secondary (i.e., IgE- or non-IgE-mediated hypersensitivity), idiopathic, or combined (i.e., both criteria for primary and secondary MCAS). Clonal MCAS (c-MCAS) occurs in patients with cutaneous mastocytosis (CM), systemic mastocytosis (SM), and MMAS that fulfil criteria for both MC clonality and MCAS (28, 33). Methods Members of the EAACI Task Force “Bringing the spotlight to mastocytosis and mast cell activation syndrome: promoting the inclusion of mast cell disorders in national standards of postgraduate Allergology specialist training in Europe” first developed ten preliminary recommendations reflecting expert opinion on the core aspects of mast cell disorders that allergists and clinical immunologists should be trained to recognize and manage. These recommendations were iteratively refined and ultimately approved by all participants following plenary discussion and adjustment. After the formulation of the recommendations (Box 1), an extensive review of the literature published up to August 2025 was conducted in PubMed to contextualize and support each statement (main text) and, for recommendations 1 to 9, to provide key knowledge for trainees (supplementary material). Additionally, further details for the rationale for recommendations 1, 2, 3, 5, 6, 7, 8, and 9 have been provided in the Supplementary Material. Search terms included: mastocytosis, systemic mastocytosis, cutaneous mastocytosis, mast cell activation syndrome, monoclonal mast cell activation syndrome, mast cell disorders, hereditary alpha tryptasemia , combined with pathogenesis, diagnosis, and management . Recommendations and statements were incorporated into the final manuscript only after consensus was reached, defined as full agreement among all Task Force members. Place Box 1 here Recommendation 1: Allergists and clinical immunologists should understand the biology of mast cells and pathogenesis of mast cell clonality. A comprehensive understanding of MC biology is crucial for allergists and clinical immunologists. Trainees should acquire in-depth knowledge of MC development and function, including their ontogeny, surface phenotype, activation pathways, mediator profiles, and the mechanisms underlying mast cell clonality. MC originate from hematopoietic stem cells and express a wide range of receptors which when bound to their ligand(s) lead to distinct activation pathways (i.e., degranulation, piece-meal degranulation and differential release of mediators). These include the high-affinity IgE receptor (FcεRI), the Mas-related G protein–coupled receptor X2 (MRGPRX2), multiple pattern recognition receptors (PRRs) such as Toll-like receptors and complement receptors (34). MC mediators may be broadly categorized into preformed granule-associated compounds (e.g., histamine and tryptase), and de novo synthesized membrane-derived lipid mediators, and cytokines. While classically known for the actions on smooth-muscle (i.e., leading to vasodilation, bronchoconstriction, and contraction of smooth-muscle in the gastrointestinal tract), pruritus, and edema, many of these mediators are also responsible for many other actions, including inflammation, tissue remodeling, and bone metabolism. MC represent the only hematopoietic-derived cells that retain a high expression of KIT/CD117 when terminally differentiated (35). KIT is expressed as a cell membrane-bound monomer, which dimerizes upon binding to stem cell factor (SCF) (36). In the presence of activation mutations, KIT undergoes ligand-independent dimerization leading to a constitutive phosphorylation cascades which promote proliferation/accumulation of the mutated MC clone, and may decrease the threshold for MC activation (36). Activating KIT mutations are the main cause of clonal MC disorders. The most common is the D816V mutation in exon 17, which may lead to constitutive KIT phosphorylation and MC proliferation and activation (36). Gain-of-function mutations can be restricted to MC or involve upstream hematopoietic progenitors, with the extent of lineage involvement correlating with disease aggressiveness and prognosis (37-40). Among preformed granule-associated compounds, tryptases deserve particular attention. β-tryptase is released as active tetramers during mast cell activation and its elevation in the serum can be detected in a considerable proportion of anaphylactic reactions, whereas pro-α-tryptase is constitutively secreted by mast cells and accounts for serum baseline tryptase (sBT) levels (41, 42). α-tryptase is encoded by α-alleles of the TPSAB1 gene, while both TPSAB1 and TPSB2 encode β-tryptase (43, 44). Multiplication mutations of the TPSAB1 gene lead to hereditary alpha-tryptasemia, a genetic trait whose clinical impact remains a matter of debate (45). Recommendation 2: Allergists and clinical immunologists should acquire expertise on the clinical evaluation of systemic manifestations of mast cell activation and, or accumulation. Clinical manifestations of MCD are extraordinarily heterogenous (46). A deep understanding of the clinical spectrum of mast cell-related disorders is essential for Allergology and Clinical immunology trainees. Core competencies should include the recognition of both clonal and non-clonal mast cell activation disorders, the distinction between mediator-driven and infiltration-related symptoms, and familiarity with the full range of organ system involvement, from cutaneous and gastrointestinal to cardiovascular, skeletal, and neuropsychiatric manifestations. Trainees should be aware that, by definition, non-clonal MCAS present with recurrent, IgE- or non-IgE-mediated anaphylaxis, and that around half of patients with clonal MCD present with anaphylaxis (11). Special attention should be given to those presenting with syncope or presyncope during anaphylaxis in the absence of mucocutaneous involvement (i.e., no urticaria, pruritus, or angioedema), even if anaphylaxis has occurred only once, as these patients should be thoroughly evaluated for MC clonality (47, 48). The presence of cutaneous lesions of mastocytosis establishes the diagnosis of clonal MCD, while recurrent presyncope, syncope, or fainting spells (47) and skeletal manifestations such as osteopenia, osteoporosis, or (less often) osteosclerosis (49) in patients with anaphylaxis should prompt further diagnostic work-up. Additionally, patients with MC disorders may concomitantly present with cutaneous (i.e., wheals (hives) angioedema) gastrointestinal (i.e., nausea/emesis, heartburn, abdominal pain, diarrhea, malabsorption, hepatic failure, ascites and secondary hypoalbuminemia), hematological (i.e., anemia, cytopenias, eosinophilia, monocytosis), cardiovascular (i.e., fainting spells, syncope, hypotension), neuropsychiatric (i.e., migraines, dysautonomia, cognitive impairment, amnestic alterations, attention challenges), constitutional (i.e., fatigue, weight loss) manifestations and organic dysfunction (due to MC infiltration) in advanced cases (46). Noteworthy, when isolated, the latter manifestations should not, by themselves, raise suspicion for either clonal or non-clonal MCD (28). Furthermore, current evidence does not consistently support a pathophysiological association between mast cell disorders and other conditions, including long COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome, Ehlers–Danlos syndromes, fibromyalgia, or the so-called “histamine intolerance.” Recommendation 3: Allergists and clinical immunologists should attain profound knowledge in distinguishing clonal from non-clonal mast cell disorders, and the indications for tryptase genotyping. Accurate differentiation between clonal and non-clonal MCD is a fundamental competency for Allergology and Clinical Immunology trainees. Training should encompass the diagnostic criteria (see the Definitions section) and tools used to detect mast cell clonality, including bone marrow histopathology, bone marrow flow cytometry, high- (50-52) and ultra-sensitivity (53) molecular assays for KIT mutations, and predictive algorithms such as the REMA (26, 47), the NICAS (54) and the Karolinska (48) scores. Trainees must also understand the interpretation and limitations of baseline serum tryptase and the diagnostic relevance of hereditary alpha tryptasemia. The main clinical presentations of non-advanced clonal mast cell disorders include anaphylaxis, mastocytosis skin lesions, and osteoporosis, while advanced SM may present with the former as well as associated constitutional manifestations and organic dysfunction (55). MC clonality is demonstrated when at least one of the following is present: expression of CD25, CD30 or CD2 by MC (cutaneous in the case of CM, extracutaneous in the case of SM), detection of an activating KIT mutation, or the presence of cutaneous or extracutaneous (e.g., bone mastocytoma) mastocytosis lesions (56) and should be clinically considered in all patients with a history of anaphylaxis. Allergists and clinical immunologists are uniquely positioned to assess MC clonality in patients with a history of anaphylaxis, by conducting a detailed history (actively enquiring for features mentioned in Recommendation 2) and thorough examination (looking for typical cutaneous mastocytosis lesions, lymphadenopathy, or organomegaly). Clinical features associated with an increased likelihood of MC clonality among patients with a history of anaphylaxis are summarized in Box 4. Trainees ought to acquire familiarity with the use of MC clonality predictive tools and with the Fuchs score, that predicts the risk of SM in patients presenting with mastocytosis in the skin (57). The REMA score has been shown to be more accurate than the NICAS (26) and may be applied in patients with a history of anaphylaxis (i.e., irrespective of the number of anaphylactic events) who do not exhibit skin lesions. A comparison of the REMA, the NICAS and the Karolinska scores and the Fuchs score are depicted in Supplementary table 1. Moreover, trainees should be aware of the indications and potential pitfalls of advanced techniques for detecting clonality, such as flow cytometry and molecular diagnostics, as well as the indications for tryptase genotyping. sBT is frequently incorrectly used to both diagnose and to exclude systemic mastocytosis and mast cell clonality, when facing patients with anaphylaxis. sBT levels should never be used to exclude systemic mastocytosis as up to 24% of SM patients presenting with anaphylaxis show values below the manufacturer’s classically-defined cut-off: 11.4 ng/mL (26, 48). In addition to mastocytosis, several conditions may be associated with elevated sBT levels, the most common being hereditary alpha-tryptasemia (HαT) and occurring in 4% to 6% of the general population (43). HαT can be present in patients with sBT levels below 8 ng/mL (58) and its diagnosis is technically demanding, requiring digital PCR (43, 59). Still, it is less invasive than BM studies, and its assessment is reasonable in patients with unexplained sBT elevation, prior to pursuing a BM biopsy and aspirate (56), always bearing in mind that its presence does not exclude MC clonality (60). In fact, HαT is significantly more frequent in mastocytosis than in the general population (60). Recommendation 4: Allergists and clinical immunologists should understand the principles and methodologies of techniques critical for the diagnosis and follow-up of mast cell disorders. Allergists and clinical immunologists in training should develop a working knowledge of the diagnostic techniques relevant to MCD, both to ensure early recognition and to interpret results critically. While several of these techniques are not routinely performed in allergy departments, understanding their principles, limitations, and clinical utility is crucial in order to better communicate findings within multidisciplinary teams. Biopsy of extracutaneous tissues, in particular bone marrow studies, are essential for the diagnosis of systemic mastocytosis and require both aspirate and biopsy specimens. Trainees should be able to distinguish molecular biology techniques according to their most relevant characteristics and should know that these may be applied in whole or fractioned BM or blood samples. Regarding sensitivity, it is crucial to distinguish ultra- (i.e., rolling-circle amplification [RCA]-PCR for KIT D816V detection) (53), from highly- (i.e., ASOqPCR, and digital PCR for KIT D816V detection) from low-sensitivity techniques (i.e., peptide nucleic acid (PNA)-PCR for the detection of other exon 17 mutations, and Sanger sequencing and next-generation sequencing [NGS] for KIT mutations in exons 2, 8–15, and 17) (61). Moreover, it is important to distinguish those which allow for the quantitation of the variant allele frequency (VAF) (i.e., RCA-PCR, ASOqPCR, dPCR and NGS) from those who do not (i.e., PNA-PCR and Sanger sequencing) (61). Flow cytometry is performed on fresh BM samples and should involve a minimum panel that includes CD45, CD117, CD25, CD2, and CD30. Given the rarity and autofluorescence of mast cells, trainees should be made aware of technical challenges such as low event counts, cell complexity, and the importance of proper gating strategies (373, 432, 433). High-event acquisition (i.e., at least 500,000 events) is often required to detect clonal MC in low burden SM and MMAS (62). Tissue biopsies (i.e., skin biopsy and BM biopsy) remain crucial for the diagnosis of mastocytosis. In the skin, MC aggregates or interstitial diffuse infiltrates containing 20 or more MC per high-power field are suggestive of cutaneous mastocytosis (62). However, various dermatoses may exhibit increased MC density, and applying a threshold exceeding 26 MC per high-power field may improve specificity (63). In BM, histology should evaluate compact mast cell aggregates (≥15 cells), interstitial MC increases, and fibrosis. For both, immunohistochemical staining with anti-tryptase and anti-KIT monoclonal antibodies is standard (423, 424, 426). Cytologic analysis should include Giemsa and/or toluidine blue staining and allow for identification of atypical MC morphologies: spindle-shaped, hypogranulated (type I), multilobated/promastocyte (type II), and blast-like forms (423, 424, 426). Non-MC lineages should also be assessed for proliferation and dysplasia. Serum tryptase quantification is a cornerstone in both acute and baseline settings, requiring knowledge of pre-analytical factors, timing (e.g., half to 2 hours post-event for acute samples), and the use of FEIA-based systems (e.g., ImmunoCAP, Phadia/Thermo Fisher Scientific Inc, Uppsala, Sweden). Trainees should understand that tryptase alone is not diagnostic. In cases with tryptase above 8 ng/mL, TPSAB1 genotyping by digital PCR can identify hereditary alpha tryptasemia. Training should address the interpretation of gene copy number variation (105, 230, 520). Proper classification of SM and associated diseases further requires laboratory and imaging/nuclear medicine assessments meant to investigate the presence of bone disease (i.e., osteopenia/osteoporosis and, or bone sclerosis, osteolytic lesions and pathologic fractures), organic dysfunction (e.g., cytopenias, hepatic dysfunction), severe malabsorption (i.e., hypoalbuminemia), and organomegalies (i.e., hepatomegaly, splenomegaly and lymphadenopathy). Findings should be framed within the B- (indicative of high MC burden) and C-findings (indicative of organ dysfunction) (Box 3) (56). Regular follow-up is needed for MCD patients. In patients with CM, indolent SM or bone marrow mastocytosis, whose MC activation symptoms are well-controlled, follow-up may consist of a yearly consultation, in which tryptase and other blood parameters are assessed, while assessment of KIT D816V VAF, organomegalies, and bone disease may be performed in an individualized manner. Patients with smoldering SM and advanced SM will require a more frequent follow-up that should be done together with hematologists with experience in SM. Overall, allergology/immunology trainees must be equipped with a theoretical and practical understanding of these diagnostic and follow-up tools to effectively collaborate with hematologists, dermatologists, and pathologists in the multidisciplinary care of mast cell disorder patients. Place Box 2,3 and 4 here Recommendation 5: Allergists and clinical immunologists should know the pharmacological agents for controlling mast cell activation symptoms and their relevant pharmacokinetic and pharmacodynamic features. It is essential that trainees acquire in-depth knowledge of the pharmacological management of manifestations driven by mast cell mediator release. This entails understanding the mechanisms of action, efficacy, and pharmacokinetic properties of the main drug classes, including H1- and H2-antihistamines, mast cell membrane stabilizers (e.g., sodium cromoglycate, ketotifen), leukotriene modifiers, cyclooxygenase (COX) inhibitors, biologics such as omalizumab, and tyrosine kinase inhibitors (TKIs) (64). Although older cytoreductive agents are used in advanced systemic mastocytosis, these are not the core focus of early pharmacologic training for Allergists and Clinical Immunologists. Moreover, trainees should also be familiar with the use of patient reported outcomes measures (PROMs) (e.g., Mastocytosis Quality-of-Life Questionnaire [MQLQ] (65), Mastocytosis Symptom Assessment Form [MSAF] (65), Mastocytosis Activity Score [MAS] (66), Symptom-Focused Outcome Measures for Advanced and Indolent Systemic Mastocytosis [AdvSM-SAF and ISM-SAF, respectively] (67), Mastocytosis Quality-of-Life Questionnaire [MC-QoL] (68) for an optimized therapeutic management. H1 antihistamines are the mainstay of the anti-mediator treatment for both clonal and nonclonal MCD, and similarly to what has been proposed for chronic spontaneous urticaria, updosing with up to a daily dose four times of the label may be performed (69). Those with refractory anaphylaxis may benefit from receiving omalizumab, H2 antihistamines and sodium cromoglycate (70). Besides the latter, refractory flushing may benefit from acetylsalicylic acid (for patients with proven tolerance) and leukotriene antagonists, and abdominal cramping and, or chronic diarrhea may improve with sodium cromoglycate, H2 antihistamines, oral budesonide cycles, leukotriene antagonists, COX-2 inhibitors and low-dose glucocorticoid (other than budesonide) cycles (70). Per EAACI anaphylaxis guidelines, patients with a history of anaphylaxis (except if strictly drug-related) should be prescribed two adrenaline autoinjectors (71), and the need for indiscriminate prescription of adrenaline autoinjectors to all patients with MCD is controversial. Recommendation 6: Allergist and clinical immunologist should know preventive measures to avoid mast cell activation episodes. Allergists and Clinical Immunologists ought to be aware of preventive measures to avoid MC activation episodes, including the judicious application of elimination strategies and premedication, as well as the proper use of allergy testing, including drug and food challenges, where applicable. Patients with mastocytosis and other MCD may suffer from severe MC activation episodes caused by different triggers. Each patient typically reacts to a limited number of triggers, and indiscriminate avoidance of potential triggers for MC activation is not recommended, as it may hinder children’s growth and worsen the overall patient’s quality of life. Some experts have suggested administering general pre-medications, including H1 and H2-antihistamines, leukotriene receptor antagonists, and glucocorticoids, before surgical procedures, general anesthesia, and radiographic imaging using radiocontrast media (16). Additionally, H1 antihistamines have been recommended prior to procedures performed under local anesthesia (not requiring sedation/general anesthesia) (72) and vaccines (73). Still, these premedication protocols have not been the subject of controlled studies and their use in mastocytosis (or MCAS) patients remains controversial (15, 22) Recommendation 7: Allergists and clinical immunologists should acquire clear knowledge of the indications, protocols, safety measures, complications and the required duration of venom immunotherapy. Hymenoptera venom allergy is the most frequent trigger for anaphylaxis in adult patients with clonal mast cell disorders (74). In fact, this is the clinical presentation that leads to suspicion of mastocytosis in many patients, especially those with bone marrow mastocytosis and MMAS (75). Therefore, it is crucial that trainees become proficient on the diagnostic and treatment specificities of comorbid HVA and MCD. Venom immunotherapy (VIT) is indicated in all patients with HVA in whom an IgE-mediated mechanism is detected (76). However, it is common for patients with clonal MCD, despite being allergic, to have low levels of total and specific IgE, so it is important to be familiar with the different techniques that have proven useful in detecting IgE-sensitization (i.e., lowering the threshold that defines IgE sensitization from 0.35 kUA/L to 0.15 kUA/L or even 0.1 kUA/L, and using component-resolved diagnostics (77-79)). With appropriate protocols and recommendations, venom immunotherapy (VIT) is both safe and effective. However, the duration of the tolerance to venoms appears to be shorter in patients with mastocytosis than in the general population, supporting the recommendation to extend the duration of therapy (76). Recommendation 8: Allergology and clinical immunology trainees should be able to identify and characterize the main clinical forms of childhood-onset mastocytosis. A structured understanding of childhood-onset mastocytosis is essential for allergology and clinical immunology trainees, even for those who do not routinely manage pediatric patients. Core training should cover the recognition of typical cutaneous variants, prognostic features, and risk factors for systemic involvement. Familiarity with individualized management strategies, including safe vaccination practices, avoidance of unnecessary restrictions, and effective communication with caregivers, is crucial to minimize morbidity and anxiety in this population. Mastocytosis usually onsets at two stages of life: during childhood or during adulthood, with a small number of cases onsetting during adolescence. Childhood-onset mastocytosis predominantly presents with strict cutaneous involvement, with systemic forms being uncommon, while clinically relevant (80). These patients are significantly less prone to anaphylaxis than adults and those with cutaneous mastocytoma and DCM carry the higher risk for anaphylaxis (81). Other risk factors for anaphylaxis include elevated tryptase (81, 82), extensive skin involvement (81, 83), high lesional MC density (83), and lesional blistering (84). Notably, neither anaphylaxis nor systemic MC activation symptoms are a sign of SM, while persistently high basal serum tryptase (usually above 100 ng/mL), cytopenias, and especially organomegaly, should prompt further investigation (85). Recommendation 9: Allergologists and clinical immunologists should develop essential communication skills to deliver bad news effectively and manage highly complex clinical cases. In most patients with mastocytosis, several years often elapse between the onset of symptoms and the definitive diagnosis (3). Physicians’ general knowledge of these conditions is usually limited, so patients often feel misunderstood (86). Furthermore, although advanced mastocytosis accounts for a small percentage of SM cases, they can sometimes be fatal. For all these reasons, it is necessary to acquire communication skills that are useful not only for showing empathy and emotional support, but also for providing information in cases with poor clinical outcomes. Recommendation 10: Trainees should procure knowledge on mast cell disorders, either through a rotation in an experienced center, or through continuous medical education. MCD are heterogeneous disorders that require highly specialized diagnostic and therapeutic approaches. Diagnostic procedures seem to be more accurate when performed in experienced reference centers (87). Due to their complexity and rarity, exposure to a significant number of patients may be limited in general Allergology/Clinical Immunology training programs. Clinical rotations at reference centers with expertise in mast cell disorders offer trainees unique opportunities to consolidate theoretical knowledge through practical experience, particularly in the application of WHO diagnostic criteria, interpretation of advanced flow cytometry and molecular diagnostics (e.g., KIT mutation testing), and implementation of personalized avoidance and therapeutic strategies, in a multidisciplinary context. Continuous medical education delivered by experienced clinicians, specific literature and (online) training programs can provide key knowledge on the diagnosis and management of MCD and may be a valid alternative to clinical rotations, when necessary. Conclusions The rapid evolution in MCD-related research and the expanding clinical applications of molecular diagnostics, pharmacogenomics, and biologics, requires that future allergologists and clinical immunologists be equipped with foundational competencies. Uniform training frameworks that incorporate both basic science and pragmatic clinical knowledge are essential for ensuring early diagnosis, proper risk stratification, and evidence-based treatment of MCD across Europe. Mastering these skills is essential not only to ensure accurate diagnosis and effective treatment of MCD, but to enable the appropriate use of emerging diagnostic methods and targeted therapies in clinical practice. Harmonized and competency-based training across Europe will contribute to earlier recognition, improved management, and better long-term outcomes for patients with MCD. It is therefore vital that residency training curricula across European countries accommodate these recommendations in order to significantly improve the care of patients with MCD. Figure Legends Box 1. Recommendations for standards for the training in mast cell disorders for allergology/clinical immunology trainees. Box 2. Diagnostic criteria for systemic mastocytosis, according to the World Health Organization. Box 3. B- and C- findings, used in the subdiagnostic classification of patients with systemic mastocytosis according to the World Health Organization. Box 4. Features associated with risk for mast cell clonality in patients with a history of anaphylaxis. Author contributions All authors (Clive Gratan, David Gonzalez-de-Olano, Frank Siebenhaar, Jolanta Walusiak-Skorupa, Knut Brockow, Patrizia Bonadonna, Sabine Altrichter, Sigurd Broesby Olsen, Theo Gulen, Tiago Azenha Rama and Vito Sabato) contributed to the formulation of the recommendations. Tiago Azenha Rama proposed and chaired the task force, and drafted the manuscript, together with David Gonzalez-de-Olano. All authors revised and contributed to the final version of the manuscript. The authors would like to thank the European Academy of Allergy and Clinical Immunology (EAACI) for their financial support in the development of the Task Force “Bringing the spotlight to mastocytosis and mast cell activation syndrome: promoting the inclusion of mast cell disorders in national standards of postgraduate Allergology specialist training in Europe.” within the Mast Cell disorder Working Group; Budget code number 40110; Year 2025. Conflicts of interest TAR declares the following conflicts of interest: consultancy for Blueprint Medicines, Alfasigma, and lecture fees for Novartis and Thermo Fisher. TG declares lecture fees for ALK. SA reports support for clinical trials/research funding/honorary/non-financial support from Allakos, AstraZeneca, ALK, Biocryst, Blueprint, Celltrion, CSL Behring, Incyte, Kalvista, LEOPharma, Lilly, Menarini, Moxie, Novartis, Phavaris, Sanofi, Takeda, Thermo Fisher, and UCB outside the submitted work. FS received research funding from and/or is or recently was a speaker/advisor for Allakos, Alys, Blueprint, Celldex, Cogent, Escient, GSK, Granular, Invea, Medison, Moxie, Noucor, Novartis, Pharvaris, Regeneron, Sanofi, Swixx, Telios, ThirdHarmonicBio, and UCB. DGO declares the following conflicts of interest: consultancy for Blueprint Medicines, Sanofi, and lecture fees for AstraZeneca. VSO research funding from Blueprint Medicines Corporation for clinical trials; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, educational events from Blueprint Medicines Corporation, Novartis, and Cogent Biosciences. Data safety monitoring board or advisory board for Blueprint Medicines Corporation and Cogent Biosciences. CG reports consultancies with Themo Fisher, Blueprint Medicines and Celltrion References 1. Valent P, Akin C, Hartmann K, Alvarez-Twose I, Brockow K, Hermine O, et al. 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Sanchez-Munoz L, Morgado JM, Alvarez-Twose I, Matito A, Garcia-Montero AC, Teodosio C, et al. Diagnosis and classification of mastocytosis in non-specialized versus reference centres: a Spanish Network on Mastocytosis (REMA) study on 122 patients. Br J Haematol. 2016;172(1):56-63. Supplementary Material File (position paper mast cell disorders box 1.docx) Download 14.95 KB File (position paper mast cell disorders box 2.docx) Download 18.18 KB File (position paper mast cell disorders box 3.docx) Download 18.64 KB File (position paper mast cell disorders box 4.docx) Download 24.86 KB Information & Authors Information Version history V1 Version 1 29 January 2026 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords anaphylaxis education mast cells Authors Affiliations Tiago Rama 0000-0003-0134-617X Unidade Local de Saude de Matosinhos EPE View all articles by this author Theo Gulen Karolinska Universitetsjukhuset i Huddinge View all articles by this author Knut Brockow 0000-0002-2775-3681 Klinikum rechts der Isar der Technischen Universitat Munchen Klinik und Poliklinik fur Dermatologie und Allergologie am Biederstein View all articles by this author Patrizia Bonadonna Azienda Ospedaliera Universitaria Integrata Verona View all articles by this author Vito Sabato 0000-0002-1321-314X [email protected] Universiteit Antwerpen Afdeling Immunologie View all articles by this author C. Grattan St John's Institute of Dermatology View all articles by this author Sigurd Broesby-Olsen 0000-0002-1558-8471 Odense Universitetshospital View all articles by this author Sabine Altrichter 0000-0001-9955-385X Kepler Universitatsklinikum GmbH View all articles by this author Frank Siebenhaar 0000-0003-4532-1644 Charite - Universitatsmedizin Berlin View all articles by this author Jolanta Walusiak-Skorupa Instytut Medycyny Pracy im prof dr med Jerzego Nofera View all articles by this author David González-de-Olano 0000-0001-6653-4900 Hospital Universitario Ramon y Cajal View all articles by this author Metrics & Citations Metrics Article Usage 242 views 120 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Tiago Rama, Theo Gulen, Knut Brockow, et al. Definition of standards for allergology specialty/subspecialty training in mast cell disorders, in Europe: a EAACI position paper. Authorea . 29 January 2026. 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