SARS-CoV-2 vaccines are recommended for mastocytosis patients. We describe clinical symptoms, chemokine, cytokine, metabolomic and lipidomic derangements in a systemic mastocytosis patient following mRNA-1273 booster vaccination.

Twenty-eight chemokines and cytokines, 41 amino acids and 16 lipid classes were quantified with state-of-the-art methods.

Mast cell activation (MCA) symptoms started 24 h after the mRNA-1273 booster vaccination with significant metabolic, lipidomic and cytokine derangements. Histamine concentrations peaked at life-threatening 18 ng/ml concomitant with high tryptase. Peak plasma IL-1Ra, IL-5, IL-6, IL-10, IL-11, CXCL10 and GM-CSF concentrations were elevated 54-, 4.9-, 85-, 54-, 6.1-, 19- and 6.4-fold respectively. Tocilizumab, an IL-6 receptor antagonist, was administered 6 h after admission, because of the highly elevated IL-6 concentrations. More than one year later IL-6 was highly elevated during another MCA attack likely caused by a PCR-proven SARS-CoV-2 infection and tocilizumab was again used. Clinical symptoms improved during the following 12 h similar to the vaccine booster MCA attack.

A mRNA-1273 first booster vaccination likely caused a delayed severe MCA attack with highly elevated Th2-biased cytokines with metabolic and lipidomic derangements. Administration of an IL-6 receptor blocker during both MCA attacks might have shortened the duration of clinical symptoms.

The close association of syndromes of orthostatic intolerance with and without postural orthostatic tachycardia syndrome (POTS) with Joint Hypermobility Disorders (JHD) including Hypermobility Spectrum Disorder (HSD) and hypermobile Ehlers Danlos Syndrome (hEDS) and with Mast Cell Activation Syndrome (MCAS) is now firmly established. However, the prevalence of each entity relative to the other is not well established and is affected greatly by the various definitions used for each syndrome. Use of restricting definitions for each syndrome can be problematic in the clinical setting as it under-estimates the presence of disease, thereby preventing clinicians from considering potentially helpful therapeutic options.

A retrospective review of the clinical records of 100 young patients meeting POTS criteria was undertaken to determine the frequency of HSD, near-hEDS, and hEDS as well as the frequency of MCAS using consensus-1, conservative consensus-2, and clinical criteria regardless of lab support. Effectiveness of MCAS therapies was assessed in relation to the method of MCAS diagnosis.

From records of 392 patients with orthostatic intolerance syndromes, 100 patients met POTS criteria. The frequency of JHD ranged from 13% using strict criteria of hEDS to 34% using HSD Criteria. The frequency of MCAS ranged from 2% using consensus-1 criteria, to 37% using conservative consensus-2 criteria, to 87% using clinical criteria. Patients diagnosed by clinical criteria with or without the aid of labs responded to therapy similarly to those diagnosed with stricter criteria.

Using overly strict criteria to diagnose conditions which have a high prevalence of co-occurrence misses opportunities for potential therapeutic strategies.

Mastocytosis is a spectrum of clonal myeloid disorders defined by abnormal growth and accumulation of mast cells in various organ systems. The disease is divided into cutaneous mastocytosis, systemic mastocytosis (SM) and mast cell sarcoma. SM is further categorized into several non-advanced and advanced forms. The prognosis of cutaneous mastocytosis and non-advanced SM is mostly favourable, whereas prognosis and survival in advanced SM and mast cell sarcoma are poor. During the past 15 years, major advances have been made in the diagnosis, prognosis and management of patients with mast cell neoplasms. Management of mastocytosis consists of symptomatic therapy, including anti-mast cell mediator drugs, and cytoreductive agents for patients with advanced disease and selected individuals with non-advanced disease, as well as recognition and prevention of comorbidities such as osteoporosis and anaphylaxis. The preclinical and clinical development of KIT-D816V-targeting drugs, such as midostaurin or avapritinib, mark a milestone in improving management, the quality of life and survival in patients with SM. These agents induce major responses or even remission in people with advanced SM and lead to rapid improvement of mediator-related symptoms and quality of life in symptomatic patients.

Postural orthostatic tachycardia syndrome (POTS) and Ehlers-Danlos syndrome (EDS) are often reported to occur concurrently with mast cell activation disorders (MCADs) and hereditary alpha tryptasemia (HAT). However, it remains unclear whether evidence supporting this relationship exists.

To determine the prevalence of MCADs and HAT in patients diagnosed with having EDS and or POTS.

We conducted a systematic search of MEDLINE (OVID), EMBASE (OVID), Scopus, and Web of Science with the assistance of an experienced medical librarian. We focused on patients with any MCAD or HAT in conjunction with a diagnosis of POTS and/or EDS.

A total of 200 records were screened, 107 were excluded based on the title or abstract, 92 full texts were reviewed, and 1 record was not retrieved. No studies were identified that met our primary criterion of including patients diagnosed with any MCAD or HAT alongside POTS and/or EDS based on our prespecified diagnostic criteria.

Our review did not find evidence to confirm a relationship between MCADs, HAT, POTS, and EDS. However, it must be mentioned that 1 study revealed an association between mast cell activation syndrome, POTS, and EDS and came close to meeting the full diagnostic criteria for mast cell activation syndrome, unlike other studies. This indicates that further research using strict and validated diagnostic criteria is needed to clarify whether a true association between conditions exists.

Background: Patients with mast cell activation syndrome (MCAS) can be refractory to standard antimediator therapy. Alternative treatment options to reduce disease burden and improve quality of life are needed. Objective: To compile the evidence that supports the use of omalizumab for patients with refractory MCAS. Methods: Through a systematic review of the PubMed database, we compiled and analyzed the characteristics of patients with refractory MCAS, unresponsive to histamine 1 receptor antihistamines plus another antimediator agent (refractory MCAS), and who were treated with omalizumab. We categorized the clinical response to omalizumab as no, partial, or complete response. Results: We identified nine studies that described a total of 28 patients (median age, 48 years; males, 54%) with refractory MCAS. Twenty-one patients (75%) had nonclonal MCAS, and seven patients (25%) had clonal MCAS. The omalizumab dose ranged from 150 mg every 4 weeks to 300 mg every 3 weeks, with the most common dose being 150 mg every 2 weeks. Most patients had a partial response (61%), and five patients achieved a complete response. Omalizumab was successful in ameliorating anaphylaxis and allowed for discontinuation of systemic glucocorticoids in two of three patients. The response pattern was not influenced by sex or mast cell clonality, but a complete response was reported more commonly among receivers of a higher omalizumab dose (≥300 mg/month). No major adverse events were reported. Conclusion: The majority of patients with refractory MCAS reported in the literature had a reduction in mast cell mediator-related symptoms with the addition of omalizumab.

The rate of diagnosis of mast cell activation syndrome (MCAS) has increased since the disorder's original description as a mastocytosis-like phenotype. While a set of consortium MCAS criteria is well described and widely accepted, this increase occurs in the setting of a broader set of proposed alternative MCAS criteria.

Effective diagnostic criteria must minimize the range of unrelated diagnoses that can be erroneously classified as the condition of interest. We sought to determine if the symptoms associated with alternative MCAS criteria result in less concise or consistent diagnostic alternatives, reducing diagnostic specificity.

We used multiple large language models, including ChatGPT, Claude, and Gemini, to bootstrap the probabilities of diagnoses that are compatible with consortium or alternative MCAS criteria. We utilized diversity and network analyses to quantify diagnostic precision and specificity compared to control diagnostic criteria including systemic lupus erythematosus, Kawasaki disease, and migraines.

Compared to consortium MCAS criteria, alternative MCAS criteria are associated with more variable (Shannon diversity 5.8 vs 4.6, respectively; P = .004) and less precise (mean Bray-Curtis similarity 0.07 vs 0.19, respectively; P = .004) diagnoses. The diagnosis networks derived from consortium and alternative MCAS criteria had lower between-network similarity compared to the similarity between diagnosis networks derived from 2 distinct systemic lupus erythematosus criteria (cosine similarity 0.55 vs 0.86, respectively; P = .0022).

Alternative MCAS criteria are associated with a distinct set of diagnoses compared to consortium MCAS criteria and have lower diagnostic consistency. This lack of specificity is pronounced in relation to multiple control criteria, raising the concern that alternative criteria could disproportionately contribute to MCAS overdiagnosis, to the exclusion of more appropriate diagnoses.

Mastocytosis is a clonal myeloid disorder defined by an increase and accumulation of mast cells (MCs) in one or multiple organ systems. The complex pathology of mastocytosis results in variable clinical presentations, courses, and outcomes. The World Health Organization (WHO) divides the disease into cutaneous mastocytosis (CM), several forms of systemic mastocytosis (SM), and MC sarcoma. In most patients with SM, a somatic KIT mutation, usually D816V, is identified. Patients diagnosed with CM or nonadvanced SM, including indolent SM, have a near-normal life expectancy, whereas those with advanced SM, including aggressive SM and MC leukemia, have limited life expectancy. Since 2001, a multidisciplinary consensus group consisting of experts from the European Competence Network on Mastocytosis and the American Initiative in Mast Cell Diseases has supported the field by developing diagnostic criteria for mastocytosis. These criteria served as the basis for the WHO classification of mastocytosis over 2 decades. More recently, an International Consensus Classification group proposed slightly modified diagnostic criteria and a slightly revised classification. In this article, these changes are discussed. Furthermore, we propose harmonization among the proposals of the American Initiative in Mast Cell Diseases/European Competence Network on Mastocytosis consensus group, WHO, and the International Consensus Classification Group. Such harmonization will facilitate comparisons of retrospective study results and the conduct of prospective trials.

In patients who require venom immunotherapy (VIT), there is a need to identify underlying mast cell (MC) disorders since these may affect the risk and severity of future sting reactions and the long-term effectiveness of VIT.

1319 individuals with Hymenoptera venom allergy (HVA) who needed VIT from referral centers in Slovenia, Austria, Croatia, and Poland underwent examination for KIT p.D816V in peripheral blood leukocytes (PBL) using a highly sensitive PCR test and tryptase genotyping by digital droplet PCR. We also included 183 control individuals with large local reactions (LLRs) to Hymenoptera stings and with asymptomatic sensitization to Hymenoptera venoms.

285 of 1319 individuals recommended for VIT (21.6%) were positive for KIT p.D816V in PBL, preferably those who present with severe reaction (33.9% [n = 207 of 610] with Ring-Messmer grade 3-4 vs. 11% [n = 78 of 709] with Grade 1-2; p < .0001), whereas only 1.3% (n = 2 of 152) of controls with LLR and none with asymptomatic sensitization (n = 31) had KIT p.D816V. KIT p.D816V allelic burden was higher in those with severe reaction (median 0.018% [n = 207] in Grade 3-4 vs. 0.001% [n = 78] in Grade 1-2; p < .0001), and the majority had normal baseline serum tryptase levels (69% [n = 196 of 285]). All KIT p.D816V-positive individuals (n = 41) who underwent bone marrow (BM) biopsy were found to have underlying clonal diseases, principally BM mastocytosis. HαT was also associated with severe HVA and symptoms (p < .01), and remarkably, 31.0% (n = 31 of 100) were found to have concomitant KIT p.D816V. Concomitant HαT and KIT p.D816V showed an additive effect, and having both was associated with the highest risk for severe HVA, even higher than having either HαT or KIT p.D816V alone (OR = 3.8; p < .01).

By employing prospective universal tryptase genotyping and examination for KIT p.D816V in PBL in large HVA populations, we have demonstrated a high burden of clonal MC disorders and HαT in patients who require VIT.

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve, mortality rates of coronavirus disease 2019 (COVID-19) have significantly decreased. However, a variable proportion of patients exhibit persistent prolonged symptoms of COVID-19 infection (long COVID). This virus primarily attacks respiratory system, but numerous individuals complain persistent skeletal muscle pain or worsening pre-existing muscle pain post COVID-19, which severely affects the quality of life and recovery. Currently, there is limited research on the skeletal muscle pain in long COVID. In this brief review, we review potential pathological mechanisms of skeletal muscle pain in long COVID, and summarize the various auxiliary examinations and treatments for skeletal muscle pain in long COVID. We consider abnormal activation of inflammatory response, myopathy, and neurological damages as pivotal pathological mechanisms of skeletal muscle pain in long COVID. A comprehensive examination is significantly important in order to work out effective treatment plans and relieve skeletal muscle pain. So far, rehabilitation interventions for myalgia in long COVID contain but are not limited to drug, nutraceutical therapy, gut microbiome-targeted therapy, interventional therapy and strength training. Our study provides a potential mechanism reference for clinical researches, highlighting the importance of comprehensive approach and management of skeletal muscle pain in long COVID. The relief of skeletal muscle pain will accelerate rehabilitation process, improve activities of daily living and enhance the quality of life, promoting individuals return to society with profound significance.

Postural orthostatic tachycardia syndrome (POTS) is one of the orthostatic intolerance syndromes that are common in young adolescents and impair quality of life. POTS is a multi-systemic disease. Many mechanisms have been defined in POTS etiology, such as autonomic denervation, hypovolemia, hyperadrenergic stimulation, low condition, and hypervigilance. Recently, mast cell activation (MCA) has also been on the agenda in etiology. There are few studies in the literature on the relationship between MCA and POTS in adulthood. However, data on children and adolescents is limited. In light of this information, we aimed to evaluate the relationship between POTS and MCA by measuring serum tryptase levels, a specific marker for MCA.

This prospective study included patients who were admitted to Kocaeli University Faculty of Medicine Hospital Pediatric Cardiology outpatient clinic for syncope-presyncope between November 2018 and August 2019. Patients who underwent the TILT-table test were enrolled in the study. Patients with structural heart disease or chronic heart disease were not included in this study. Serum tryptase levels were obtained from all patients before the TILT-table test, and serum tryptase levels were re-studied after the test was terminated in patients with positive TILT-table tests for POTS. Patients diagnosed with POTS were classified as Group 1, and other patients were classified as Group 2.

Twenty-eight of the 58 patients included in the study (mean: 14.4±2.0 years; 38 girls, 20 boys) were diagnosed with POTS. The remaining 30 patients were diagnosed with vasovagal syncope and included in Group 2. The increase in mean heart rate during the test was 38±6 beats/min and 47.05%±15.65% in patients with POTS. Basal serum tryptase levels were not different between groups (3.2±1.3 ng/ml and 3.84±1.78 ng/ml, respectively; p=0.129), while serum tryptase levels (both baseline and after 45-60 min of the TILT-table test) were higher in patients presenting with symptoms related to MCA compared to others.

In the literature, MCA was considered to be one of the mechanisms leading to POTS. Although other mechanisms, such as neuropathic and hypovolemic POTS, may be active in the patients, the symptoms of MCA in these patients should be routinely questioned.

Mast cell activation syndrome (MCAS) is a term applied to several clinical entities that have gained increased attention from patients and medical providers. Although several descriptive publications about MCAS exist, there are many gaps in knowledge, resulting in confusion about this clinical syndrome. Whether MCAS is a primary syndrome or exists as a constellation of symptoms in the context of known inflammatory, allergic, or clonal disorders associated with systemic mast cell activation is not well understood. More importantly, the underlying mechanisms and pathways that lead to mast cell activation in MCAS patients remain to be elucidated. Here we summarize the known literature, identify gaps in knowledge, and highlight research needs. Covered topics include contextualization of MCAS and MCAS-like endotypes and related diagnostic evaluations; mechanistic research; management of typical and refractory symptoms; and MCAS-specific education for patients and health care providers.

Initiation of the bradykinin generation cascade is responsible for the occurrence of attacks in some types of angioedema without wheals. Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is one such clinical entity. In this paper, we explore the existing evidence that mast cells (MCs) degranulation may contribute to the activation of the kallikrein-kinin system cascade, followed by bradykinin formation and angioedema. We present the multidirectional effects of MC-derived heparin and other polyanions on the major components of the kinin-kallikrein system, particularly on the factor XII activation. Although, bradykinin- and histamine-mediated symptoms are distinct clinical phenomena, they share some common features, such as some similar triggers and a predilection to occur at sites where mast cells reside, namely the skin and mucous membranes. In addition, recent observations indicate a high incidence of hypersensitivity reactions associated with MC degranulation in the HAE-C1-INH patient population. However, not all of these can be explained by IgE-dependent mechanisms. Mast cell-related G protein-coupled receptor-X2 (MRGPRX2), which has recently attracted scientific interest, may be involved in the activation of MCs through a different pathway. Therefore, we reviewed MRGPRX2 ligands that HAE-C1-INH patients may be exposed to in their daily lives and that may affect MCs degranulation. We also discussed the known inter- and intra-individual variability in the course of HAE-C1-INH in relation to factors responsible for possible variability in the strength of the response to MRGPRX2 receptor stimulation. The above issues raise several questions for future research. It is not known to what extent a prophylactic or therapeutic intervention targeting the pathways of one mechanism (mast cell degranulation) may affect the other (bradykinin production), or whether the number of mast cells at a specific body site and their reactivity to triggers such as pressure, allergens or MRGPRX2 agonists may influence the occurrence of HAE-C1-INH attacks at that site.

Mast cell activation syndrome (MCAS) is a clinical disorder that may explain irritable bowel syndrome (IBS) type symptoms as well as other allergic symptoms experienced by an individual. The diagnosis and treatment of MCAS with specific focus on gastrointestinal (GI) manifestations is reviewed.

Although biomarkers for MCAS remain elusive, testing for baseline serum tryptase will distinguish the type of mast cell disorder and urine tests for mast cell mediator metabolites may support the diagnosis. Endoscopy and Colonoscopy with biopsies is not used to diagnose MCAS but is important to rule out other conditions that may cause symptoms. There is increased awareness of the association between MCAS and autonomic dysfunction, small fiber neuropathy, and connective tissue disorders which all impact GI symptoms. MCAS is a disorder often of unknown etiology (idiopathic) and characterized by intermittent allergy type symptoms that affect multiple organ systems after exposure to a trigger. GI symptoms including abdominal cramping and loose stool are prominent and mimic those of IBS. Diagnostic testing is performed to assess for elevations in mast cell mediators during symptoms and to rule out other conditions. A comprehensive treatment plan includes medications that target mast cells, treatments for associated conditions including autonomic dysfunction, and management of comorbid psychiatric illness and nutritional deficits.

2,3-dinor 11β-Prostaglandin F2α (BPG) is an arachidonic acid derivative and the most abundant metabolic byproduct of prostaglandin D2, which is released during mast cell activation. Therefore, measurements of BPG in urine using liquid chromatography-tandem mass spectrometry (LC-MS/MS) provide a noninvasive method for evaluation and management of mast cell disorders. Measurements obtained by LC-MS/MS exhibit a high prevalence of chromatographic interferences resulting in challenges with optimal determination of BGP. In this investigation, differential mobility spectrometry (DMS) is utilized to overcome the limitations of current testing.

Urine samples were extracted using an automated solid-phase extraction method. Samples were then analyzed with and without DMS devices installed on two commercially available mass spectrometry platforms to assess the benefits of DMS. Following promising results from a preliminary analytical evaluation, LC-DMS-MS/MS measurements of BPG in urine were fully validated to assess the analytical implications of using this technology.

The addition of DMS devices to the LC-MS/MS systems evaluated in this investigation significantly reduced interferences observed in the chromatograms. Concomitantly, DMS reduced the number of discordant quantifier/qualifier fragment ion results that significantly exceeded the ± 20 % limits, suggesting greater analytical specificity. The validation studies yielded low interday imprecision, with %CVs less than 6.5 % across 20 replicate measurements. Validation studies assessing other aspects of analytical performance also met acceptance criteria.

Incorporating DMS devices greatly improved the specificity of BPG measurements by LC-MS/MS, as evidenced by the comparison of chromatograms and fragment ion results. Validation studies showed exceptional performance for established analytical metrics, indicating that this technology can be used to minimize the impact of interferences without adversely impacting other aspects of analytical or clinical performance.

Mast cells (MC) are ubiquitous in the body, and they are critical for not only in allergic diseases but also in immunity and inflammation, including having potential involvement in the pathophysiology of dysautonomias and neuroinflammatory disorders. MC are located perivascularly close to nerve endings and sites such as the carotid bodies, heart, hypothalamus, the pineal gland, and the adrenal gland that would allow them not only to regulate but also to be affected by the autonomic nervous system (ANS). MC are stimulated not only by allergens but also many other triggers including some from the ANS that can affect MC release of neurosensitizing, proinflammatory, and vasoactive mediators. Hence, MC may be able to regulate homeostatic functions that seem to be dysfunctional in many conditions, such as postural orthostatic tachycardia syndrome, autism spectrum disorder, myalgic encephalomyelitis/chronic fatigue syndrome, and Long-COVID syndrome. The evidence indicates that there is a possible association between these conditions and diseases associated with MC activation. There is no effective treatment for any form of these conditions other than minimizing symptoms. Given the many ways MC could be activated and the numerous mediators released, it would be important to develop ways to inhibit stimulation of MC and the release of ANS-relevant mediators.

Mast cell (MC) activation syndromes (MCAS) are conditions defined by recurrent episodes of severe systemic anaphylaxis or similar systemic events triggered by MC-derived mediators that can be measured in biological fluids. Since some symptoms of MC activation may occur due to other, non-MC etiologies and lead to confusion over diagnosis, it is of crucial importance to document the involvement of MC and their products in the patients´ symptomatology.

The most specific and generally accepted marker of severe systemic MC activation is an event-related, transient increase in the serum tryptase level over the individual baseline of the affected individual. However, baseline concentrations of serum tryptase vary among donors, depending on the genetic background, age, kidney function, and underlying disease. As a result, it is of critical importance to provide a flexible equation that defines the diagnostic increase in tryptase qualifying as MCAS criterion in all patients, all situations, and all ranges of baseline serum tryptase. In 2012, the consensus group proposed the 120% + 2 ng/ml formula, which covers the great majority of groups, including cases with low, normal, or elevated basal serum tryptase level. This formula has been validated in subsequent studies and has proven to be a robust and consistent diagnostic criterion of MCAS. The present article is discussing the impact of this formula and possible limitations as well as alternative markers and mediators that may be indicative of MCAS.

Provide an overview of the expanding landscape of mast cell (MC)-targeting treatments in mast cell activation syndromes (MCAS).

Tyrosine-kinase inhibitors (TKIs) targeting wild-type and mutated KIT can efficiently induce MC depletion. Avapritinib and midostaurin can also temper IgE-mediated degranulation. Avapritinib has been recently approved by the FDA for the treatment of indolent systemic mastocytosis (ISM). Targeting activation pathways and inhibitory receptors is a promising therapeutic frontier. Recently, the anti Siglec-8 antibody lirentelimab showed promising results in ISM. MCAS is a heterogeneous disorder demanding a personalized therapeutic approach and, especially when presenting as anaphylaxis, has not been formally captured as outcome in prospective clinical trials with TKI. Long-term safety of TKI needs to be addressed. New drugs under investigation in diseases in which non-neoplastic MCs play a pivotal role can provide important inputs to identify new efficient and safe treatments for MCAS.

The current article aims to provide a comprehensive update on diagnostic criteria for mast cell activation syndrome (MCAS), addressing challenges in diagnosing and classifying MCAS and its variants.

In recent years, there has been a significant increase in our knowledge regarding the underlying mechanisms responsible for the activation of mast cells (MCs) in various pathological conditions. Furthermore, a set of criteria and a classification for MCASs have been established. MCAS is characterized by the presence of typical clinical symptoms, a substantial elevation in serum tryptase levels during an attack compared to the patient's baseline tryptase levels, and a response to MC mediator-targeting therapy. In this report, a thorough examination was conducted on the contemporary literature relating to MCAS, with a focus on comparing the specificity, sensitivity, and robustness of MCAS-related parameters within proposals for diagnosing and classifying MCAS and its variants. Moreover, the significance of employing specific consensus criteria in the assessment and categorization of MCAS in individual patients was underscored, due to the escalating occurrence of patients receiving a misdiagnosis of MCAS based on nonspecific criteria.

Mast cell (MC) activation can present with a wide range of symptoms. The mechanisms that cause such activation are varied. One of them is the presence of clonal MCs which is defined, within other possible changes, by the presence of a somatic, activating mutation in the KIT gene. The clinical course and prognosis of patients with this underlying disease may be different from other causes of MC activation (MCA). For this reason, it is important to early diagnose, or at least suspect, which patients with MCA are due to clonal MCs.

The diagnosis of clonality must be made in a comprehensive manner. However, this paper reviews chronologically each of the stages from the patient's first visit to the doctor's office which can be indicative of clonality: clinical presentation of MCA, physical examination, analytical determinations of tryptase, and/or KIT mutational analysis and bone involvement, among others. The different clonality predictive scores proposed are also reviewed and compared. Although the gold standard for the diagnosis of certainty of MC clonality is the performance of a bone marrow (BM) biopsy, there are clinical symptoms, signs, and biological parameters suggestive of clonality, as well as predictive scores, which can guide (or rule out) an early diagnosis and avoid unnecessary BM biopsies.

Chronic urticaria (CU) is a mast cell (MC)-dependent disease with limited therapeutic options. Current management strategies are directed at inhibiting IgE-mediated activation of MCs and antagonizing effects of released mediators. Due to the complexity and heterogeneity of CU and other MC diseases and mechanisms of MC activation-including multiple activating receptors and ligands, diverse signaling pathways, and a menagerie of mediators-strategies of MC depletion or MC silencing (i.e., inhibition of MC activation via binding of inhibitory receptors) have been developed to overcome limitations of singularly targeted agents. MC silencers, such as agonist monoclonal antibodies that engage inhibitory receptors (e.g., sialic acid-binding immunoglobulin-like lectin8 -[Siglec-8] [lirentelimab/AK002], Siglec-6 [AK006], and CD200R [LY3454738]), have reached preclinical and clinical stages of development. In this review, we (1) describe the role of MCs in the pathogenesis of CU, highlighting similarities with other MC diseases in disease mechanisms and response to treatment; (2) explore current therapeutic strategies, categorized by nonspecific immunosuppression, targeted inhibition of MC activation or mediators, and targeted modulation of MC activity; and (3) introduce the concept of MC silencing as an emerging strategy that could selectively block activation of MCs without eliciting or exacerbating on- or off-target, immunosuppressive adverse effects.

Experts of the European Competence Network on Mastocytosis (ECNM) and the American Initiative on Mast Cell Disorders have discussed and updated diagnostic criteria and the classification of mastocytosis, based on new insights in the field and data collected in recent years, mostly within ECNM registry projects in which studies on several thousand cases have been performed. Based on this proposal, the World Health Organization has updated its classification of mastocytosis. This article discusses the revised classification of mastocytosis in light of a rapidly moving field and the advent of new diagnostic parameters, new prognostication tools, and new therapies.

Mastocytosis is characterized by expansion and activation of clonally aberrant mast cells (MCs) in one or more organ systems. Inappropriate MC activation is a key finding in both allergy and mastocytosis; therefore, symptoms in both conditions show some degree of overlap. When mediator release is excessive and involves multiple systems, anaphylaxis may occur. In mastocytosis, the prevalence of atopy is similar to those of the general population, whereas the incidence of anaphylaxis is significantly higher. The purpose of this review is to discuss features of allergy and anaphylaxis as well as the principles of managing MC mediator release symptoms in mastocytosis.

Our knowledge of biology and mast cell (MC) function, as well as disorders associated with the pathologic activation of MCs, has evolved over the last few decades. Anaphylaxis, mast cell activation syndrome (MCAS), and mastocytosis are interrelated yet distinct conditions within the spectrum of mast cell activation disorders. Nevertheless, all three conditions can co-exist in one and the same patient, as pathologic MC activation is the key finding in all three. When mediator release is excessive and involves multiple systems, anaphylaxis and MCAS may occur. Furthermore, mastocytosis is a clonal disorder of MCs and often presents with anaphylaxis and MCAS. Nevertheless, in some cases, even the proliferative and accumulative features of MCs in mastocytosis can account for symptoms and disease progression. In each case, diagnosis can be only made when the diagnostic consensus criteria are fulfilled. The current article aims to provide a concise clinical update and pinpoint the main difficulties in diagnosing these puzzling disorders of MCs in medical practice.

Familial Mediterranean Fever (FMF) is the most frequent monogenic autoinflammatory disease (AID). Some patients have persistent symptoms despite colchicine intake. Mast cells (MC) are innate immune cells involved in inflammatory conditions including AID. Their activation is responsible for various symptoms such as abdominal pain, bloating and pruritus.

Our objective was to evaluate features of a systemic MC activation in FMF adult patients.

FMF adult patients prospectively filled a MC activation survey and usual MC mediators (tryptase and histamine in whole blood, plasma and urine) were measured. They were compared with a healthy control group (HC) and a systemic mastocytosis (SM) group. When digestive biopsies were realized during follow-up, MC infiltration in digestive mucosa was analyzed in FMF, in comparison with SM, Crohn disease (CD) and normal biopsies.

Forty-four FMF patients, 44 HC and 44 SM patients were included. Thirty-one (70%) FMF patients had symptoms of mast cell activation, versus 14 (32%) in the HC group (p = 0.0006). Thirty (68%) FMF patients had at least one elevated MC mediator: mainly whole blood histamine, in 19 (43%) and urinary histamine, in 14 (32%), which were significantly higher than in HC subjects. MC infiltration was comparable in FMF digestive biopsies, biopsies of CD and normal biopsies but was lower than in SM biopsies.

FMF patients show frequent symptoms of MC activation and an increase of blood or urinary histamine never described before in this disease. This suggests an implication of MC and possibly basophils in FMF pathophysiology.

Physiological levels of basal serum tryptase vary among healthy individuals, depending on the numbers of mast cells, basal secretion rate, copy numbers of the TPSAB1 gene encoding alpha tryptase, and renal function. Recently, there has been a growing debate about the normal range of tryptase because individuals with the hereditary alpha tryptasemia (HαT) trait may or may not be symptomatic, and if symptomatic, uncertainty exists as to whether this trait directly causes clinical phenotypes or aggravates certain conditions. In fact, most HαT-positive cases are regarded as asymptomatic concerning mast cell activation. To address this point, experts of the European Competence Network on Mastocytosis (ECNM) and the American Initiative in Mast Cell Diseases met at the 2022 Annual ECNM meeting and discussed the physiological tryptase range. Based on this discussion, our faculty concluded that the normal serum tryptase range should be defined in asymptomatic controls, inclusive of individuals with HαT, and based on 2 SDs covering the 95% confidence interval. By applying this definition in a literature screen, the normal basal tryptase in asymptomatic controls (HαT-positive persons included) ranges between 1 and 15 ng/mL. This definition should avoid overinterpretation, unnecessary referrals, and unnecessary anxiety or anticipatory fear of illness in healthy individuals.

Mast Cell Activation Syndrome (MCAS) is only a recently recognized, multisystem disorder that has been historically underrecognized due its estimated high prevalence. Recognition, testing, and treatment all pose unique challenges to condition management. The condition warrants more concern due to its prevalence and under recognition. Of equal importance in this case is the overlap seen between conditions such as MCAS, gastric dysmotility often manifesting as small intestine bacterial overgrowth (SIBO), dysautonomia, joint hypermobility disorders such as hypermobile Ehlers Danlos Syndrome (h-EDS) or other hypermobility spectrum disorders (HSD), and autoimmunity. This case involves a 42 year-old female who initially presented to the clinic for chronic SIBO and associated gastrointestinal complaints. Upon further examination into the patient's history and unique presentation as visits progressed, important factors affecting treatment considerations were discovered. The patient was ultimately deemed to have other associated conditions including a mast cell-mediated disorder as well as joint hypermobility due to her response to antihistamine and mast cell stabilizing agents. Final outcomes include immense improvement upon mast cell stabilization with ketotifen, and remission of SIBO with low-dose naltrexone (LDN). Although the patient did not undergo testing beyond a serum tryptase test, this case represents the importance of careful history taking and the role of clinical suspicion on patient outcomes.

One requirement for diagnosing mast cell activation syndrome (MCAS) is an increase, above an established baseline level, in serum tryptase by 20% plus 2 ng/mL. However, there is no consensus of what constitutes excretion of a substantial increase in metabolites from prostaglandin D2, histamine, or leukotriene E4 in MCAS.

Ratios of acute/baseline levels for each urinary metabolite that accompanied tryptase increases of 20% plus 2 ng/mL were determined.

Mayo Clinic databases of patients with systemic mastocytosis with or without MCAS were reviewed. Patients with the requisite increase in serum tryptase during MCAS were examined for those who also had acute/baseline measurements of urinary mediator metabolite(s).

Ratios of acute/baseline levels for tryptase and for each urinary metabolite were calculated. For all patients, the average acute/baseline ratio (SD) for tryptase was 4.88 (3.77). Average ratios of urinary mediator metabolites were: leukotriene E4: 35.98 (50.59), 2,3-dinor-11β-prostaglandin F2α: 7.28 (6.89), and N-methyl histamine: 3.2 (2.31). The lowest acute-baseline ratios for each of the three metabolites accompanying a tryptase increase of 20% plus 2 ng/mL were similar, with values of about 1.3.

To the author's knowledge, this is the largest series of mast cell mediator metabolite measurements during episodes of MCAS that were verified by the requisite tryptase increase above baseline. Unexpectedly, leukotriene E4 showed the greatest average increase. Acute/baseline increase of 1.3 or greater in any of these mediators could be useful for corroborating a diagnosis of MCAS.

Mast cells (MCs) are infamous for their role in potentially fatal anaphylaxis reactions. In the last two decades, a more complex picture has emerged, as it has become obvious that MCs are much more than just IgE effectors of anaphylaxis. MCs are defenders against a host of infectious and toxic aggressions (their interactions with other components of the immune system are not yet fully understood) and after the insult has ended, MCs continue to play a role in inflammation regulation and tissue repair. Unfortunately, MC involvement in pathology is also significant. Apart from their role in allergies, MCs can proliferate clonally to produce systemic mastocytosis. They have also been implicated in excessive fibrosis, keloid scaring, graft rejection and chronic inflammation, especially at the level of the skin and gut. In recent years, the term MC activation syndrome (MCAS) was proposed to account for symptoms caused by MC activation, and clear diagnostic criteria have been defined. However, not all authors agree with these criteria, as some find them too restrictive, potentially leaving much of the MC-related pathology unaccounted for. Here, we review the current knowledge on the physiological and pathological roles of MCs, with a dermatological emphasis, and discuss the MCAS classification.

In 2002, the European Competence Network on Mastocytosis (ECNM) was launched as a multidisciplinary collaborative initiative to increase the awareness and to improve diagnosis and management of patients with mast cell (MC) disorders. The ECNM consists of a net of specialized centers, expert physicians, and scientists who dedicate their work to MC diseases. One essential aim of the ECNM is to timely distribute all available information about the disease to patients, doctors, and scientists. In the past 20 years, the ECNM has expanded substantially and contributed successfully to the development of new diagnostic concepts, and to the classification, prognostication, and treatments of patients with mastocytosis and MC activation disorders. The ECNM also organized annual meetings and several working conferences, thereby supporting the development of the World Health Organization classification between 2002 and 2022. In addition, the ECNM established a robust and rapidly expanding patient registry and supported the development of new prognostic scoring systems and new treatment approaches. In all projects, ECNM representatives collaborated closely with their U.S. colleagues, various patient organizations, and other scientific networks. Finally, ECNM members have started several collaborations with industrial partners, leading to the preclinical development and clinical testing of KIT-targeting drugs in systemic mastocytosis, and some of these drugs received licensing approval in recent years. All these networking activities and collaborations have strengthened the ECNM and supported our efforts to increase awareness of MC disorders and to improve diagnosis, prognostication, and therapy in patients.

Mastocytosis is a heterogeneous neoplasm characterized by accumulation of neoplastic mast cells in various organs. There are three main types: cutaneous mastocytosis (CM), systemic mastocytosis (SM), and mast cell sarcoma. CM mainly affects children and is confined to the skin, whereas SM affects adults and is characterized by extracutaneous involvement, with or without cutaneous involvement. Most cases of SM have an indolent clinical course; however, some types of SM have aggressive behavior and a poor prognosis. Recent advances in the understanding of the molecular changes in SM have changed the diagnosis and treatment of aggressive and advanced SM subtypes. The International Consensus Classification and World Health Organization refined the diagnostic criteria and classification of SM as a result of accumulation of clinical experience and advances in molecular diagnostics. Somatic mutations in the KIT gene, most frequently KIT D816V, are detected in 90% of patients with SM. Expression of CD30 and any KIT mutation were introduced as minor diagnostic criteria after the introduction of highly sensitive screening methods. SM has a wide spectrum of clinical features, and only a few drugs are effective at treating advanced SM. Currently, the mainstay of SM treatment is limited to the management of chronic symptoms related to release of mast cell mediators. Small-molecule kinase inhibitors targeting the KIT-downstream and KIT-independent pathways were recently approved for treating advanced SM. I describe recent advances in diagnosis of SM, and review the currently available and emerging therapeutic options for SM management.

Under physiological conditions, skin mast cells play an important role as guardians that quickly react to stimuli that disturb homeostasis. These cells efficiently support, fight infection, and heal the injured tissue. The substances secreted by mast cells allow for communication inside the body, including the immune, nervous, and blood systems. Pathologically non-cancerous mast cells participate in allergic processes but also may promote the development of autoinflammatory or neoplastic disease. In this article, we review the current literature regarding the role of mast cells in autoinflammatory, allergic, neoplastic skin disease, as well as the importance of these cells in systemic diseases with a pronounced course with skin symptoms.

Orthostatic intolerance and other autonomic dysfunction syndromes are emerging as distinct symptom clusters in Long Covid. Often accompanying these are common, multi-system constitutional features such as fatigue, malaise and skin rashes which can signify generalized immune dysregulation. At the same time, multiple autoantibodies are identified in both Covid-related autonomic disorders and non-Covid autonomic disorders, implying a possible underlying autoimmune pathology. The lack of specificity of these findings precludes direct interpretations of cause and association, but their prevalence with its supporting evidence is compelling.

Mast cells are residents of the tubular gastrointestinal (GI) tract, where they play an important role in host defence and other vital functions. Dysregulation of mast cells has been implicated in the pathogenesis of several neoplastic, inflammatory, and functional disorders, some of which may manifest with GI symptoms. Surgical pathologists must therefore confront when and how to evaluate GI biopsies for mast cells, and whether such decisions should be based on morphologic criteria, clinical context, or direct request from clinical colleagues. The pathologist's role in evaluation of mast cell infiltrates is best defined in the diagnosis of systemic mastocytosis, where the utility of morphologic assessment coupled with ancillary studies is well established. In contrast, in nonneoplastic mast cell disorders such as mast cell activation syndrome, irritable bowel syndrome, or so-called 'mastocytic enterocolitis', a role for histopathology, if any, is controversial. Despite this, pathologists have seen a sharp increase in requests for mast cell quantification in the latter setting, despite these requests not being supported by published evidence. Moreover, what constitutes a 'normal' number of mast cells in a luminal GI biopsy is not well established. As a result, there is considerable variation in how these requests are handled in practice. This review evaluates and summarizes the published evidence relating to mast cell evaluation in endoscopic GI biopsies in various clinical scenarios, with a goal of providing practical, evidence-based guidance for the surgical pathologist when approached with requests for mast cell quantification in GI biopsies.

Mastocytosis is a heterogeneous group of neoplasms defined by a numerical increase and accumulation of clonal mast cells (MCs) in various organ systems. The disease may present as cutaneous mastocytosis or systemic mastocytosis (SM). On the basis of histopathological and molecular features, clinical variables, and organ involvement, SM is divided into indolent SM, smoldering SM, SM with an associated hematologic neoplasm, aggressive SM, and MC leukemia. Each variant is defined by unique diagnostic criteria and a unique spectrum of clinical presentations. A key driver of MC expansion and disease evolution is the oncogenic machinery triggered by mutant forms of KIT. The genetic background, additional somatic mutations, and comorbidities also contribute to the course and prognosis. Patients with SM may also suffer from mediator-related symptoms or even an MC activation syndrome. This article provides an update of concepts on the genetics, etiology, and pathology of mastocytosis, with emphasis on diagnostic criteria and new treatment concepts.

Mast cell disorders include mastocytosis and mast cell activation syndromes. Mastocytosis is a rare clonal disorder of the mast cell, driven by KIT D816V mutation in most cases. Mastocytosis is diagnosed and classified according to World Health Organization criteria. Mast cell activation syndromes encompass a diverse group of disorders and may have clonal or nonclonal etiologies. Hematologists may be consulted to assist in the diagnostic workup and/or management of mast cell disorders. A consult to the hematologist for mast cell disorders may provoke anxiety due to the rare nature of these diseases and the management of nonhematologic mast cell activation symptoms. This article presents recommendations on how to approach the diagnosis and management of patients referred for common clinical scenarios.

Most COVID-19 patients recovered with low mortality; however, some patients experienced long-term symptoms described as "long-COVID" or "Post-COVID syndrome" (PCS). Patients may have persisting symptoms for weeks after acute SARS-CoV-2 infection, including dyspnea, fatigue, myalgia, insomnia, cognitive and olfactory disorders. These symptoms may last for months in some patients. PCS may progress in association with the development of mast cell activation syndrome (MCAS), which is a distinct kind of mast cell activation disorder, characterized by hyper-activation of mast cells with inappropriate and excessive release of chemical mediators. COVID-19 survivors, mainly women, and patients with persistent severe fatigue for 10 weeks after recovery with a history of neuropsychiatric disorders are more prone to develop PCS. High D-dimer levels and blood urea nitrogen were observed to be risk factors associated with pulmonary dysfunction in COVID-19 survivors 3 months post-hospital discharge with the development of PCS. PCS has systemic manifestations that resolve with time with no further complications. However, the final outcomes of PCS are chiefly unknown. Persistence of inflammatory reactions, autoimmune mimicry, and reactivation of pathogens together with host microbiome alterations may contribute to the development of PCS. The deregulated release of inflammatory mediators in MCAS produces extraordinary symptoms in patients with PCS. The development of MCAS during the course of SARS-CoV-2 infection is correlated to COVID-19 severity and the development of PCS. Therefore, MCAS is treated by antihistamines, inhibition of synthesis of mediators, inhibition of mediator release, and inhibition of degranulation of mast cells.

Sinus tachycardia (ST) is ubiquitous, but its presence outside of normal physiological triggers in otherwise healthy individuals remains a commonly encountered phenomenon in medical practice. In many cases, ST can be readily explained by a current medical condition that precipitates an increase in the sinus rate, but ST at rest without physiological triggers may also represent a spectrum of normal. In other cases, ST may not have an easily explainable cause but may represent serious underlying pathology and can be associated with intolerable symptoms. The classification of ST, consideration of possible etiologies, as well as the decisions of when and how to intervene can be difficult. ST can be classified as secondary to a specific, usually treatable, medical condition (eg, pulmonary embolism, anemia, infection, or hyperthyroidism) or be related to several incompletely defined conditions (eg, inappropriate ST, postural tachycardia syndrome, mast cell disorder, or post-COVID syndrome). While cardiologists and cardiac electrophysiologists often evaluate patients with symptoms associated with persistent or paroxysmal ST, an optimal approach remains uncertain. Due to the many possible conditions associated with ST, and an overlap in medical specialists who see these patients, the inclusion of experts in different fields is essential for a more comprehensive understanding. This article is unique in that it was composed by international experts in Neurology, Psychology, Autonomic Medicine, Allergy and Immunology, Exercise Physiology, Pulmonology and Critical Care Medicine, Endocrinology, Cardiology, and Cardiac Electrophysiology in the hope that it will facilitate a more complete understanding and thereby result in the better care of patients with ST.