Search

Patients with systemic mastocytosis often have symptoms of mast cell activation, which is associated with elevated levels of urinary mast cell mediator metabolites. Patients with hereditary α-tryptasemia (HαT) may present with symptoms of mast cell activation. Whether levels of mast cell mediators are elevated in this patient population is not known.The purpose of this study was to determine whether patients with HαT and symptoms of mast cell activation have elevated levels of urinary mediators and compare the levels with those in patients with systemic mastocytosis.We retrospectively analyzed mast cell mediators in 63 patients with a confirmed diagnosis of HαT, 20 patients with a confirmed diagnosis of indolent systemic mastocytosis (ISM), and 23 healthy controls. All patients were referred to the Brigham and Women's Hospital Mastocytosis Center or the Mayo Clinic for evaluation of mast cell activation disorders.Our population was predominantly female (85.7%) with an average age of 53.8 years. The average baseline serum tryptase level was significantly higher in patients with ISM than in those with HαT (65.9 vs 19.3 ng/mL [P lt; .01]). When compared with patients with HαT, those with ISM had statistically significant increases in their levels of urinary N-methylhistamine (P lt; .01) and 2,3-dinor-11β-prostaglandin F2α (P lt; .05).Patients with symptomatic HαT do not have elevations of mast cell urinary metabolites, suggesting that granule- and membrane-derived mediators may not drive symptoms in HαT.

Idiopathic anaphylaxis is a condition caused by paroxysmal episodes of sudden-onset multiorgan involvement variably including laryngeal edema, urticaria, bronchoconstriction, dyspnea, hypoxia, abdominal pain, nausea, vomiting, diarrhea, and hypotension. Rarely, the episodes can lead to cardiovascular collapse and death in the absence of a clear trigger, especially in the presence of other cardiovascular comorbidities. Elevated mast cell mediators such as tryptase and histamine have been reported during episodes, and mast cells are considered the primary cells responsible for driving anaphylaxis in humans. Basophils also secrete histamine and LTC4 when activated and theoretically can contribute to symptoms. As our understanding of mast cell disorders continue to grow, the classification for these disorders evolves. The purpose of this article was 2-fold: to review the epidemiology, clinical manifestations, and diagnosis of idiopathic anaphylaxis and to discuss the classification of idiopathic anaphylaxis within the broader context of mast cell activation disorders.

Mast cell disorders including hereditary alpha tryptasemia (HαT) and idiopathic mast cell activation syndrome (MCAS) can be associated with neurologic symptoms such as orthostatic intolerance, pain, and cognitive impairment. The origin of these symptoms is not well understood.To characterize neurologic findings in patients with HαT and MCAS through objective measurements.Patients with a confirmed diagnosis of HαT or MCAS with neurologic symptoms were referred for standardized autonomic testing encompassing Valsalva maneuver, deep breathing, sudomotor and tilt tests with cerebral blood flow velocity (CBFv) determination, and skin biopsies for small fiber neuropathy (SFN).There were 15 patients with HαT (age 44.4 ± 15.9 years), 16 with MCAS (34.4 ± 15.5), and 14 matched controls who were evaluated. Baseline serum tryptase level was increased in patients with HαT when compared with patients with MCAS (14.3 ± 2.5 ng/mL vs 3.8 ± 1.8; P.001) and neurologic symptoms were similar between the 2 groups. When compared with controls, orthostatic CBFv was reduced in HαT (-24.2 ± 14.3%; P.001) and MCAS (-20.8 ± 5.5%; P.001). Reduced nerve fibers consistent with SFN were found in 80% of patients with HαT and 81% of those with MCAS. Mild-to-moderate dysautonomia was detected in all patients with HαT and MCAS when results of sympathetic, parasympathetic, and sudomotor tests were combined.We provide evidence of reduced orthostatic CBFv and SFN associated with mild-to-moderate autonomic dysfunction in patients with HαT and MCAS. Our findings suggest that comprehensive autonomic testing may be helpful to explain neurologic symptoms and guide treatment in patients with HαT and MCAS.

Systemic mastocytosis (SM) is a myeloproliferative disorder characterized by symptoms of mast cell (MC) activation and/or organ dysfunction related to MC tissue accumulation. Treatment of this condition is evolving as our understanding of the pathophysiology of the disease advances. This article aims to highlight novel and experimental therapies for SM.PubMed literature search and ClinicalTrials.gov.Peer-reviewed studies involving therapies for SM were included. There was a particular focus on preclinical and clinical trial studies.SM presents with a wide range of symptoms including symptoms of MC activation such as anaphylaxis, urticaria, diarrhea, and organ failure secondary to aggressive tissue infiltration. The treatment of the disease is dependent on the variant; patients with aggressive disease warrant advanced therapies and higher tolerance of adverse effects. As our understanding of the disease has advanced, several novel therapeutic options have emerged. These include tyrosine kinase inhibitors directed at the KIT protein and targeted monoclonal antibodies, which decrease MC activation or reduce mast cell burden. There are a variety of new medications under development that will revolutionize the treatment for patients with SM.Current treatment options for SM have inherent limitations and, in many cases, unacceptable adverse effects. As our molecular understanding of the disease advances, novel, and experimental therapies are changing treatment paradigms of the disease.

Mast cells (MCs) play a pathobiologic role in type 2 (T2) allergic inflammatory diseases of the airway, including asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP). Distinct MC subsets infiltrate the airway mucosa in T2 disease, including subepithelial MCs expressing the proteases tryptase and chymase (MC(TC)) and epithelial MCs expressing tryptase without chymase (MC(T)). However, mechanisms underlying MC expansion and the transcriptional programs underlying their heterogeneity are poorly understood. Here we use flow cytometry and single-cell RNA-sequencing (scRNA-seq) to conduct a comprehensive analysis of human MC hyperplasia in CRSwNP, a T2 cytokine-mediated inflammatory disease. We link discrete cell surface phenotypes to the distinct transcriptomes of CRSwNP MC(T) and MC(TC), which represent polarized ends of a transcriptional gradient of nasal polyp MCs. We discover a subepithelial population of CD38(high)CD117(high) MCs that is markedly expanded during T2 inflammation. These CD38(high)CD117(high) MCs exhibit an intermediate phenotype relative to the expanded MC(T) and MC(TC) subsets. CD38(high)CD117(high) MCs are distinct from circulating MC progenitors and are enriched for proliferation, which is markedly increased in CRSwNP patients with aspirin-exacerbated respiratory disease (AERD), a severe disease subset characterized by increased MC burden and elevated MC activation. We observe that MCs expressing a polyp MC(T)-like effector program are also found within the lung during fibrotic diseases and asthma, and further identify marked differences between MC(TC) in nasal polyps and skin. These results indicate that MCs display distinct inflammation-associated effector programs and suggest in situ MC proliferation is a major component of MC hyperplasia in human T2 inflammation.

SARS-CoV-2 is a novel coronavirus responsible for the clinical syndrome COVID-19. This virus was initially recognized in December 2019 in Wuhan, China and has since spread leading to a global pandemic. Mast cells (MCs) are tissue resident innate immune cells that play a pathobiologic role in a range of diseases, such as asthma, rhinitis and food allergy and MC activation disorders. MC activation leads to the release of inflammatory mediators, including tryptase and several cytokines such as interleukin (IL)-6. MCs are often active participants in propagation of inflammation during viral infection.(1) Reports of serious COVID-19 infections have identified IL-6, TNF and IL-1β as hallmarks of cytokine storm leading to severe outcomes.(2) MCs are a source of IL-6 and other proinflammatory mediators, leading to the possibility of MCs directly contributing to the severity of SARS-CoV-2 infection. However, studies involving allergic asthma, a disease associated with increased lung MC numbers and activation, have not shown an increased risk for severe outcomes.(3) Thus, the role of MCs in SARS-CoV-2 infection remains unknown.

Mast cells (MCs) are important in intestinal homeostasis and pathogen defense but are also implicated in many of the clinical manifestations in disorders such as irritable bowel syndrome. The utility of specifically staining for MCs in order to quantify and phenotype them in intestinal biopsies in patients with gastrointestinal (GI) symptoms is controversial and is not a widely adopted practice. Whether or not intestinal MCs are increased or have a unique phenotype in individuals with hereditary alpha-tryptasemia (HαT), who have extra copies of the mast cell tryptase gene TPSAB1 and typically elevated baseline serum tryptase levels >8ng/mL is not known. We examined the duodenal biopsies of 17 patients with HαT and compared them to 15 patients with mast cell activation syndrome who had baseline serum tryptases

Background Hereditary alpha-tryptasemia (HαT) is an autosomal dominant genetic trait characterized by multiple copies of the alpha-tryptase gene at the TPSAB1 locus. Previously described symptomatology involves multiple organ systems and anaphylaxis. The spectrum of mast cell activation symptoms is unknown, as is its association with specific genotypes. Objective To describe clinical, laboratory, and genetic characteristics of patients referred for the evaluation of mast cell activation–related symptoms and genotype-confirmed HαT. Methods We retrospectively describe clinical characteristics, baseline tryptase, and tryptase genotype in 101 patients. Patients were referred for mast cell activation–related symptoms and underwent genotyping to confirm diagnosis of HαT. Results Of 101 patients, 80% were female with average tryptase of 17.2 ng/mL. Tryptase was less than 11.4 ng/mL in 8.9% and greater than 20 ng/mL in 22.3% (range 6.2-51.3 ng/mL). KIT D816V mutation was negative in all subjects tested. 2α:3β was the most common genotype but did not correlate with tryptase levels. Unprovoked anaphylaxis was noted in 57% of the subjects with heterogeneous genotypes. Most common symptoms include gastrointestinal, cutaneous, psychiatric, pulmonary, cardiovascular, and neurologic. A total of 85% of patients were taking H1- or H2-antihistamines with partial symptom relief. Omalizumab was effective at suppressing anaphylaxis or urticaria in 94% of the patients. Conclusion HαT encompasses a broad range of baseline tryptase and should be considered in patients with symptoms of mast cell activation and tryptase levels greater than 6.2 ng/mL. Patients may present with complex symptomatology including cutaneous, gastrointestinal, neurologic, and psychiatric symptoms and anaphylaxis, some of which respond to omalizumab.

Background: Patients with mast cell (MC) activation symptoms and elevated baseline serum tryptase level (MCAS-T) may not necessarily have a clonal MC disorder. Many are diagnosed with hereditary a-tryptasemia (HaT), a genetic trait characterized by autosomal dominant inheritance of multiple copies of TPSAB1 encoding a-tryptase and increased risk for severe anaphylaxis.Objective: The aim of our study was to identify and characterize bone marrow MC histopathologic features specific for MCAS-T.Methods: A total of 43 patients with MCAS-T underwent evaluation, including bone marrow biopsy, for a MC disorder. The results of the work-up for clonal MC disorders such as systemic mastocytosis and monoclonal MC activation syndrome were negative. Bone marrow MC histopathology was reviewed to identify characteristic features of MCAS-T. A subgroup of patients was available for tryptase genotyping.Results: Patients with MCAS-T showed unique morphologic and histologic features when compared with controls. MCs were larger (P < .01), hypogranular (P < .01), frequently detected in paratrabecular (P < .05) and perivascular (P < .01) locations, and associated with bone marrow eosinophilia (P < .01). A total of 10 patients who were available for tryptase genotyping were all confirmed to have HaT. This subgroup was representative of the larger MCAS-T cohort.Conclusion: We report unique bone marrow MC phenotypic and histopathologic changes in patients with MCAS-T. These morphologic changes are associated with an elevated tryptase level that has been confirmed to be caused by HaT in all patients available for testing. (J Allergy Clin Immunol 2021;147:1497-501.)