Pathogenesis and Treatment of Anaphylaxis

我们正在评估超过90例因特发性过敏反应（IA）和抗原特异性过敏反应（SA）而转诊的患者，以探索发病机制并识别克隆性肥大细胞病患者。在IA患者组中，15%患有克隆性肥大细胞病，9.6%被诊断为α-gal敏感性，12.8%被诊断为遗传性α-类胰蛋白酶血症综合征。 在抗原诱导的过敏反应患者中，据报道，欧洲队列中的毒液过敏反应患者克隆性肥大细胞病的患病率较高。迄今为止，在我们的毒液过敏反应患者队列中（n=5），有4例被诊断为克隆性肥大细胞病。 在2019财年，我们继续收治IA和S患者。大多数患者被送入住院部并接受骨髓程序，以试图阐明病因并评估其疾病的发病机制。我们与NIH临床中心的髓样核心设施合作，根据当前WHO诊断系统性肥大细胞增多症的标准评估所有患者的骨髓抽吸物和活检。 加塔-2是造血干细胞的发生和/或功能所必需的转录因子，并且在各种造血和非造血组织中表达。在2019财年完成的一项研究中，我们评估了加塔-2突变对肥大细胞区室的影响。与加塔-2缺乏患者相比，IA患者骨髓肥大细胞上的KIT表达相当，但骨髓肥大细胞总数较低。肥大细胞脱颗粒的减少与加塔-2缺陷患者中KIT和FcepsilonRI表达的减少相关，这与IgE介导的肥大细胞活化的减少和IgE介导的临床过敏性疾病的可能性一致。IA患者的通路完整。 奥马珠单抗被批准用于治疗重度哮喘，并通过下调嗜碱性粒细胞、肥大细胞和树突状细胞表面IgE受体的机制发挥作用。据报道，奥马珠单抗可作为辅助疗法用于治疗哮喘以外的疾病，包括食物过敏和慢性荨麻疹。在2019财年，我们完成了一项评估奥马珠单抗治疗IA的临床试验，并将在完成数据分析后准备我们研究结果的完整报告。未发生归因于研究药物的严重不良事件，尤其是药物诱导的速发型过敏反应。 在2019财年，我们报告了奥马珠单抗在12年期间治疗2例系统性肥大细胞增多症患者复发性过敏反应的安全性和疗效。我们发现奥马珠单抗耐受性良好，没有与其给药相关的不良事件。在这两名患者中，过敏性事件罕见。两例患者的肥大细胞增多症皮肤表现均有改善，其中一例患者的血清类胰蛋白酶和骨髓肥大细胞负荷沿着显著降低。

We are in the process of evaluating over 90 patients referred for idiopathic anaphylaxis (IA) and antigen-specific anaphylaxis (SA) to explore pathogenesis and identify patients with clonal mast cell disease. Within the patient group with IA, 15% had clonal mast cell disease, 9.6% were diagnosed with alpha-gal sensitivity, and 12.8% were diagnosed with hereditary alpha-tryptasemia syndrome. Among patients with antigen-induced anaphylaxis, those with venom anaphylaxis in European cohorts have been reported to have a higher prevalence of clonal mast cell disease. In our cohort of patients referred for venom anaphylaxis to date (n=5), four have been diagnosed with clonal mast cell disease. In fiscal year (FY) 2019, we continue to admit patients with IA and S). Most patients are admitted to the inpatient unit and undergo a bone marrow procedure in an attempt to elucidate the etiology and evaluate the pathogenesis of their disease. In collaboration with the NIH Clinical Center's myeloid core facility, we assess all patient bone marrow aspirates and biopsies obtained based on the current WHO criteria to diagnose systemic mastocytosis. GATA-2 is a transcription factor critically required for the genesis and/or function of hematopoietic stem cells and is expressed in various hematopoietic and nonhematopoietic tissues. In a study completed in FY 2019, we assessed the impact of mutations in GATA-2 on the mast cell compartment. Patients with IA had comparable KIT expression on bone marrow mast cells but lower total numbers of bone marrow mast cells when compared to patients with GATA-2 deficiency. A decrease of mast cell degranulation was associated with reduced expression of KIT and FcepsilonRI in GATA-2 deficient patients, which is consistent with a decrease in IgE-mediated mast cell activation and potential for IgE-mediated clinical allergic disease. The pathway was intact in patients with IA. Omalizumab is approved for the treatment of severe asthma and acts through a mechanism that down regulates the IgE-receptor on the surface of basophils, mast cells, and dendritic cells. Omalizumab has been reported to be useful as adjunct therapy in the treatment of diseases other than asthma including food allergy and chronic urticaria. In FY 2019, we completed a clinical trial evaluating omalizumab for the treatment of IA and will prepare a full report of our findings after completing the data analysis. There were no serious adverse events attributed to the study drug, in particular drug-induced anaphylaxis. In FY 2019, we reported the safety and efficacy of omalizumab over a 12-year period in the treatment of recurrent anaphylaxis in two patients with systemic mastocytosis. We found that omalizumab was well tolerated and there were no adverse events related to its administration. In both patients, anaphylactic episodes were rare. There was an improvement in cutaneous manifestations of mastocytosis in both individuals, along with a significant reduction in serum tryptase and bone marrow mast cell burden in one patient.