Pathogenesis and Treatment of Anaphylaxis

我们评估了112例因特发性过敏反应（IA）和抗原特异性过敏反应（SA）转诊的患者，以探讨发病机制并识别克隆性肥大细胞病患者。总的来说，22%的人被诊断患有克隆性肥大细胞病，13.4%患有IA，7.1%患有毒液过敏反应，1.8%患有食物或药物引起的过敏反应。此外，8.9%被诊断为α-半乳糖综合征，13.4%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=10），有7例（80%）被诊断为克隆性肥大细胞病。到目前为止，在入选的10例食物或药物诱导的过敏反应患者中，有2例（20%）被诊断为克隆性肥大细胞病。 2023财年，我们继续收治IA和抗原特异性过敏反应（SA）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。该队列还用于验证肥大细胞活化综合征，并进一步阐明靶向治疗的活化途径，因此对于管理策略很重要。 在2023财年，我们利用我们的速发过敏反应患者队列撰写了稿件。 将我们的IA患者队列与肥大细胞增多症患者进行比较，突出显示两个队列中GI渗透性的特异性生物标志物均升高。将54例IA患者的血清zonulin、肠脂肪酸结合蛋白（I-FABP）和可溶性CD 14（sCD 14）浓度与健康对照组（HC）的浓度进行比较，并与临床和实验室参数相关。IA患者血清中I-FABP和sCD 14升高。我们发现与IA和肥大细胞增多症相关的微生物易位标志物（MTM）谱既有重叠又有分歧。因此，在两种情况下都观察到肠脂肪酸结合蛋白（I-FABP）和可溶性CD 14（sCD 14）的升高。然而，IA的MTM特征与肥大细胞增多症不同，IA患者缺乏连蛋白升高。一个结论似乎是各种肥大细胞疾病携带特定的MTM谱。IA的这些生物标志物的升高提供了证据，表明GI渗透性增加（如在其他过敏性疾病（如食物过敏）中观察到的）是IA患者的常见发现，并提供了对该疾病发病机制的可能见解。 我是《过敏与临床免疫学杂志：实践》中关于过敏反应的主题问题的共同编辑。我还与来自加拿大和德国的作者一起在该杂志上撰写了一篇关于内在和外在调节剂在过敏反应中的作用的论文。

We have evaluated 112 patients referred for idiopathic anaphylaxis (IA) and antigen-specific anaphylaxis (SA) to explore pathogenesis and identify patients with clonal mast cell disease. Overall, 22% have been diagnosed with a clonal mast cell disease, 13.4% with IA, 7.1% with venom anaphylaxis and 1.8% with food or drug-induced anaphylaxis. In addition, 8.9% were diagnosed with alpha-gal syndrome, and 13.4% 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=10), seven (80%) have been diagnosed with clonal mast cell disease. Of the ten patients enrolled with food or drug-induced anaphylaxis, thus far, two (20%) have been diagnosed with clonal mast cell disease. In FY 2023, we continue to admit patients with IA and antigen-specific anaphylaxis (SA). 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. This cohort was also used to contribute to the validation of mast cell activation syndromes and further elucidate pathways of activation for targeted therapy and thus, important for management strategies. In FY 2023, we contributed to manuscripts utilizing our anaphylaxis patient cohort. Our patient cohort of patients with IA were compared to patients with mastocytosis highlighting specific biomarkers of GI permeability that were elevated in both cohorts. Serum concentrations of zonulin, intestinal fatty acid binding protein (I-FABP), and soluble CD14 (sCD14) measured in 54 patients with IA were compared with concentrations in healthy controls (HCs); and correlated with clinical and laboratory parameters. The I-FABP and sCD14 are elevated in the serum of patients with IA. We found both an overlap and a divergence in the microbial translocation markers (MTM) profiles associated with IA versus mastocytosis, Elevations in both intestinal fatty acid binding protein (I-FABP) and soluble CD14 (sCD14) are thus observed in both conditions. However, the MTM profile of IA diverges from that of mastocytosis, with a lack of zonulin elevation in those with IA. One conclusion appears to be that various mast cell disorders carry specific profiles of MTMs. Elevations in these biomarkers of IA provides evidence that increased GI permeability, as is observed in other allergic conditions such as food allergy, is a common finding in those with IA and offers possible insight into the pathogenesis of this disease. I was the co-Editor for a themed issue on Anaphylaxis in the Journal of Allergy and Clinical Immunology: In Practice. I also contributed to a manuscript in this journal with authors from Canada and Germany regarding the role of intrinsic and extrinsic modulators in anaphylaxis.