Pathogenesis and Treatment of Anaphylaxis

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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.