BackgroundIn 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.Methods1319 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.Results285 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).ConclusionsBy 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.

中文翻译：

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需要膜翅目毒液免疫治疗的患者患有克隆性肥大细胞疾病和遗传性 α-胰蛋白酶血症的高负担

背景在需要毒液免疫治疗 (VIT) 的患者中，需要识别潜在的肥大细胞 (MC) 疾病，因为这些疾病可能会影响未来蜇伤反应的风险和严重程度以及 VIT 的长期有效性。方法 1319 名膜翅目毒液过敏个体(HVA) 需要斯洛文尼亚、奥地利、克罗地亚和波兰转诊中心的 VIT 接受检查成套工具使用高度灵敏的 PCR 测试和数字液滴 PCR 进行类胰蛋白酶基因分型，检测外周血白细胞 (PBL) 中的 p.D816V。我们还纳入了 183 名对膜翅目昆虫叮咬具有较大局部反应 (LLR) 且对膜翅目昆虫毒液无症状过敏的对照个体。结果推荐进行 VIT 的 1319 名个体中的 285 名 (21.6%) 呈阳性成套工具PBL 中的 p.D816V，最好是出现严重反应的患者（33.9% [n= 207 of 610] 环-Messmer 等级 3–4 vs. 11% [n= 709 中的 78] 1-2 级；p< .0001)，而只有 1.3% (n= 152 名对照中的 2 名患有 LLR，没有一名患有无症状致敏（n= 31) 有成套工具p.D816V。成套工具p.D816V 等位基因负荷在严重反应的患者中较高（中位数 0.018% [n= 207] 3-4 年级 vs. 0.001% [n= 78] 1-2 年级；p< .0001），大多数人的基线血清类胰蛋白酶水平正常（69% [n= 196 / 285]）。全部成套工具p.D816V 阳性个体（n= 41) 接受骨髓 (BM) 活检的人被发现患有潜在的克隆性疾病，主要是 BM 肥大细胞增多症。HαT 还与严重的 HVA 和症状相关（p< .01)，值得注意的是，31.0% (n= 100 人中的 31 人）被发现有伴随症状成套工具p.D816V。伴随的 HαT 和成套工具p.D816V 显示出累加效应，并且同时具有两者与严重 HVA 的最高风险相关，甚至高于具有 HαT 或成套工具p.D816V 单独使用（OR = 3.8；p< .01).结论通过采用前瞻性通用类胰蛋白酶基因分型和检查成套工具p.D816V 在大量 HVA 人群的 PBL 中，我们已经证明需要 VIT 的患者患有克隆性 MC 疾病和 HαT 的高负担。