Efficacy and safety of oral immunotherapy in children aged 1-3 years with peanut allergy (the Immune Tolerance Network IMPACT trial): a randomised placebo-controlled study.
Efficacy and safety of oral immunotherapy in children aged 1-3 years with peanut allergy (the Immune Tolerance Network IMPACT trial): a randomised placebo-controlled study.
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DOI：
10.1016/s0140-6736(21)02390-4
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发表时间：
2022-01-22
期刊：
影响因子：
168.9
通讯作者：
Burks, A. Wesley
中科院分区：
文献类型：
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作者：
Jones, Stacie M.;Kim, Edwin H.;Nadeau, Kari C.;Nowak-Wegrzyn, Anna;Wood, Robert A.;Sampson, Hugh A.;Scurlock, Amy M.;Chinthrajah, Sharon;Wang, Julie;Pesek, Robert D.;Sindher, Sayantani B.;Kulis, Mike;Johnson, Jacqueline;Spain, Katharine;Babineau, Denise C.;Chin, Hyunsook;Laurienzo-Panza, Joy;Yan, Rachel;Larson, David;Qin, Tian;Whitehouse, Don;Sever, Michelle L.;Sanda, Srinath;Plaut, Marshall;Wheatley, Lisa M.;Burks, A. Wesley
对于对花生过敏的幼儿，避免饮食是目前的护理标准。我们评估了花生口服免疫疗法（PnOIT）是否可以在该人群中诱导脱敏（治疗期间过敏反应阈值增加）和/或缓解（停止免疫治疗后的无反应状态）。在美国 5 个中心针对儿童（年龄 12-<48 个月）进行了一项随机、双盲、安慰剂对照研究，这些儿童在双盲、安慰剂对照食物挑战 (DBPCFC) 期间对 ≤500 毫克花生蛋白有反应。使用 2:1 的分配比例对参与者进行计算机随机分配，接受 PnOIT 或安慰剂治疗 134 周（2000 毫克花生蛋白/天），然后回避 26 周，参与者和研究人员/研究人员对治疗组分配不知情。 DBPCFC 将治疗结束时（第 134 周）的脱敏作为主要结局，以及回避后的缓解（第 160 周）作为关键的次要结局，由 DBPCFC 评估为 5000 mg。评估安全性和免疫学参数。 2013 年 8 月至 2015 年 10 月期间，随机抽取了 146 名儿童，中位年龄为 39.3（IQR：30.8,44.7）个月，其中 96 名儿童被分配到 PnOIT 治疗组并进行分析，50 名儿童被分配到安慰剂治疗组并进行分析。在第 134 周时，68/96 (71%; 95% CI:61%,80%) 的 PnOIT 治疗参与者与 1/50 (2%; 95% CI:0.05%,11%) 的安慰剂治疗参与者达到脱敏的主要结果（风险差异 (RD)=69%; 95% CI:59%,79%; p<0.0001）。 DBPCFC 第 134 周期间，PnOIT 治疗组的中位累积耐受剂量 (CTD) 为 5005 mg（四分位距 (IQR)：3755,5005），而安慰剂治疗组为 5 mg（IQR：0,105）（p<0.0001）。避免后，PnOIT 组中有 20/96 (21%; 95% CI:13%,30%) 达到缓解标准，而安慰剂组中有 1/50 (2%; 95% CI:0.05%,11%) 达到缓解标准 (RD:19%; 95% CI:10%,28%; p=0.0021)。在 160 DBPCFC 周期间，PnOIT 治疗组的中位 CTD 为 755 mg（IQR：0.2755），安慰剂治疗组为 0 mg（IQR：0.55）（p<0.0001）。在第 134 周通过 5000 mg DBPCFC 的 PnOIT 参与者中，很大一部分在第 160 周时不再耐受 5000 mg（p<0.001）。在第 134 周脱敏的安慰剂参与者也在第 160 周实现缓解。与安慰剂治疗相比，在第 134 周和第 160 周，PnOIT 治疗的参与者中花生和 Ara h2 特异性 IgE、皮肤点刺试验和嗜碱性粒细胞活化降低，而花生和 Ara h2 特异性 IgG4 增加。对 PnOIT 治疗参与者进行多变量回归分析，年龄较小且基线花生特异性较低IgE 可预测病情缓解。大多数参与者（98% PnOIT 与 80% 安慰剂）经历了至少 1 次 OIT 给药反应，主要是轻度至中度反应，并且在 PnOIT 治疗的参与者中发生得更频繁； 21 名 PnOIT 参与者使用肾上腺素治疗 35 起具有中度症状的 OIT 给药事件。在花生过敏儿童中，4 岁之前开始 PnOIT 与脱敏和缓解的增加相关。缓解的发展与免疫生物标志物相关。结果表明，在年轻时有一个进行干预以诱导缓解的机会之窗。美国国家过敏和传染病研究所免疫耐受网络 该试验已在 ClinicalTrials.gov 上注册 (NCT03345160)。
For young, peanut-allergic children, dietary avoidance is the current standard of care. We evaluated whether peanut oral immunotherapy (PnOIT) can induce desensitization (an increased allergic reaction threshold while on therapy) and/or remission (a state of nonresponsiveness following discontinuation of immunotherapy) in this population. A randomized, double-blind, placebo-controlled study was conducted in 5 US centers among children (ages 12–<48 months), reactive to ≤500 mg peanut protein during double-blind, placebo-controlled food challenge (DBPCFC). Participants were computer-randomized using a 2:1 allocation ratio to receive PnOIT or placebo for 134 weeks (2000 mg peanut protein/day) followed by 26 weeks of avoidance with participants and study staff/investigators blinded to treatment arm assignment. Desensitization at the end of treatment (week 134), as the primary outcome, and remission after avoidance (week 160), as the key secondary outcome, were assessed by DBPCFC to 5000 mg. Safety and immunological parameters were assessed. Of 146 children, with a median age of 39.3 (IQR:30.8,44.7) months, randomized from August 2013 to October 2015, 96 were assigned and analyzed in the PnOIT-treatment arm and 50 in the placebo-treatment arm. At week 134, 68/96 (71%; 95% CI:61%,80%) PnOIT-treated compared to 1/50 (2%; 95% CI:0.05%,11%) placebo-treated participants met the primary outcome of desensitization (risk difference (RD)=69%; 95% CI:59%,79%; p<0.0001). The median cumulative tolerated dose (CTD) during the week 134 DBPCFC was 5005 mg (Interquartile Range (IQR):3755,5005) for PnOIT-treated versus 5 mg (IQR:0,105) for placebo-treated (p<0.0001). After avoidance, 20/96 (21%; 95% CI:13%,30%) on PnOIT compared to 1/50 (2%; 95% CI:0.05%,11%) on placebo met remission criteria (RD:19%; 95% CI:10%,28%; p=0.0021). The median CTD during the week 160 DBPCFC was 755 mg (IQR:0,2755) for the PnOIT-treated and 0 mg (IQR:0,55) for placebo-treated (p<0.0001). A significant proportion of PnOIT participants who passed the 5000 mg DBPCFC at week 134 could no longer tolerate 5000 mg at week 160 (p<0.001). The placebo participant who was desensitized at week 134 also achieved remission at week 160. Compared to placebo treatment, peanut- and Ara h2-specific-IgE, skin prick test, and basophil activation decreased, while peanut- and Ara h2-specific-IgG4 increased in PnOIT-treated participants at weeks 134 and 160. Using multivariable regression analysis of PnOIT-treated participants, younger age and lower baseline peanut-specific IgE was predictive of remission. Most participants (98% PnOIT vs. 80% placebo) experienced at least 1 OIT dosing reaction, predominantly mild-moderate and occurring more frequently in PnOIT-treated participants; 35 OIT dosing events with moderate symptoms were treated with epinephrine in 21 PnOIT participants. In peanut-allergic children, initiation of PnOIT before age 4 years is associated with an increase in both desensitization and remission. Development of remission correlates with immunologic biomarkers. The outcomes suggest a window of opportunity at a young age for intervention to induce remission. National Institute of Allergy and Infectious Disease, Immune Tolerance Network The trial is registered on clinicaltrials.gov (NCT03345160).