Peanut allergy, one of the most common food allergies, can result in severe and potentially life-threatening reactions.^{1, 2} Immunotherapy aims to reduce the likelihood of allergic reactions due to accidental allergen ingestion, a noted treatment goal of caregivers, by increasing the threshold eliciting dose (ED).^3-5 Another important caregiver-expressed outcome of peanut allergy immunotherapy is reduction in severity of allergic reactions.⁵

Investigational epicutaneous immunotherapy with Viaskin™ Peanut (DBV712) 250 µg, a patch containing 250 µg of peanut protein (~1/1000 one peanut), demonstrated statistically significant superiority to placebo in desensitizing peanut-allergic children aged 4 to 11 years after 12 months of daily treatment in the phase 3 PEPITES trial and treatment-associated improvement in food allergy quality of life.^{3, 4, 6} In PEPITES, double-blind placebo-controlled food challenges (DBPCFCs) were conducted according to PRACTALL guidelines at month 0 (M0, baseline) and month 12 (M12) using a standardized blinded food matrix.³ DBPCFCs were stopped when sufficient objective signs or symptoms met prespecified stopping criteria and required treatment³; the peanut protein dose resulting in stopping was considered the subjects’ ED. Reaction severity was assessed based on prespecified PRACTALL symptoms; severity for each symptom was graded by the investigator (none [0], mild [1], moderate [2], or severe [3]) at each dosing increment. Written and informed consent and assent (where applicable, depending upon the country) were obtained from the caregiver and subject, respectively.

To examine the potential role of Viaskin Peanut 250 µg in reducing allergic reaction severity, a post hoc analysis of PEPITES was conducted comparing the severity of allergic symptoms elicited during the DBPCFCs at M0 and M12 between subjects who received Viaskin Peanut 250 µg and placebo. Maximum symptom severity was assessed among all assessable organ systems (AOS) as the primary endpoint (which included objective symptoms in skin, upper respiratory, lower respiratory, objective gastrointestinal, and cardiovascular/neurologic systems) and in 5 specific symptom domains (wheezing, cardiovascular, laryngeal, vomiting, and diarrhea) as a sensitivity analysis (to target symptoms more commonly associated with life-threatening reactions, based upon their relationship to the physiology underlying the symptom) as well as by subjects’ M12 ED status (increased, decreased, or unchanged). Analyses included all randomized subjects who underwent at least the peanut M12 DBPCFC (Viaskin Peanut 250 µg, n = 222; placebo, n = 109).

At M0, the proportion of subjects with mild, moderate, or severe objective signs/symptoms for AOS was similar between treatment groups (p =.931) (Table 1). In contrast, there was a significant between-group difference (p <.001) in the distribution of symptom severity at M12. Nearly twice as many Viaskin Peanut 250 µg-treated subjects (31.1%) as placebo-treated subjects (16.5%) had maximum symptom severity scores of “none” or “mild.” The proportion of subjects with a maximum severity score of “severe” was also lower in subjects who received Viaskin Peanut 250 µg (16.2%) compared with placebo (27.5%; p =.019).

For the 5-domain sensitivity analysis, the proportion of subjects with mild, moderate, or severe signs/symptoms was similar at M0 in subjects treated with Viaskin Peanut 250 µg and placebo (p =.946) and differed significantly at M12 (p =.016) (Table 1). Additionally, 20.7% of subjects in the Viaskin Peanut 250 µg group had severity scores of “none” compared with 11.0% in the placebo group (p =.031).

To investigate possible confounding effects of ED on severity, the maximum symptom severity was also analyzed by subjects’ M12 ED status. The proportion of subjects with maximum severity scores of “severe” remained lower in subjects who received Viaskin Peanut 250 µg versus placebo regardless of whether their ED increased, decreased, or was unchanged. Subgroup analysis demonstrated a significant difference among those whose ED decreased (increasing their reaction risk) or remained unchanged in the Viaskin Peanut 250 µg group compared with the placebo group (Table 2).

Limitations of the findings include those inherent in any post hoc analysis, although all data used in the analysis were collected prospectively, in accordance with the study protocol. Although it is possible that there is the potential for variability between assessors related to grading allergic reactions during DBPCFC, the blinded randomized nature of the study design is likely adequate to control for such variability. In addition, a strict well-known PRACTALL system was utilized, requiring prespecified stopping criteria based on objective reaction signs. Finally, although all assessors at DBPCFC were blinded to treatment allocation, some may have had knowledge of the subjects, gained during prior study visits. It is unclear to what extent, if any, this would have influenced the results of this analysis.

Overall, this post hoc analysis of prospectively collected prespecified data demonstrates that in addition and independent of increasing reactivity threshold in peanut-allergic children aged 4 to 11 years, Viaskin Peanut 250 µg may also reduce the severity of allergic reactions to accidental peanut ingestion, meeting two important caregiver-stated goals of peanut allergy immunotherapy.

花生过敏是最常见的食物过敏之一，可导致严重且可能危及生命的反应。^{1, 2}免疫疗法旨在通过增加阈值诱发剂量 (ED) 来降低因意外摄入过敏原而引起过敏反应的可能性，这是护理人员的一个显着治疗目标。^3-5花生过敏免疫疗法的另一个重要的护理人员表达的结果是过敏反应的严重程度降低。⁵

Viaskin™ Peanut (DBV712) 250 µg 的研究性表皮免疫疗法是一种含有 250 µg 花生蛋白（约 1/1000 个花生）的贴剂，在 12 个月后对 4 至 11 岁的花生过敏儿童脱敏方面显示出统计学上显着的优势3 期 PEPITES 试验中的日常治疗以及与治疗相关的食物过敏生活质量改善。^{3, 4, 6}在 PEPITES 中，根据 PRACTALL 指南在第 0 个月（M0，基线）和第 12 个月 (M12) 使用标准化的盲法食物矩阵进行双盲安慰剂对照食物挑战 (DBPCFC)。³当有足够的客观体征或症状满足预先指定的停止标准并需要治疗时，停止使用 DBPCFC ³; 导致停止的花生蛋白剂量被认为是受试者的 ED。根据预先指定的 PRACTALL 症状评估反应严重程度；在每次给药增量时，研究者对每种症状的严重程度进行分级（无 [0]、轻度 [1]、中度 [2] 或重度 [3]）。分别从护理人员和受试者获得书面和知情同意和同意（如果适用，取决于国家/地区）。

为了检查 Viaskin Peanut 250 µg 在降低过敏反应严重程度方面的潜在作用，对 PEPITES 进行了事后分析，比较了接受 Viaskin Peanut 250 µg 和安慰剂的受试者在 M0 和 M12 的 DBPCFC 期间引发的过敏症状的严重程度。在所有可评估器官系统 (AOS) 作为主要终点（包括皮肤、上呼吸道、下呼吸道、客观胃肠道和心血管/神经系统的客观症状）和 5 个特定症状领域（喘息、心血管、喉、呕吐和腹泻）作为敏感性分析（针对更常见的与危及生命的反应相关的症状，基于它们与症状背后的生理学的关系）以及受试者的 M12 ED 状态（增加、减少或不变）。分析包括至少接受花生 M12 DBPCFC（Viaskin Peanut 250 µg，n = 222；安慰剂，n = 109）的所有随机受试者。

在 M0 时，治疗组之间具有轻度、中度或重度 AOS 客观体征/症状的受试者比例相似（p =.931）（表 1）。相比之下，M12 时症状严重程度的分布存在显着的组间差异 ( p <.001)。Viaskin Peanut 250 µg 治疗的受试者（31.1%）几乎是安慰剂治疗的受试者（16.5%）的两倍，其最大症状严重程度评分为“无”或“轻度”。与安慰剂（27.5%； p =.019）相比，接受 Viaskin Peanut 250 µg 的受试者（16.2%）的最大严重程度评分为“严重”的受试者比例也较低。

对于 5 域敏感性分析，接受 Viaskin Peanut 250 µg 和安慰剂治疗的受试者在 M0 时具有轻度、中度或重度体征/症状的受试者比例相似 ( p =.946)，而在 M12 ( p = .016）（表 1）。此外，Viaskin Peanut 250 µg 组 20.7% 的受试者的严重程度评分为“无”，而安慰剂组为 11.0% ( p =.031)。

为了研究 ED 对严重程度的可能混杂影响，还通过受试者的 M12 ED 状态分析了最大症状严重程度。与安慰剂相比，接受 Viaskin Peanut 250 µg 的受试者的最大严重程度评分为“严重”的受试者比例仍然较低，无论他们的 ED 是增加、减少还是不变。亚组分析表明，与安慰剂组相比，Viaskin Peanut 250 µg 组 ED 降低（增加其反应风险）或保持不变的患者之间存在显着差异（表 2）。

研究结果的局限性包括任何事后分析中固有的局限性，尽管分析中使用的所有数据都是根据研究方案前瞻性收集的。尽管在 DBPCFC 期间，与分级过敏反应相关的评估者之间可能存在变异性，但研究设计的盲随机性质可能足以控制这种变异性。此外，使用了严格的众所周知的 PRACTALL 系统，要求基于客观反应迹象预先指定停止标准。最后，尽管 DBPCFC 的所有评估员都对治疗分配视而不见，但有些人可能已经了解了受试者，这些知识是在之前的研究访问中获得的。目前尚不清楚这会在多大程度上（如果有的话）影响该分析的结果。

总体而言，这项对前瞻性收集的预先指定数据的事后分析表明，除了增加 4 至 11 岁花生过敏儿童的反应阈值之外，Viaskin Peanut 250 µg 还可以降低对意外摄入花生的过敏反应的严重程度，满足花生过敏免疫治疗的两个重要照顾者陈述的目标。