To the Editor, In adolescents and adults, up to 60% of all food allergies are associated with a respiratory allergy.1 Around 70 per cent of birch allergic individuals develop allergic symptoms against certain foods such as nuts and apples containing homologous cross-reactive allergens to the major birch allergen Bet v 1.2-4 The symptoms are manifested as a condition called pollen food syndrome (PFS), and its occurrence typically involves presensitization to pollen allergens from the Fagales order. PFS is IgE-mediated and is caused by cross-reactivity between Bet v 1 and other protein family 10 (PR-10) proteins in a number of common food items such as apple, hazelnut, carrot and peach.2,3 PFS interferes with activities of daily living, as patients will experience local oral symptoms such as itching, tingling, swelling in the mouth or oral angioedema after intake of a number of common food items.2,5 Some patients may also experience systemic reactions,2,3 but PR-10 triggered PFS is not a severe condition in most cases.3 Birch allergen immunotherapy treatment (AIT) could be beneficial in the treatment of PFS due to the cross-reactivity between Bet v 1 and common PR-10 allergens.6 In a recently published position paper from EAACI on PFS, the authors concluded that trials were needed to assess the effect of birch AIT on PFS.1 The original purpose of the study presented here investigates the potential treatment effect on PFS of a sublingual immunotherapy tablet for the treatment of tree pollen allergy, the SQ tree SLITtablet (12 SQ-Bet, ALK). The treatment effect was measured in an open-label apple challenge conducted at the end of a double-blind, placebo-controlled phase III trial in a subgroup of the trial participants after 6.59.5 months of once-daily treatment with the SQ tree SLIT-tablet or placebo. The primary phase III trial results were reported previously.7 In total, 124 participants (63 placebo, 61 SQ tree SLIT-tablet) from 12 centres in Germany and 12 centres in Poland with tree pollen allergy accepted to participate (Figure S1 and Table S1, online supporting information). They were challenged with apple slices (cut by standardized apple slicer) in 5 steps with increasing amounts corresponding to 4, 8, 16, 32 and 64 g given in intervals of 15 minutes. Objective and subjective PFS symptoms in response to the challenge were recorded. Participants reported a global evaluation of efficacy on PFS symptoms after intake of apple by comparing subjective PFS symptoms before and after treatment (see also endpoints and assessments in online supplementary material). Specific IgE and IgG4 responses to the apple PR-10 allergen Mal d 1 were measured throughout the trial. The majority of participants in both groups (75% for SQ tree SLIT-tablet and 68% for placebo) managed to consume the highest dose of apple (64 g) without relevant objective symptoms. The subject-reported PFS symptoms by VAS during the apple challenge were generally low and many participants reported no symptoms (Figure 1). However, the mean levels of PFS symptoms after apple intake were lower for participants in the active group compared with placebo. Especially, the increase in symptoms from before the apple challenge to after the first dose of apple (4 g) was more pronounced for participants in the placebo group, suggesting improved tolerance in the active group. This tendency was similar for individual symptoms and the overall PFS VAS score. A global evaluation of efficacy on PFS symptoms showed that more participants in the active group reported improved PFS symptoms after treatment compared with placebo (87% vs 64%, OR = 0.27, P = .0028). Treatment with the SQ tree SLIT-tablet increased serum levels of apple-specific IgE and IgG4 compared with placebo at all measured time points (changes from baseline, Figure 2). Apple-specific IgE increased in the active group until the off-season visit, after which it began to decrease. However, at end of trial serum levels of apple-specific IgE (log-transformed) were still significantly higher in the active group than for placebo (P < .001 for difference in change from baseline). The change from baseline in apple-specific IgG4 (log-transformed) increased throughout the duration of the trial in the active group (P < .001 for difference between groups at end of trial). No increases in apple-specific IgE or IgG4 were seen for the placebo group. The apple-specific immunological responses resembled that seen for birch. The ratio of IgG4/IgE showed that the immunoglobulin production was in favour of Mal d 1 reactive IgG4 over IgE from 4 weeks of treatment (Figure 2). The apple challenge did not lead to any serious adverse events, severe local swellings and/or systemic allergic reactions. A summary of adverse events reported during the entire trial period showed that a slightly higher proportion of participants with PFS reported

中文翻译：

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SQ树SLIT片对苹果引起的花粉食物综合征的潜在治疗作用

致编辑，在青少年和成人中，多达 60% 的食物过敏与呼吸道过敏有关。1 大约 70% 的桦木过敏个体对某些食物（如含有同源交叉反应性过敏原的坚果和苹果）出现过敏症状对主要桦树过敏原 Bet v 1.2-4 症状表现为称为花粉食物综合征 (PFS) 的病症，其发生通常涉及对来自 Fagales 命令的花粉过敏原的预致敏。PFS 是 IgE 介导的，是由 Bet v 1 和其他蛋白质家族 10 (PR-10) 蛋白质之间的交叉反应引起的，这些蛋白质在许多常见食品中，例如苹果、榛子、胡萝卜和桃子。2,3 PFS 会干扰日常生活活动，因为患者会出现局部口腔症状，如瘙痒、刺痛、摄入多种常见食物后口腔肿胀或口腔血管性水肿。2,5 一些患者也可能出现全身反应，2,3 但 PR-10 引发的 PFS 在大多数情况下并不严重。3 Birch 过敏原免疫疗法由于 Bet v 1 和常见 PR-10 过敏原之间存在交叉反应，因此治疗 (AIT) 可能有益于治疗 PFS。6 在 EAACI 最近发表的关于 PFS 的立场文件中，作者得出结论，需要进行试验来评估桦木 AIT 对 PFS 的影响。1 本研究的最初目的是调查舌下免疫治疗片剂 SQ tree SLITtablet (12 SQ-Bet, ALK) 对 PFS 的潜在治疗效果，用于治疗树花粉过敏。在双盲结束时进行的开放标签苹果挑战中测量了治疗效果，在接受 SQ 树 SLIT 片剂或安慰剂每日一次治疗 6.59.5 个月后，在试验参与者的一个亚组中进行安慰剂对照 III 期试验。先前已报告了主要的 III 期试验结果。 7 总共有来自德国 12 个中心和波兰 12 个中心的树木花粉过敏的 124 名参与者（63 名安慰剂，61 名 SQ 树 SLIT 片剂）接受参与（图 S1 和表 S1 ，在线支持信息）。他们分 5 个步骤用苹果片（由标准苹果切片机切割）进行挑战，每 15 分钟增加 4、8、16、32 和 64 克的量。记录响应挑战的客观和主观 PFS 症状。参与者通过比较治疗前后的主观 PFS 症状，报告了对摄入苹果后 PFS 症状疗效的总体评估（另见在线补充材料中的终点和评估）。在整个试验过程中测量了对苹果 PR-10 过敏原 Mal d 1 的特异性 IgE 和 IgG4 反应。两组的大多数参与者（SQ 树 SLIT 片剂为 75%，安慰剂为 68%）设法食用了最高剂量的苹果（64 克），而没有相关的客观症状。苹果挑战期间 VAS 报告的受试者 PFS 症状通常较低，许多参与者报告没有症状（图 1）。然而，与安慰剂相比，活性组参与者摄入苹果后 PFS 症状的平均水平较低。尤其，对于安慰剂组的参与者来说，从苹果攻击之前到第一剂苹果（4 克）之后症状的增加更为明显，这表明活性组的耐受性有所提高。这种趋势对于个体症状和总体 PFS VAS 评分是相似的。对 PFS 症状疗效的全球评估表明，与安慰剂相比，治疗后更多的参与者报告了治疗后 PFS 症状的改善（87% 对 64%，OR = 0.27，P = .0028）。与安慰剂相比，使用 SQ 树 SLIT 片剂治疗在所有测量时间点都增加了苹果特异性 IgE 和 IgG4 的血清水平（与基线相比的变化，图 2）。活跃组中苹果特异性 IgE 增加，直到淡季访问，之后开始减少。然而，在试验结束时，活性组的苹果特异性 IgE（对数转换）血清水平仍显着高于安慰剂组（P < .001 与基线变化的差异）。在整个试验期间，活性组中苹果特异性 IgG4（对数转换）相对于基线的变化增加（试验结束时各组之间的差异 P < .001）。安慰剂组没有观察到苹果特异性 IgE 或 IgG4 的增加。苹果特异性免疫反应类似于桦树的免疫反应。IgG4/IgE 的比率表明，从 4 周的治疗开始，免疫球蛋白的产生有利于 Mal d 1 反应性 IgG4 而非 IgE（图 2）。苹果挑战没有导致任何严重的不良事件、严重的局部肿胀和/或全身过敏反应。