Can Peanut Allergy Prevention Be Translated to the Pediatric Population.pdf

The potential to prevent food allergy has been a topic of increasing interest over the past 40 to 50 years. Studies on this topic date back to at least 1936, and a series of studies in the 1980s and 1990s produced inconsistent, but often compelling, data on the potential benefits of breastfeeding, specialized infant formulas, or delaying introduction of allergenic foods. Based on this body of evidence, as well as substantial expert opinion, a guideline by the American Academy of Pediatrics published in 2000 recommended the use of hydrolyzed formulas and delayed introduction of allergenic foods, including peanut, until the age of 3 years. However, expert opinion turned out to be wrong and some of the most persuasive studies were subsequently retracted as fraudulent. As new data emerged and the prevalence of food allergy continued to increase, the 2000 guidelines were replaced by updated recommendations in 2008 that essentially left these decisions “to personal and family preference,” because the available evidence was insufficient to justify any specific guidelines.

预防食物过敏的潜力在过去的 40 到 50 年间，它一直是人们越来越感兴趣的话题。关于这一主题的研究至少可以追溯到 1936 年，而 1980 年代和 1990 年代的一系列研究产生了关于母乳喂养、特殊婴儿配方奶粉或延迟引入过敏性食物的潜在益处的不一致但通常令人信服的数据。基于这些证据以及大量专家意见，美国儿科学会于 2000 年发布的指南建议使用水解配方食品并将包括花生在内的过敏性食物推迟到 3 岁。然而，专家意见被证明是错误的，一些最有说服力的研究随后因欺诈而被撤回。随着新数据的出现和食物过敏的患病率持续增加，2000 年的指南被 2008 年的更新建议所取代，这些建议基本上将这些决定“取决于个人和家庭的偏好”，因为现有证据不足以证明任何具体指南的合理性。

In 2015, the results of the Learning Early About Peanut (LEAP) trial were published. This open-label trial included 640 high-risk infants (with eczema, egg allergy, or both) aged 4 to 11 months who were enrolled at a single site in the UK from December 2006 to May 2009. Participants were randomized to receive early peanut introduction, eating at least 6 g of peanut protein per week until the age of 5 years, or complete peanut avoidance. In this trial, among 640 infants in the intentionto-treat population, early and regular peanut ingestion was highly effective in preventing the development of peanut allergy. At 60 months of age, the prevalence of peanut allergy was 4.7% (25 children) in the early peanut introduction group and 16.8% (91 children) in the peanut avoidance group, and this benefit persisted even after a 12-month period of avoidance.

2015 年，早期学习花生 (LEAP) 试验的结果公布。这项开放标签试验包括 2006 年 12 月至 2009 年 5 月在英国单一地点登记的 640 名 4 至 11 个月的高危婴儿（患有湿疹、鸡蛋过敏或两者兼有）。参与者被随机分配接受早期花生 介绍，每周至少吃 6 克花生蛋白，直到 5 岁，或完全避免花生。在这项试验中，在意向治疗人群的 640 名婴儿中，早期和定期摄入花生对于预防花生过敏的发展非常有效。在 60 个月大时，花生过敏的患病率在早期引入花生组为 4.7%（25 名儿童），在避免花生组为 16.8%（91 名儿童），即使在 12 个月的避免期后，这种益处仍然存在。

The results of the LEAP study prompted changes in infant feeding guidelines around the world. To date, at least 23 separate guidelines have been published regarding the prevention of peanut allergy or food allergy in general. These guidelines vary substantially, even among key features such as optimal age, a focus on high-risk infants vs the general population, and the value of allergy testing. Even with the most straightforward strategies, such as to recommend early peanut introduction for all infants, there are barriers to implementation, and the optimal approaches to clinical application remain largely unknown. Most important, it is unclear whether any of the guidelines have led or will lead to meaningful reductions in the prevalence of peanut allergy.

LEAP 研究的结果促使世界各地的婴儿喂养指南发生变化。迄今为止，至少有 23 份单独的指南已发布，涉及预防花生过敏或一般食物过敏。这些指南差异很大，即使在最佳年龄、关注高危婴儿与普通人群以及过敏测试的价值等关键特征之间也是如此。即使采用最直接的策略，例如建议所有婴儿早期引入花生，实施也存在障碍，临床应用的最佳方法仍然很大程度上未知。最重要的是，尚不清楚任何指南是否已经或将导致花生过敏患病率的显着降低。

In this issue of JAMA, Soriano et al report results of 2 population-based cross-sectional samples in Australia thatwere used to evaluate the prevalence of peanut allergy before and after introduction of Australia’s new infant feeding guidelines. These guidelines took the most straightforward approach by simply recommending that peanut be introduced to all infants before 12 months of age, which is in sharp contrast to the initial US guidelines that focused on peanut introduction for high-risk infants. The authors used this extraordinary opportunity for their study because they had previously conducted detailed studies on peanut allergy prevalence at a time when infants were usually not fed peanut in the first year of life.

在本期 JAMA 中，索里亚诺等人报告了澳大利亚 2 个基于人群的横断面样本的结果，这些样本用于评估澳大利亚新婴儿喂养指南引入前后花生过敏的患病率。这些指南采取了最直接的方法，简单地建议在 12 个月大之前将花生引入所有婴儿，这与美国最初专注于高危婴儿引入花生的指南形成鲜明对比。作者利用这个难得的机会进行研究，因为他们之前曾在婴儿出生后第一年通常不喂花生的时候对花生过敏患病率进行了详细研究。

In this study, the investigators recruited infants in 2018- 2019 (n = 1933; median age, 12.5 months) using the same sampling methods that had been used in their 2007-2011 study (n = 5276; median age, 12.4 months). Data were collected on demographic characteristics, food allergy risk factors, peanut introduction, and reactions. In addition, infants had skin prick testing for peanut allergy at 12months of age and, if results were positive, underwent an oral food challenge. Peanut was introduced in the first year far more often in the 2018-2019 sample than in 2007-2011 sample (85.6% vs 21.6%).However,there was no significant difference in the prevalence of peanut allergy in the later vs earlier cohort (2.6% vs 3.1%). In both samples, there was no significant association overall between the age of peanut introduction and the development of peanut allergy; however, among children of Australian ancestry (but not East Asian ancestry) in the 2018-2019 sample, peanut introduction in early infancy was associated with lower risk of peanut allergy than introduction at 12 months or older.

在这项研究中，研究人员在 2018-2019 年（n = 1933；中位年龄，12.5 个月）使用与 2007-2011 年研究（n = 5276；中位年龄，12.4 个月）相同的抽样方法招募了婴儿。收集了关于人口特征、食物过敏风险因素、花生引入和反应的数据。此外，婴儿在 12 个月大时进行了花生过敏的皮肤点刺测试，如果结果呈阳性，则接受口服食物挑战。与 2007-2011 年样本相比，2018-2019 样本在第一年引入花生的频率远高于 2007-2011 样本（85.6% vs 21.6%）。然而，后期与早期队列中花生过敏的患病率没有显着差异（ 2.6% 对 3.1%）。在这两个样本中，花生引入的年龄与花生过敏的发展总体上没有显着相关性；然而，在 2018-2019 年样本中具有澳大利亚血统（但不是东亚血统）的儿童中，与 12 个月或以上的婴儿相比，在婴儿早期引入花生与较低的花生过敏风险相关。

These results present a fascinating conundrum. Despite guidelines based on clinical trial evidence, the findings from the observational study by Soriano et al failed to demonstrate generalizability in the population-based setting. One possibility is that results from the LEAP trial are really not applicable to the general population, either because the benefits of early introduction are specific to high-risk infants or because the benefit requires consistent ingestion of high doses of peanut. Another possibility involves several important caveats about the study population and ecologic design that need to be considered. First, there were significant demographic changes in the study populations being compared. Although both samples were recruited from Melbourne using similar methodologies, the 2018- 2019 group included a higher percentage of participants with a family history of food allergy, parent-reported eczema, and East Asian ancestry, all of which have been associated with an increased risk of food allergy. Second, given the significant difference in the prevalence of peanut allergy among children of Australian ancestry in the 2018-2019 cohort when comparing those with and without early peanut introduction, it is possible that the widespread practice of early introduction substantially attenuatedwhatmight have otherwise been a continued increase in peanut allergy over time.

这些结果提出了一个引人入胜的难题。尽管指南基于临床试验证据，但索里亚诺等人的观察性研究结果未能证明在基于人群的环境中的普遍性。一种可能性是 LEAP 试验的结果确实不适用于普通人群，要么是因为早期引入的好处是高危婴儿特有的，要么是因为这种好处需要持续摄入高剂量的花生。另一种可能性涉及需要考虑的关于研究人群和生态设计的几个重要警告。首先，被比较的研究人群中存在显着的人口统计学变化。尽管这两个样本都是使用类似的方法从墨尔本招募的，但 2018-2019 年组中具有食物过敏家族史、父母报告的湿疹和东亚血统的参与者比例更高，所有这些都与风险增加有关的食物过敏。其次，鉴于 2018-2019 年队列中澳大利亚血统儿童的花生过敏患病率与早期引入和未引入花生的儿童相比存在显着差异，因此早期引入的普遍做法可能会大大减弱原本可能会持续下去的情况花生过敏随着时间的推移而增加。

Studies such as the investigation by Soriano et al are difficult to accomplish, and, to our knowledge, these data represent the only evaluation of early peanut introduction in a population-based setting. Other clinical trials have been conducted, but when it comes to widespread implementation of a novel guideline, other studies have not had the capacity to study prevalence, but have rather utilized surveys to assess guideline awareness and implementation. For example, in 2018, Johnson et al administered a cross-sectional survey to 825 allergists in the US to assess their awareness and implementation of the 2017 National Institute of Allergy and Infectious Diseases (NIAID) Addendum Guidelines for the Prevention of Peanut Allergy. The survey found that nearly all allergists (97.1%) were aware of the guidelines and 64.5% reported full and 34.4% reported partial implementation. Reported barriers to implementation included physician and parent concern about allergic reactions, parent lack of interest in early feeding, lack of referrals, and lack of clinic time. Two other studies or surveys administered to nonallergist physicians in the US (total sample sizes of 50 and 1781 participants) found an overall high rate of awareness, but very low rates of implementation. Both studies found that parental concern or acceptance was a common barrier to implementation and physicians reported a need for further training. However, this field is still evolving. For example, although the 2017 NIAID guidelines that focused on high-risk infants remain in place, the 3 major North American allergy societies have published very different recommendations in an attempt to encourage more widespread early introduction.

诸如索里亚诺等人的调查之类的研究很难完成，而且据我们所知，这些数据代表了在基于人群的环境中对早期花生引入的唯一评估。已经进行了其他临床试验，但是当涉及到新指南的广泛实施时，其他研究没有能力研究患病率，而是利用调查来评估指南的认识和实施。例如，2018 年，约翰逊等人对美国 825 名过敏症专家进行了一项横断面调查，以评估他们对 2017 年美国国家过敏和传染病研究所 (NIAID) 预防花生过敏的附录指南的认识和实施情况。调查发现，几乎所有过敏症患者 (97.1%) 都知道该指南，64.5% 报告完全实施，34.4% 报告部分实施。报告的实施障碍包括医生和家长对过敏反应的担忧、家长对早期喂养缺乏兴趣、缺乏转诊以及缺乏就诊时间。对美国非过敏症医师进行的另外两项研究或调查（总样本量为 50 和 1781 名参与者）发现总体认识率很高，但实施率非常低。两项研究都发现，父母的关心或接受是实施的常见障碍，医生报告需要进一步培训。然而，这个领域仍在不断发展。例如，尽管 2017 年针对高危婴儿的 NIAID 指南仍然有效，但北美 3 个主要过敏学会发布了截然不同的建议，试图鼓励更广泛的早期引入。

The findings of the study on early peanut introduction reported by Soriano et al in this issue of JAMA provide several important insights. First, population-level changes in infant feeding practice are possible. Whether this can be replicated elsewhere is unknown, but the results in Australia clearly demonstrate that feeding practice change is a feasible goal. Second, a general recommendation for early introduction of peanut, even if widely adopted, may not lead to a change in the prevalence of peanut allergy. This suggests that other environmental factors might need to be modified to influence the prevalence of peanut allergy. Further research is needed to determine whether other approaches, such as introducing peanut in doses and frequency similar to those used in the LEAP trial, could reduce peanut allergy. However, in the interim, given the potential for benefit and the low risk of harm, the results of this important study should not dissuade clinicians from following current consensus guidance that recommends early peanut introduction for infants.

索里亚诺等人在本期 JAMA 上报道的关于早期花生引入的研究结果提供了几个重要的见解。首先，婴儿喂养实践的人口水平变化是可能的。这是否可以在其他地方复制尚不清楚，但澳大利亚的结果清楚地表明，改变喂养方式是一个可行的目标。其次，早期引入花生的一般性建议即使被广泛采用，也可能不会改变花生过敏的患病率。这表明可能需要修改其他环境因素以影响花生过敏的流行。需要进一步研究以确定其他方法是否可以减少花生过敏，例如以类似于 LEAP 试验中使用的剂量和频率引入花生。然而，在此期间，鉴于潜在的益处和低危害风险，这项重要研究的结果不应阻止临床医生遵循当前建议婴儿早期引入花生的共识指南。