MICA: Identifying risks for severe life-threatening allergic reactions to foods (IRIS-Allergy)

在英国，食物过敏影响多达3%的成年人和6%的儿童，并会引起严重的反应(过敏反应)，可能是致命的。管理的关键是避免饮食；尽管如此，意外反应还是很常见的。因此，食物过敏的患者会被开出抢救性药物(如肾上腺素自动注射器)来治疗过敏反应。大多数过敏反应不会危及生命，对抢救药物有反应。然而，即使及时注射肾上腺素，也会发生非常严重的反应，并可能导致死亡。目前，我们无法确定最有可能出现严重反应的患者。这对生活质量有很大的不利影响，因为所有对食物过敏的人都必须被视为有生命危险的反应。因此，食物过敏患者、他们的家人和照顾者、食品企业和监管机构必须将安全放在首位，并采取最大限度地规避风险的方法来管理-这是一个重大的公共卫生问题。在这个项目中，我们将解决一个关键问题：为什么一些食物过敏患者会出现近乎致命的反应或死于过敏反应，而大多数人在一生中多次接触和反应食物，却永远不会出现真正威胁生命的反应？我们的团队发现，大多数食物过敏患者如果在医院的食物挑战中多次接触他们过敏的食物，会出现类似的“刻板印象”症状。例如，有些人总是腹痛，而另一些人没有肠道症状，但出现过敏反应。这似乎也是由于社区中发生的意外暴露而引起的反应。此外，食物挑战时症状的严重程度与摄入的过敏原数量没有很好的相关性。这些数据表明，一些患者容易发生非常严重的(和致命的)过敏反应--例如，当他们有过敏反应时，无法补偿。这代表了一种新的范式，可以理解导致严重过敏反应的因素，并表明致命/接近致命的食物过敏反应可以被认为是一种孤儿疾病。我们的假设是，真正威胁生命的过敏反应的患者对食物过敏原有不同的反应，可以识别和预测风险。NHS的基础设施为我们提供了一个独特的机会来调查这一点。PROJECT计划使用NHS数据集，并完全遵守数据保护立法，我们将识别之前在英国NHS医院经历过需要重症监护的生命威胁反应的食物过敏个人(“病例”)。我们还将招募对同一过敏原有较轻过敏反应的患者作为“对照组”。“病例”和对照组都将被邀请参加详细的评估，其中将包括一次彻底的面谈，以评估他们的食物过敏反应情况(S)，以及他们哮喘的倾向和严重程度(这可能会增加严重反应的风险)。我们将使用新的基于芯片的技术来完成对他们过敏的免疫分析。过敏反应是由肥大细胞和嗜碱性粒细胞等“效应”细胞激活引起的。我们将调查过敏反应严重程度的差异是否与皮肤和血液中这些“效应”细胞的反应性差异有关。我们还将为未来的遗传分析收集样本，以评估可能导致更严重反应的特征。通过进行这项评估，我们将能够将病例与对照进行比较，确定对食物近乎致命的过敏反应的情况，并确定严重后果的风险因素。我们的长期目标是开发一种风险计算器，可供临床医生用于识别那些潜在致命反应风险最高的人。

Food allergy affects up to 3% of adults and 6% of children in the UK, and causes serious reactions (anaphylaxis) which can be fatal. Key to management is dietary avoidance; despite this, accidental reactions are common. Food-allergic patients are therefore prescribed rescue medication (such as adrenaline auto-injectors) to treat anaphylaxis. Most allergic reactions are not life-threatening, and respond to rescue medication. However, very severe reactions do occur and can cause death, even if adrenaline is injected in a timely manner.Currently, we are unable to identify patients at greatest risk of severe reactions. This has a significant adverse impact on quality of life, since all food-allergic individuals must be considered as being at risk of life-threatening reactions. As a result, food-allergic patients, their family and carers, food businesses and regulatory authorities have to prioritise safety and take a maximum risk-averse approach to management - creating a major public health issue.In this project, we will address a key question: can we explain why some food-allergic individuals have near-fatal reactions or die from anaphylaxis, whereas the majority will never have a truly life-threatening reaction despite multiple food exposures and reactions during their lifetime?Our group has discovered that most food-allergic patients have a similar pattern of 'stereotypical' symptoms if exposed to the food they are allergic to on multiple occasions at in-hospital food challenges. For example, some always suffer abdominal pain, whilst others do not experience gut symptoms but present with anaphylaxis. This also seems to be the case for reactions due to accidental exposure happening in the community. Furthermore, the severity of symptoms at food challenge do not correlate well to the amount of allergen eaten. These data suggest that some patients have a predisposition towards very severe (and fatal) anaphylaxis - for example, an inability to compensate when they have an allergic reaction. This represents a new paradigm in understanding factors which contribute to severe outcomes in anaphylaxis, and suggests that fatal/near-fatal food-anaphylaxis could be considered an orphan disease.Our hypothesis is that patients with truly life-threatening anaphylaxis have a different response to food allergen, which can be identified and used to predict risk. The infrastructure of the NHS provides a unique opportunity for us to investigate this.PROJECT PLANUsing NHS datasets, and in full compliance with data protection legislation, we will identify food-allergic individuals who have experienced a previous life-threatening reaction requiring intensive care in an NHS hospital in England ("cases"). We will also recruit patients who experienced a less severe anaphylaxis reaction to the same allergen around the same time, as "controls".Both "cases" and controls will be invited to attend for a detailed assessment, which will include a thorough interview to assess the circumstances of their food allergic reaction(s), and their tendency to asthma and its severity (which could increase the risk of severe reactions). We will complete immune profiling of their allergies using novel chip-based technologies. Anaphylaxis is caused by the activation of "effector" cells such as mast cells and basophils. We will investigate whether differences in anaphylaxis severity can be linked to differences in reactivity of these "effector" cells in the skin and blood. We will also collect samples for future genetic analyses to assess for traits which might predispose towards more severe reactions.By undertaking this evaluation, we will be able to compare cases to controls, to define the circumstances of near-fatal anaphylaxis reactions to food, and identify risk factors for severe outcomes.Our longer-term aim is to develop a risk calculator which can be used by clinicians to identify those at greatest risk of potentially fatal reactions.