Improved diagnostics in food allergy (ID-in-FA) Study

食物过敏是一个日益严重的公共卫生问题，影响了英国2%的成年人和6%的儿童。它是危及生命的过敏反应（过敏反应）的最常见原因。过敏反应是过敏原特异性免疫球蛋白E （IgE）抗体与食物过敏原相互作用的结果，引起全身免疫细胞（包括肥大细胞）的激活。诊断的“金标准”测试是一种正式的食物挑战，在医疗监督下增加食物剂量。然而，由于可能诱发严重甚至致命的过敏反应，食物挑战既耗时又昂贵，而且并非没有风险。在实践中，通常使用替代方法诊断IgE介导的食物过敏：检测相关食物的特定IgE（称为“致敏”），要么在皮肤中（通过皮肤点刺试验），要么在血液中。不幸的是，这些措施高估了真正的临床过敏率。在以人群为基础的大型研究中，超过50%的对某种食物进行皮肤试验呈阳性的人可以食用这种食物，而不会出现临床症状。抗体存在，但不导致肥大细胞活化。使用单独评估致敏性的测试会导致过度诊断，造成不必要的饮食/社会限制和焦虑，从而损害营养和生活质量：儿童食物过敏的不利影响比糖尿病和其他慢性疾病造成的影响更大。这反过来又增加了对食品挑战的需求，这对于明确诊断是必要的。因此，在门诊环境中进行更安全、负担更少的诊断是一个重要目标。在本提案中，我们将评估两种新的互补测试准确诊断食物过敏的能力。我们将招募从我们的过敏专科诊所招募的过敏状态不确定的儿童和年轻人，他们将接受正式的食物挑战，以明确对花生，鸡蛋或牛奶的食物过敏的诊断。除了在食物挑战之前立即进行常规过敏测试外，我们还将进行：肥大细胞活化试验——将肥大细胞（由捐献血液中的前体细胞产生）与患者的少量血液一起培养，然后暴露于食物过敏原中，测量肥大细胞的反应。我们的试点数据表明，这是一个强大的测试，具有出色的能力区分真正的过敏和单纯的致敏。鼻内食物刺激——一种快速而直接的过程，将少量的食物蛋白质注入鼻腔，在过敏人群中引起轻微的类似花粉热的反应，而非过敏人群则不会。作为英国国家免疫计划的一部分，该技术与用于初级保健的鼻内流感疫苗相同。参与一项初步研究的参与者反馈说，他们发现鼻内刺激没有临床症状，这让人放心，减少了他们自己和家人对随后食用这种食物证明没有临床过敏的担忧。我们将评估这些测试与传统过敏测试的比较，以确定准确诊断食物过敏的最佳策略，而无需正式的食物挑战。我们的初步数据表明，这两种技术可能赋予显著的诊断准确性比现有的过敏试验。这项研究将提供必要的验证，以确保后续的转化资金和商业投资，加速产品开发，通过监管部门的批准，最终进入临床应用。这将有助于医疗保健专业人员提供更准确的诊断，让患者和家长放心，以及为NHS提供经济节省。

Food allergy is an increasing public health issue, affecting up to 2% of adults and 6% of children in the UK. It is the most common cause of life-threatening allergic reactions (anaphylaxis). An allergic reaction is a consequence of an interaction between allergen-specific Immunoglobulin E (IgE) antibodies and a food allergen, causing activation of immune cells including mast cells found throughout the body. The "gold standard" test for diagnosis is a formal food challenge, in which increasing doses of food are given under medical supervision. However, food challenges are time-consuming, costly, and not without risk, due to the potential for inducing severe or even fatal anaphylaxis. In practice, IgE-mediated food allergy is usually diagnosed using a surrogate: the detection of specific IgE to the implicated food (called "sensitisation"), either in the skin (through skin prick testing) or blood. Unfortunately, these measures over-estimate the rate of true clinical allergy. In large, population-based studies, over 50% of those with a positive skin test to a food can eat that food without clinical symptoms ie. the antibody is present, but does not result in mast cell activation. The use of tests which assess sensitisation alone results in over-diagnosis, causing unnecessary dietary/social restrictions and anxiety which can impair nutrition and quality of life: the adverse impact of food allergy in children is greater than that caused by diabetes and other chronic illnesses. This, in turn, increases demand for food challenges which become necessary to clarify the diagnosis. Safer and less burdensome diagnostics which can be performed in the outpatient setting are therefore an important goal.In this proposal, we will assess the ability of 2 novel, complementary tests to accurately diagnose food allergy. We will recruit children and young people with indeterminate allergic status despite conventional allergy testing, who have been recruited from our specialist allergy clinic and are due to undergo formal food challenge to clarify a diagnosis of food allergy to peanut, egg or cow's milk.In addition to undertaking conventional allergy tests immediately prior to the food challenge, we will perform:1. Mast cell activation test - in which mast cells (generated from precursor cells in donated blood) are incubated with a small amount of blood from the patient and then exposed to the food allergen, and the mast cell response measured. Our pilot data indicates this is a robust test, with excellent ability to distinguish between true allergy and sensitisation alone.2. Intranasal food challenge - a quick and straightforward procedure in which very small amounts of food protein are administered into the nose, causing a mild hay fever-like response in allergic, but not non-allergic individuals. The technique is identical to that used for the intranasal influenza vaccine given in primary care as part of the UK National Immunisation Schedule. Feedback from participants who participated in a pilot study reported that they found the lack of clinical symptoms at intranasal challenge to be reassuring, reducing both their own and their families' concern over subsequently eating the food to demonstrate no clinical allergy.We will assess how these tests compare to conventional allergy testing, to determine the best strategy to accurately diagnose food allergy without the need for formal food challenge.Our preliminary data indicates that both techniques may confer significant diagnostic accuracy over existing allergy tests. This study will provide the necessary validation to secure follow-on translational funding and commercial investment, to accelerate product development through to regulatory approvals and, ultimately, clinical use. This will assist healthcare professionals in providing more accurate diagnoses, reassurance to patients and parents alike, as well as delivering economic savings to the NHS.