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

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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.