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

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.

AIM
To determine the diagnostic accuracy of two complementary, novel approaches to diagnose food allergy, in a representative clinical cohort.

BACKGROUND
Food allergy is an increasing public health issue affecting up to 6% of UK children, and can cause life-threatening anaphylaxis. Conventional tests assess the presence of allergen-specific IgE ("sensitisation") rather than true clinical reactivity, and are associated with a false positive rate of over 50%. This results in over-diagnosis, causing unnecessary dietary/social restrictions and anxiety. Improved diagnostics which can be performed in the outpatient setting are thus an important goal.

METHODS
We will recruit children with indeterminate allergic status despite conventional testing, recruited from our specialist clinic and undergoing open, oral food challenge (FC) to clarify a diagnosis of food allergy to peanut, egg or cow's milk.
Skin prick testing, blood tests (incl. components) will be performed immediately prior to oral FC, together with:
1. Intranasal food challenge - a straightforward procedure in which low doses of food protein are administered into the nasal mucosa, causing a mild hay fever-like response in allergic but not non-allergic individuals.
2. Mast cell activation test (MAT) - in which patient sera are incubated with primary human mast cells and subsequently stimulated by allergen in vitro: pilot data indicates this is a robust test, with excellent diagnostic performance.

The results of these tests will be compared to conventional tests, using Receiver Operating Characteristic curve analysis (with oral FC as the gold standard).

TRANSLATIONAL CAPABILITY
Pilot data indicates both techniques confer significant diagnostic accuracy over existing conventional testing. 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.

1. Health and Social Outputs : Individuals

Our experience from ongoing studies in food-allergic individuals is that families (and often their affected child) wish to know as much as possible about their food allergy (FA). Our study participants will benefit from additional contact with the research team and opportunity to ask questions. The intranasal challenge may also provide further reassurance than low-level allergen exposure does not usually cause significant allergic reactions. Participation may therefore provide additional opportunities for education and reassurance in terms of risk-minimisation strategies in the future.

2. Health and Social Outputs : Public Services and Health Policy

Health policy: IgE-mediated food allergy is an increasing public health issue, affecting 6% of UK children. Our inability to diagnose food allergy accurately without formal food challenge is a significant contributor to the burden of FA to individuals, and healthcare systems. Conventional testing is associated with a significant false positive rate of over 50% in population-based studies. This causes over-diagnosis, anxiety in affected individuals and their families, and unnecessary dietary/social restrictions. Healthcare costs for a person with FA are increased (~$1000 per annum in a study conducted in USA, twice this for those with previous severe allergic reaction). If we can improve the accuracy of the diagnostic algorithm, this will lead to improved quality of life and reduced healthcare costs.

Voluntary sector: A number of support groups and charities have been established to support food-allergic patients and their families. Food allergy has a high impact on quality of life measures. By providing improved diagnostics, the study will empower these groups to provide more comprehensive information to allergic individuals in the UK, within a timeframe similar to that of the publication of the study results.

3. Economic benefits : National and Global

Food allergy is increasing throughout the world, and is now a global issue. Cheaper, more accurate diagnostics will reduce both healthcare costs and the impact of a diagnosis of food allergy for individuals; given that up to 6% of children have food allergy and many more are given an incorrect diagnosis of food allergy, this could potentially have more widespread benefits affecting a significant proportion of the population at a national level and beyond.

Industry may benefit from the Knowledge developed in this study, particularly in the development of human primary mast cells that are non-tumour derived, and the development of mast cell activation assay in screening for unintended allergen presence during food manufacture / allergenicity assessments of novel foods and processes, by the food industry and government regulators.