Risk Factors and Severity (Module 2)

Severe, potentially life-threatening, allergic reactions to food have a significant impact on the quality of life of food allergic patients. They are at the basis of the anxiety and fear common to these patients and their relatives. An important knowledge gap, which is relevant to evidence based risk management of food allergies, is the inability to predict accurately whether, and if so when, food allergic patients will develop such reactions.

Biomarkers, which are bedded in the mechanisms of disease, are more powerful than markers identified simply by association and there are three factors that appear to be involved in driving more severe reactions, the food and food allergens themselves, patient-associated intrinsic factors and, extrinsic factors:

Food and food allergens

Some foods are known potentially to induce severe anaphylactic reactions, such as egg and milk in early childhood, and peanut, tree nuts, fish and shellfish persistently throughout life. Preliminary analyses on the EuroPrevall dataset have revealed that other, lesser known foods such as sunflower seeds are probably associated with anaphylaxis, especially in some Mediterranean and Central European countries.

It is well-accepted that a ‘dangerous’ food contains allergens that are sufficiently resistant to gastro-intestinal proteolysis allowing them to cross the gut epithelial barrier and cause systemic reactions. Legume and tree nut storage proteins such as peanut 2S albumin (Ara h 2) and, lipid transfer proteins (LTP) such as peach LTP (Pru p 3) are probably the best characterised molecules in this category. They are both highly resistant to proteolysis and have been identified as risk factors for severe symptoms.

Nevertheless, a highly significant number of patients (60 to 70 per cent) sensitised to such stable allergens only experience mild symptoms, usually limited to the oral cavity. This means that, besides protease-resistance, other factors determine the clinical outcome of exposure to potentially severe (stable) allergens.

Patient-associated intrinsic factors

Patients with a severe food allergy often report an almost immediate tingling sensation in the mouth, upon exposure to tiny quantities of the offending food. An anaphylactic reaction can occur within a few minutes, a significant amount of time before the food allergen has had the chance to pass through the stomach into the intestinal tract and interact with the relevant sub-epithelial mast cells. This suggests that the process of anaphylaxis begins when the allergen is exposed to the oral (or oesophageal) mucosal/epithelial barrier.

The kinetics of the uptake of food proteins over the oral mucosal barrier is a poorly understood process that may differ between patients with mild and severe food allergy. Anaphylactic patients may have a more permeable mucosal/epithelial barrier in the oral cavity but possibly also in the intestinal tract.

In addition to differences in the physical barrier function, the innate immune function of epithelial cells may also differ, and the number of sub-epithelial tissue mast cells and/or their sensitivity to allergen may distinguish mild from severe patients. Also, differences in the responsiveness of basophils may play a role.

Extrinsic factors (food, lifestyle, environment and infections)

Thresholds for allergic reactions to food have considerable inter-individual variability. However, it is assumed that each patient can develop severe reactions, even the ones with a high threshold, if exposure is high enough. As well as the dose of a food, the way it is consumed (pure unprocessed, processed and/or as part of a composite food) may also play a role. The matrix in which a food allergen is presented to mucosal surfaces, both with respect to its composition and its way of processing, is an extrinsic factor that has a significant impact on the release and uptake of food allergens (see also Module 4).

Other extrinsic factors that may influence allergen uptake include: exercise shortly after food consumption (exercise-induced anaphylaxis); alcohol use; and, the use of non-steroidal anti-inflammatory drugs (NSAID) and antacids. Exercise-induced anaphylaxis is most commonly, but not exclusively, associated with wheat allergy. All these extrinsic factors are thought to increase gut permeability thereby lowering the threshold for severe reactions. However, quantitative data are not available. Some of these extrinsic factors may very well synergize into a ‘party challenge’ (dinner, alcohol, dance, preventive aspirin or antacid), of which the quantitative impact is even more complex.

Stress and sleep-deprivation are also considered extrinsic factors that increase the risk for severe reactions. Infections such as the common cold (rhinovirus) and flu (influenza virus) have been implicated in the increase of hyper-responsiveness and may lower thresholds or increase the severity of a reaction. Available literature shows that the effects attributed to most of these extrinsic factors are largely based on anecdotal information. Experimental evidence, both clinically and at laboratory level, is needed to facilitate better understanding of the mechanisms by which severe reactions occur, but also to be able to quantify their impact on threshold doses. This information is crucial for appropriate risk management of food allergy.

Module 2 will identify biomarkers and risk factors for severe allergic reactions to food and provide solid experimental evidence as to how intrinsic and extrinsic factors modulate the risk for severe reactions to food.