Adverse food reactions can be classified into toxic and non-toxic; ¹ toxic reactions occur in any individual exposed to a sufficient dose of a substance, but non-toxic ones only occur in an individual susceptible to certain foods. Non-toxic reactions are classified as food hypersensitivity (FHS) reactions, with reactions to foods involving immunologic mechanisms defined as food allergy (FA), and divided into IgE and non-IgE mediated reactions (see Figure 7.1). ^2,3

FHS reactions not known to involve the immune system are classified as non-allergic FHS, but may also be referred to as non-toxic, non-immunologic reactions. ^3,4 These reactions include enzymatic reactions such as lactose intolerance and carbohydrate malabsorption, and pharmacological reactions related to the ingestion of foods containing vasoactive amines or salicylates. Conditions such as food-dependant, exercise-induced anaphylaxis (FDEIA) and reactions to food additives may involve the immune system, but the aetiology and pathogenic mechanisms are uncertain. ⁴

About 20% of the population alter their diet because they believe they react to a food or food component; however, perceived prevalence is usually much greater than actual prevalence. ^{5.6. and 7.} The prevalence of allergic disorders is associated with age and commonly referred to as the ‘allergic march’ with food allergy and atopic dermatitis predominating in early years and asthma and allergic rhinitis peaking in teenage and adult years. ⁸ Most IgE-mediated FA is acquired in the first 1–2 years of life, but it is still unknown whether most FA in adults represents a persistence of childhood symptoms or is a response primarily initiated in adulthood. ⁹ Up to 4% of adults may have an IgE-mediated FA, with prevalence often linked to aero-allergen sensitisation. ^{10.11.12. and 13.} The most prevalent non-IgE mediated FA is coeliac disease, common in Europe, southern Asia, the Middle East, Africa and South America and thought to affect 1% of the UK population. ^14,15

The prevalence of non-immune mediated FHS is variable. Lactose intolerance affects on average 6–12% of Caucasians, but the range is very wide with 2% of Scandinavians and 70% of Sicilians being intolerant, and as many as 80–100% of Africans and Asians. ¹⁶ About 70% of people with irritable bowel disorder feel they have a problem with food and often link the consumption of milk and wheat to their symptoms. In one study, 42% of subjects perceived milk to cause their symptoms, and about 15% felt wheat in the form of bread or flour caused intolerance. ¹⁷

Food allergic reactions are mediated by the immune system. There are two types of immunity, innate and adaptive. The main cells involved in adaptive immunity, the T and B lymphocytes, can recognise substances produced by microbes and non-infectious molecules known as antigens. ¹⁸ Sometimes antigens from pollens, animal dander or food proteins elicit immune responses known as hypersensitivity reactions; when this happens the antigens are known as allergens. ¹⁹ B lymphocytes (B cells) produce the antibodies immunoglobulin M (IgM), IgG, IgA and IgE; IgE is the main antibody involved in food allergy. ²⁰ T lymphocytes (T cells) can be either cytotoxic T cells or T helper (Th) cells, and it is the latter that are involved in FHS reactions. When activated by the antigen, Th cells develop into either Th1 cells or Th2 cells, depending on the type of mediator proteins (cytokines) the antigen-presenting cell (APC) is secreting. ¹⁸ When a Th2 cell is activated, it produces cytokines which make B cells produce IgE antibodies specific to the antigen presented to the T cell. ²¹ This antigen-specific IgE does not circulate freely but attaches itself to surfaces of mast cells and blood basophils. ²² Re-exposure enables the antigen to bind onto the specific antibody and when several IgE antibodies on the mast cell bind to the antigen, the mast cell degranulates and releases preformed mediators which cause the symptoms of food allergy (see Figure 7.2).

This response is immediate hypersensitivity or type I hypersensitivity and is the response that predominates in FHS. There are three other types of hypersensitivity reactions; types II and III are not thought to be involved in food allergy, but non-IgE-mediated food allergy may involve a type IV hypersensitivity which is cell-mediated and generally involves Th1 cells. Whereas type I hypersensitivity is immediate, type IV reactions are delayed; examples of type IV hypersensitivity include contact dermatitis and food-protein-induced entercolitis. In coeliac disease, a response to allergens found in cereals promotes an inflammatory reaction which involves both innate and adaptive immunity.

For non-immune-mediated FHS, the pathogenic mechanisms underlying the reactions are diverse and often unknown. There is evidence that in IBS patients, the anti-inflammatory response in respect to cytokine production may be suboptimal and also that there are increased levels of food-specific IgG antibodies. ²³ Lactose intolerance is caused by lactase activity decreasing after weaning, and this occurs in 70% of adults worldwide, mainly from non-Caucasian races. ¹⁶

Food allergen nomenclature is composed of the first three letters of the genus, the first letter of the species name followed by an Arabic number (http://www.allergen.org). ²⁴ For example, the botanical name for peanut is Arachis (genus) hypogaea (species) so the allergens are labeled Ara h 1, Ara h 2, etc. Food allergens are graded as either class 1 or class 2 allergens, and one food may have both class 1 and class 2 allergens. ²⁵ Class 1 allergens are large water-soluble glycoproteins, stable to heat, acids and proteases, which allows them to sensitise during ingestion, breaching the normal immune tolerance to foods. ^5,26 Class 2 allergens are usually heat labile, difficult to isolate and susceptible to enzymatic degradation, and so cannot sensitise upon ingestion. ²⁵

An allergen will have one or more sequences of amino acids known as epitopes, which are recognised by the antibody, thus enabling the allergen to bind with the antibody. There are two types of epitopes; sequential (linear) epitopes are composed of single segments of sequential amino acids along the polypeptide chain. Conformational epitopes are composed of amino acids from different parts of the protein sequence, brought together by folding. Conformational epitopes can be destroyed when the protein is altered due to heating or proteolysis, whereas sequential epitopes are not affected. Epitopes on different allergens can have a degree of amino acid sequence similarity, known as homology, which enables an antibody specific to one allergen to bind with another structurally similar allergen epitope. Homologous epitopes are common in food allergy, and account for the cross-reactivity between different foods and also between foods and pollens.

A wide range of foods and food additives are implicated in the spectrum of FHS; however, cow milk, eggs, fish, shellfish, soy, wheat, peanuts, tree nuts and seeds account for 90% of IgE-mediated food reactions. ²⁷ Adults are most likely to have IgE-mediated allergy to fruits, fish, shellfish, peanuts and tree nuts. ⁵

One of the most important steps in the diagnostic process is establishing a good clinical history. ⁴ The history should uncover facts about the likely foods causing the reaction, quantity associated with a reaction, speed of onset of symptoms, duration of symptoms and other factors such as whether the reaction is concurrent with exercise, medications or alcohol. ⁵ The history can help determine whether the FHS is likely to be immune-mediated and therefore likely to involve specific IgE antibodies. IgE-mediated reactions are usually immediate, and involve allergic symptoms such as pruritis (itching), which may be accompanied by flushing, angiooedema (swelling) and hives or urticaria. These symptoms may be localised or systemic and accompanied by a fall in blood pressure, tachycardia and bronchospasm. A reaction characterised by severe systemic symptoms is known as anaphylaxis and can be fatal. Other symptoms accompanying the reaction or appearing later on are nasal symptoms such as rhinorrhoea, sneeze, blockage or sinus involvement, and respiratory symptoms such as wheeze, cough and reduced lung capacity.

The symptoms of non-IgE-mediated FA may include atopic dermatitis (eczema) or non-specific GI symptoms which may appear some hours after the food has been eaten. Non-immune-mediated FHS reactions also can be delayed, although for some triggers such as histamine- or sulphite-containing foods, the symptoms can occur within 30 minutes of ingestion. The difference between FA and non-immune-mediated FHS is that the latter is often not obviously connected to just one food.

Poor dietary recall or concern about nutritional adequacy can be remedied by asking the patient to complete a diet diary. However, the clinical history can be inaccurate due to cross-reactions, or because the food has been contaminated or infested with parasites due to which the allergy is occurring. In most cases, the history should therefore be confirmed or refuted through the undertaking of different tests.

An important clue to the role of a food causing problems can be derived from the resolution of symptoms upon removal of that food. ⁶² Diagnostic diets involve the supervised exclusion of a suspected food, followed by its reintroduction in the form of an oral food challenge. All patients should keep a symptom diary, to record symptoms related to the exclusion and subsequent reintroduction of foods, and also to check that foods are actually being reintroduced in a systematic way. Where there is strongly positive specific IgE to a known food trigger which elicits immediate symptoms, there is no requirement for a diagnostic diet; the patient should be advised to avoid that food. ⁶³ Where there is discordance between the specific IgE tests and the clinical history, a 4- to 6-week avoidance of a food or food group may be helpful; if symptoms improve, then an oral food challenge should be carried out. ⁶⁴ Patients waiting for a diagnosis are often already avoiding suspect food(s); however, their dietary intake should be checked as they may be ingesting small amounts of the suspect food allergen without realising.

Where there is no obvious food trigger, or non-IgE-mediated FA or non-immune-mediated FHS is suspected, then a multiple exclusion diet or oligoantigenic might be useful. ⁶⁴ Such diets normally exclude foods most frequently implicated in allergic responses such as milk, grains, eggs and often citrus fruits, nuts, coffee and chocolate. ²⁷ This diet is followed for 2–3 weeks and then foods are reintroduced singly and gradually at intervals of a few days. However, for those who report severe symptoms, or where psychological factors including food aversion may be involved, the reintroduction of food should be viewed as a food challenge and carried out under controlled conditions. A total exclusion diet is used when other avenues fail, or when extreme self-imposed restrictions need to be assessed. The diet usually consists of one meat (e.g. turkey, rabbit or lamb), two to three vegetables such as carrots, broccoli or cauliflower, two fruits (excluding citrus fruits), and two starchy foods such as rice, sago, tapioca or buckwheat. ⁶⁵ The diet should be followed for a maximum of three weeks, and key foods reintroduced singly, two or three per week.

The aim of the oral food challenge (OFC) is to confirm or refute the involvement of a food, food additive or food component in triggering the individual’s clinical symptoms. ⁶⁶ Only 30-50% reported reactions to food are confirmed by an OFC, and since food allergy has a significant impact on the quality of life for the sufferer, challenges are essential in order to avoid unnecessary food restriction or misdiagnosis. ^27,67,68 European Guidelines suggest that OFC should be used for everyone with a history of adverse foods reactions in order to establish or exclude a diagnosis of FHS. ⁶⁹ The two main types of OFC are the open challenge (OC), where the food is not disguised, and the double-blind placebo-controlled food challenge (DBPCFC), where the food is disguised so that neither the subject nor the person administering the challenge is blinded as to the challenge dose. ²⁷

An OC is most suitable for immediate-onset IgE-mediated food allergy with objective symptoms that can be seen and recorded independently, or when a negative outcome is expected. For standard clinical practice, the OC is the most practical option and guidance suggests it can precede DBPCFC; a negative result negating the need for DBPCFC. ⁶⁹ Some protocols commence with a labial challenge; the suspect food is rubbed on the outer lip and then exposed to the oral mucosa without being swallowed. For some types of allergy to fruits and vegetables, good contact with the oral mucosa is vital and a portion of the food may be sucked/chewed and disgorged as a starting dose prior to ingestion. ^37,70 The starting dose of the suspect food should be half that reported to cause a reaction, with subsequent doses increased incrementally (usually double the preceding dose) (see Figure 7.4) given every 15 minutes, depending on the reported speed of onset of symptoms. ⁶⁴ The total amount of the suspect food given during the whole challenge should equal 8–10 g of dry food or 100 ml liquid or 200 g solid ‘wet’ food. ⁶⁴ European guidelines recommend that the final dose should equate to a standard portion of that food. ⁶⁹

For DBPCFC, the suspected food is hidden inside a carrier such as a biscuit, custard, fruit puree or even a hamburger. Coffee powder, cocoa powder or peppermint syrup can be used to disguise the taste of foods, and blackcurrants can disguise both taste and colour. Peel and pips may need to be removed from fruits although this does remove some of the allergen, making blinded challenges with fruits and vegetables difficult. It is recommended that fresh rather than dried food should be used, unless the dried food has been specially formulated for use in DBPCFC and its allergenicity tested prior to use. ^71,72 DBPCFC are best performed using two placebo and one active challenges, randomised and given sequentially, with each challenge being given as a titrated dose as with the open challenges. Best practice recommends these challenges be given on 3 separate days but if not possible then the patient needs to be symptom free before the next challenge may commence. ^73,74 Challenges for delayed reactions will need also to be given over several days, but it may be possible to complete these at home, depending on the severity of symptoms. Augmentation factors also need to be considered, such as exercise, ⁷⁵ aspirin, infection, hormonal and multiple food combinations as these may all affect the final outcome of challenge. ^4,66

The difficulties experienced when undertaking challenges lead some to suggest they may not be necessary for most patients. ^66,76 Predictive values for SPT and sIgE, together with better allergen reagents, may reduce the number of challenges needed, but some IgE-mediated hypersensitivity responses are so localised that they are undetected by IgE testing and can only be confirmed by food challenge. ⁷⁷

The main management of any FHS will be to avoid known food triggers; this is greatly facilitated by EU labelling regulations, ⁷⁸ which require specified allergens to be declared on prepackaged foods if they have been added deliberately, however small the amount. The foods covered include cereals containing gluten, crustaceans, eggs, fish, peanuts, soybeans, milk, nuts, celery, mustard, sesame seed and sulphur dioxide and sulphites at more than 10 mg/L/kg. The directive was updated in 2007 to include lupin and molluscs. ⁷⁹

Thus dietary exclusion can be straightforward although it is important to review the patient’s current diet to assess inadvertent consumption of allergens. It is also important to give advice which will minimise accidental allergen exposure, such as occurring through inhalation of aerosolised allergens, transfer of allergens during cooking, touch and absorption through the skin, traces in foods and even kissing. ⁴ The Food Standards Agency has issued guidance for industry on risk assessment, although there is as yet no legislation for unwrapped foods or foods consumed in restaurants, ⁸⁰ which is unfortunate since many reactions occur when eating out of the home. ⁸¹

Food avoidance can affect quality of life, ⁶⁸ and social life is improved after the reintroduction of foods following a negative challenge. ⁸² Children, teenagers and adults with FA experience problems associated with their FA irrespective of age. ⁸³ Adolescents and young adults with food allergy may indulge in risk-taking behaviour, knowingly and purposefully ingesting potentially unsafe foods. ⁸⁴ It is important to discuss any concerns and anxieties the patients have to help them live with a high degree of confidence and a feeling of being in control of their life. ⁸⁵