Posted: March 2017
Alessandro Fiocchi, MD and Vincenzo Fierro, MD
The Bambino Gesù Children’s Research Hospital
Rome, Holy See
The classification of allergic and hypersensitivity diseases was established by the European Academy of Allergy and Clinical Immunology (EAACI) and the World Allergy Organization (WAO) in 2004 (1). The definitions and concepts of allergic and hypersensitivity conditions beyond the allergy community have often created misunderstanding (2). For an optimal clarification:
- the term “atopy” is used when individuals have an IgE sensitization as documented by IgE antibodies in serum or by a positive skin prick test;
- “hypersensitivity” is defined as “conditions clinically resembling allergy that cause objectively reproducible symptoms or signs, initiated by exposure to a defined stimulus at a dose tolerated by normal subjects”, and
- “allergy” is defined “a hypersensitivity reaction initiated by proven or strongly suspected immunologic mechanisms”.
Based on these definitions, a correct diagnosis of allergic disease must adhere to the following conditions:
a) Compatible clinical history; and
b) Positivity to in vivo and/or in vitro tests to prove underlying mechanism and etiology.
The tests alone cannot be used because many people are sensitized (positive results to in vivo and/or in vitro tests), but not allergic (no reactions).
Specifically for ‘food allergy’, this term is used when a causal relationship (ideally, with a specific immunological mechanism) has been defined. There are three broad groups of immune reactions: IgE-mediated, non-IgE-mediated and mixed. The IgE-mediated reactions are usually divided into immediate-onset reactions (arising up to 2 hours from the food ingestion) and immediate plus late-phase (in which the immediate onset symptoms are followed by prolonged or ongoing symptoms). Non-IgE-mediated reactions, which are poorly defined both clinically and scientifically, are believed to be generally T-cell-mediated. They are typically delayed in onset, and occur 4 to 28 hours after ingestion of the offending food(s). Mixed IgE and non-IgE mediated reaction are conditions associated with food allergy involving both IgE- and non-IgE-mediated mechanisms (3).
A series of adverse reactions to foods do not involve an immune response and are not considered food allergies (4). These include metabolic disorders (for instance, lactose and alcohol intolerance), responses to pharmacologically active food components, as caffeine, theobromine in chocolate or tyramine in fermented cheeses, or toxic reactions. Toxic reactions to food can occur in any patient, if a sufficient amount of the food is ingested; they are due to toxins in the food, e.g., to histamine in scombroid fish or bacterial toxins in food.
While sometimes these, and other presumed food allergic reactions, are defined “food intolerances”, this term should not be used to define an allergic reaction (5). Host factors such as lactase deficiency, which are associated with lactose intolerance, or idiosyncratic responses may be responsible for other non-allergic reactions to foods.
Typical food allergies are IgE-mediated, but several reactions involve different immunologic mechanisms. These food allergies are defined as non–IgE-mediated or mixed IgE- and non–IgE-mediated.
The symptoms of IgE-mediated, non-IgE–mediated, and mixed IgE- and non–IgE-mediated food allergy are presented in Table 13. IgE-mediated symptoms develop within minutes to 1-2 hours of ingesting the food, non–IgE-mediated and mixed IgE- and non–IgE-mediated food allergies present with their symptoms several hours after the ingestion of the food.
All these manifestations derive from a failure to develop or a breakdown of food tolerance, resulting in excessive production of food-specific IgE antibodies or in altered cellular events, leading to allergic reactions. Environmental influences and genetic factors of the host underlie the immunopathogenesis of food allergy and its manifestations. Some clinical studies have revised our understanding of the cause of food allergy. For example, functional genetic variants in the IL-12 receptor b1, Toll-like receptor 9, and thymic stromal lymphopoietin genes and even IL-4 gene polymorphism have been associated with an increased risk of food sensitization (6). In the future, the elucidation of the gene-environment interactions will be crucial for understanding the food allergy pathogenesis. Microbiome, i.e., -omic, studies are an emerging field of interest to define allergy pathogenesis and, in a not too distant future, the microbiome could offer novel therapeutic possibilities (7).
Food allergy is described as an increasing disease over time. It is generally accepted that food allergy affects approximately 2.5% of the general population, but the spread of prevalence data is wide, ranging from 1% to 10%. Accurate determination of the prevalence is still one of the major problems with food allergy, considering that many factors influence the reported prevalence of food allergy. The varied factors include differing criteria for making food allergy diagnosis, study methodologies, geographic variation, ages, and dietary exposures to name a few. In European birth cohorts, the incidence ranges from 2.18% (United Kingdom) to 0.07% (Greece) (8).
The most common foods, eaten separately or included as an ingredient, even in trace amounts (hidden food), that elicit hypersensitivity reactions are milk, egg, wheat, fish, and nuts.
Despite the fact that up to 2.5% of newborn during the first years of life are diagnosed as allergic to cow's milk, recent European prevalence data fix the prevalence of cow’s milk allergy (CMA) to 0.7% (9).
Within the EuroPrevall birth cohort, the mean adjusted incidence of hen’s egg allergy was 1.23% (10), while the Australian Healthnuts study reports a prevalence of 9% (11).
The prevalence of peanut allergy among children in the United Kingdom, North America, and Australia has been reported doubled in 10 years and is approximately 1.8%, 1.4%, and 3.0% respectively.
Fish allergy prevalence ranges from 0% to 7% and the prevalence of shellfish allergy from 0% to 10.3%, depending on the method used for diagnosis. The only study using food challenges reports a prevalence of fish allergy of 0% - 0.3% and a prevalence of shellfish allergy ranging between 0% and 0.9%. Fish allergy seems more frequent in Asia (12) than in Western countries (13).
Epidemiological studies reveal that among food-allergic infants, approximately 80% will reach tolerance by the fifth birthday, but 35% of them may eventually develop hypersensitivity to other foods. Those with the highest IgE levels, with the most serious clinical manifestations (anaphylaxis and asthma), and with the wider co-sensitizations are less likely to overgrowth their food allergy. The natural history of food allergy also depends on the specific food sensitization, with children allergic to milk and egg displaying a better prognosis than those allergic to peanuts, tree nuts and fish(14).
Component Resolved Diagnosis (CRD) elucidated the link between a severe allergy to pollen and the increase of oral allergy syndrome (OAS), exercise induced asthma and anaphylaxis when eating certain foods. Such reactions are due to cross-reactive allergens as pathogenesis related (PR), profilins, or lipid transfer proteins (LTP). These proteins are ubiquitous in pollens, plants, fruits and food. Individuals sensitive to house dust mites have been reported with oral allergy syndrome following ingestion of shellfish(15). Children with CMA may react to beef in up to 20% of cases, to goat’s milk in 98%, and to donkey milk in 20% of cases(16).
Acute urticaria and angioedema are the most frequent manifestation of food allergy. The onset of symptoms may be rapid, within minutes, following the ingestion of the offending food. Foods most often implicated include milk, fish, vegetables and fruits. In atopic dermatitis, also a frequent symptom of food allergy, immediate reactions can be followed by late cutaneous reactions.
Symptoms caused by immediate sensitivity in the gastrointestinal tract typically develop within minutes to 2 hours of ingesting the offending food. Symptoms can include lip, tongue and palatal pruritus and swelling, laryngeal oedema, nausea, abdominal cramping, vomiting and diarrhoea. Severe reactions can result in most or all symptoms associated with anaphylaxis.
Oral allergy syndrome (OAS), a form of contact urticaria confined to the lips and oropharynx, most commonly occurs in pollen-allergic patients. Symptoms include oropharyngeal itching, with or without facial angioedema, and/or tingling of the lips, tongue, palate and throat.
Allergic rhinoconjunctivitis and asthma can occur following food challenge testing, but respiratory symptoms from food allergy in the absence of skin or gastrointestinal manifestations are rare. When respiratory symptoms occur following food challenge, both early- and late-phase IgE-mediated mechanisms are probably involved.
Systemic reaction: Anaphylaxis
Anaphylaxis is an explosive systemic reaction. About 50% of anaphylaxis reactions are due to food allergy. It occurs within few minutes to hours after food ingestion(17). Ninety per cent of patients experience skin (urticaria, angioedema) plus respiratory symptoms such as asthma, rhinitis or conjunctivitis; in 30% of the cases, they also develop gastrointestinal symptoms or hypotension, and shock and cardiac arrhythmias may occur. All of this is caused by the massive release of mediators from mast cells and basophils.
A form of anaphylaxis associated to food is the exercise-induced food-dependent anaphylaxis, occurring, generally, 2-4 hours after ingestion of a food to which the individual is allergic. Food or exercise alone will not cause this reaction. Risk factors for food-induced anaphylaxis include asthma and previous allergic reactions to the causative food.
Table 1. Specific Food-Induced Allergic Conditions3
Food allergy is also linked to manifestations of delayed hypersensitivity, partially IgE-mediated and partially non-IgE-mediated. It is implicated in Eosinophilic Esophagitis, Eosinophilic gastritis and gastroenteritis, food protein-induced enterocolitis syndrome, and allergic proctocolitis.
Food protein –induced enterocolitis syndrome (FPIES)
Primarily affects infants. In chronic forms, it presents as emesis, diarrhea, poor growth, and, in severe cases, with starvation and lethargy. In acute forms, or after re-administration of restricted foods, it may determine emesis, diarrhea, and hypotension, starting two hours following ingestion. Diarrhea may be bloody and may result in dehydration, especially in early infancy. It has been associated frequently to ingestion of cow's milk, soy, oat, wheat, and/or rice. Skin prick test to the suspected foods are generally negative, but IgE-mediated food allergy may be associated with FPIES as sometimes the two conditions co-exist or one form transforms into the another. International consensus guidelines have been developed for FPIES.(18)
Food protein-induced allergic proctocolitis (FPIAP)
FPIAP is a benign transient condition, typically starting in the first few months of life with bloody stools in well-appearing infants. About 60% of cases occur in breast-fed babies, the remainder in infants fed cow's milk or soy protein-based formulas.
Rarely, dietary protein proctitis shows mild hypoalbuminaemia and peripheral eosinophilia. Bowel lesions are usually confined to distal large bowel; endoscopy reveals linear erosions and mucosal oedema with infiltration of eosinophils in the epithelium and lamina propria.
Food-induced pulmonary haemosiderosis (Heiner's Syndrome)
This very rare syndrome, affecting infants and young children, is characterized by recurrent episodes of pneumonia associated with pulmonary infiltrates, haemosiderosis, gastrointestinal blood loss, iron deficiency, anaemia, failure to thrive. It is due to cow's milk(19); the immunologic mechanism is still unknown.
Although it is not, strictly speaking, an allergic disease, at least one-third of infants and young children with atopic eczema have IgE-mediated food allergy. Egg allergy is the most common food hypersensitivity in children with eczema. Appropriate diagnosis of food allergy and elimination of the offending allergen leads to significant clearing or improvement of eczematous lesions in many young children with eczema and food allergy. Food allergens may be triggers for some acute exacerbations (20).
Allergic eosinophilic oesophagitis (EoE).
This condition may present in children with a variety of nonspecific symptoms, e.g., feeding difficulty, nausea, vomiting, heartburn, and failure to thrive. Teenagers and adults are more likely to present with dysphagia and episodes of food impaction.
Eighty percent of patients with eosinophilic esophagitis have symptoms similar to gastroesophageal reflux, which are refractory to anti-reflux therapy. In the case of infants, the vomitus often contains stringy mucus (similar to egg albumin). Patients may also present with food refusal, dysphagia, food impaction or abdominal pain. Food induced IgE-mediated allergy has been implicated in the pathogenesis in some patients. In eosinophilic esophagitis there may be years of unrecognized childhood subclinical disease or “silent” chronic inflammation before the diagnosis is made.(21)
Allergic eosinophilic gastritis or gastroenteritis
The exact cause of these disorders remains unknown although both IgE-mediated and T-cell-mediated reactions have been implicated. These conditions are characterized by infiltration of eosinophils in the mucosal, muscular and/or serosal layers of the stomach or small intestines. Patients present with postprandial nausea and vomiting, abdominal pain, diarrhea (occasionally steatorrhea) and weight loss in adults and failure to thrive in young infants.
The results of skin prick tests (SPT), IgE total and specific antibodies, and patient histories are not predictive of true food allergy, as they are not able to establish the causal and temporal relationship between the intake of the suspect food and the hypersensitivity reaction. The negative predictive accuracy of a skin prick test weal of < 3mm greater than the negative control is high, usually > 95%, and is strong evidence that the food may be consumed without severe, immediate food-allergic reactions. A positive SPT, even a weal of 3 mm or more, may be clinically irrelevant, as the patient may tolerate the ingested food. SPTs may also remain positive after the development of tolerance to the specific food.
Specific IgE levels display a variable diagnostic accuracy according to the nature of the allergen, the studied population, the specific brand of the test. Using the most popular diagnostic systems, in is conventionally accepted that 0.35 kU/l is the cut-off level for a positive in-vitro test of specific IgE. Higher levels of specific IgE for food allergens may better correlate with clinical reactivity as evidenced by challenge testing. For this reason, decision points have been proposed. While valid in the studied populations, the value of such decision points cannot be universal (see table below).
A double blind, placebo-controlled food challenge (DBPCFC) is the preferred test to diagnose food allergy3,19. DBPCFC should be performed in specialist centers with close supervision. Resuscitation facilities and overnight admission can be necessary in severe cases. DBPCFC is difficult to organize in many clinical situations, and can be replaced by open challenges in many situations (when there is a minimal risk of false interpretations due to subjective factors). When a psychological reaction is strongly suspected, a single-blinded test may also be used (22, 23).
The in vitro diagnostics can help to identify cross-reactive allergens between pollen and foods, or foods and latex. Cross-reactive allergens include common lipid transfer proteins (LTPs), PR molecules, and profilin. Skin prick/puncture tests using commercial extracts to the implicated fruit are often negative, but a positive test may be obtained using a drop of fresh juice from the incriminated fruit.
The atopy patch test (APT) is an epicutaneous skin test in which allergens commonly associated with IgE reactions can be used, although patch testing is more commonly performed for metals such as nickel, which causes a positive patch test in nickel sensitive subjects. Although the pathogenic mechanisms of the APT have not been fully elucidated, a positive APT can predict a late phase reaction following oral food challenge. A positive APT may detect clinically relevant late phase eczematous or GI reactions in infants and children (24). This test is not useful for IgE-mediated food allergy. It is considered experimental in most parts of the world (25).
According to all the current guidelines, an infant with at least one first-degree relative (parent or sibling) with a history of allergic disease’ (26, 27) in particular allergic rhinitis, asthma, eczema, or food allergy (28, 29) is at greater risk for developing food allergy.
The first proposed recommendation for a large-scale prevention of food allergy has been the use of hypoallergenic (HA) formulae in case of breastfeeding failure. This approach has reached the level of evidence to be included in the NIAID recommendations on food allergy prevention (30), but it has subsequently been questioned. (31) Earlier guidelines on allergy prevention recommended delayed exposure to solid foods, avoidance of allergenic foods, and did not include interventions aimed at promoting the infants’ immune tolerance (32). Emerging evidence, however, has led to a paradigm shift, supporting nutritional approaches such as appropriate timing of food exposure, and use of prebiotics and probiotics for allergy prevention. The Learning Early about Peanut (LEAP) study showed that early introduction of peanuts significantly decreased the frequency of peanut allergy among children at high risk, and modulated immune responses to peanuts (33). Hence, based on these findings, the National Institutes of Health (NIH) Guidelines for the Management and Prevention of Food Allergy subsequently recommended the introduction of peanut-containing foods to “high-risk” infants early in life (4-11 months) (34).
The World Allergy Organization (WAO)/McMaster Working Group Guidelines for Allergic Disease Prevention (GLAD-P) has also published GRADE recommendations on the use of probiotics and prebiotics for allergy prevention based on current available evidence. The guideline panel suggested using probiotics in pregnant and breastfeeding women whose children and infants are at high risk for developing allergy29. Probiotics have been shown by numerous studies to be effective in allergy prevention, particularly in reducing allergic eczema at a rate of 9 fewer cases per 100 pregnant women (risk ratio [RR] 0.72), 16 fewer cases per 100 breastfeeding women (RR 0.58), and 5 fewer cases per 100 infants (RR 0.82). Ultimately, the use of probiotics should be individualized and further studies are needed to evaluate their effect in preventing other types of allergy and the differences among the strains of the same species of probiotic bacteria.
Concerning prebiotics, GLAD-P conditionally recommends prebiotic supplementation in non-exclusively breastfed infants, both at high and at low risk for developing allergy, but not in exclusively breastfed infants (35). These recommendations were largely based on a meta-analysis of available evidence showing that prebiotic supplementation reduces the risk of developing asthma or recurrent wheezing (RR: 0.37, 95 % CI: 0.17 to 0.80) and the risk of developing food allergy (RR: 0.28, 95 % CI: 0.08 to 1.00) (36). It has been proposed that these effects result from interactions between the gut microbiota and the gut mucosal immune system.
GLAD-P provides no recommendation at this time on prebiotic use in pregnant and breastfeeding women, owing to the lack of evidence from experimental and observational studies.
In the future, the GLAD-P guidelines may be expanded as more data from rigorously designed, adequately powered and well-executed trials become available. Recommendations on other interventional measures, such as vitamin D supplementation, in allergy prevention are negative (37).
Food Allergen Avoidance
The foods to which an individual is allergic should be avoided, as therapeutic intervention (tertiary prevention) in patients with food allergy. It must strike a precautionary equilibrium between the demands of prohibitive measures against allergy care and quality of life. Such a dynamic endpoint is difficult to assess for efficacy and safety. Avoidance measures need to be tailored to the individual’s life and disease requirements must take account o the needs of growth, the prevention of anaphylaxis and, of the benefits expected of allergen avoidance itself.
From the patient’s perspective, avoidance means meeting obstacles unshared by their non-allergic peers, thereby curtailing their quality of life. From the physician’s outlook, education, ensuring compliance and receptiveness of both patient and caregiver are major concerns. The role of the allergist is to review in a dialectical assessment these competing factors in concert with all parties concerned. Where avoidance of the implicated food may result in nutritional deficiency, dietary supplementation is necessary3.
Processed foods may contain hidden proteins, e.g., milk, egg and soy proteins may be added to increase the protein content or enhance flavor. Peanuts and nut products are added to thicken and flavor sauces. Patients can be taught to identify hidden food components in processed foods. Commonly used ‘hidden' proteins are casein and lactose, derived from milk, and albumin from egg. To disclose hidden food allergens, food labelling is an issue of relevance to food allergic consumers of processed or pre-packaged foods. In the European Union, 12 food items are required by law to appear on the label: cereals containing gluten, crustaceans, egg, fish, peanut, soy, milk (including lactose), tree nuts, mustard, sesame seeds, celery, and sulfites >10 mg/kg (38). Similar legislation is in effect in the US, where the 2006 Food Allergen Labeling and Consumer Protection Act provides that all food products require an ingredient statement. In these countries, the legislation has altered industry practices in some important aspects for milk, egg, peanut, tree nuts, shellfish, fish, soy and wheat. In other countries, hidden allergens can be exempt from specific labeling, and thus be inadvertently consumed by food allergic individuals. On both the sides of Atlantic, the regulatory problem is now the opposite concern, that is, whether too many foods containing trace amounts of these allergenic foods are being "overlabeled" and whether this would then potentially restrict potentially safe food choices for allergic consumers. In fact, the labeling regulations do not prescribe the indication of potential contaminants, but many manufacturers are now indicating, “may contain” as a warning of potential contaminations during food preparation (39).
Hypersensitivity reactions are often treated with medications. . Epinephrine is the only medication that is effective for the treatment of anaphylaxis. Additional medicatioons include H1 and H2 antihistamines, corticosteroids, and prostaglandin synthetase inhibitors These drugs are only symptomatic, do not modify the natural course of the disease, and sometimes have unacceptable side effects. Anti-IgE monoclonal antibodies therapy is licensed for use in asthma and for chronic urticaria in many countries, and studies are under way to determine if it has a role in the management of serious food allergies.
Any desensitisation protocol to both reduce the risk of major reactions and avoid nutritional restrictions in children suffering from food allergy would be highly beneficial. The subcutaneous administration of native (40) or modified (41) peanut extracts was attempted in the past, but the shots induced systemic reactions or serious adverse effects. In the last years, the experience with oral immunotherapy has made this a common, accepted treatment in some countries. A recent systematic review concluded that oral immunotherapy is no longer experimental, but is ready for practical application (42). It should be applied to reduce the risk of inadvertent reactions, and not to modify the natural course of the disease (43). “Tolerance” in “desensitized” children disappears if the allergen is not ingested every day in therapeutic doses. However, research is ongoing and the future use of recombinant allergens (44), synthetic peptides (45),and epicutaneous therapy for desensitization in humans looks more promising (46).
One of the most often asked parents’ questions is “How long will my child’s food allergy last?” Given the present impossibility to modify the natural history of food allergy, the answer must take into account a series of factors. There is a relationship between symptom severity after ingestion and the likelihood of outgrowing the problem; the more severe the reaction, the less likely that the food allergy will be outgrown. Other factors, such as sIgE antibody level and age at diagnosis, have also been associated with prognosis of food allergy, although these associations are not invariably consistent across studies (47, 48, 49). Milk allergy’s half-life is approximately two years while egg allergy’s half-life is approximately four years. Peanut allergy, once considered to be a life-long condition, can resolve in up to 30% of cases (50). However, it is not possible to establish a half-life for a diagnosis of peanut allergy and tree nuts should still be considered as lifelong allergies.
Similarly, fish allergy is considered a long-lasting condition and reports of recovery are rare (51). However, no study has evaluated the natural history of fish allergy in infants and fish should also be regarded as causing persistent allergies.
While peanut, tree nut, fish and seafood allergy are mostly persistent conditions, little is known about the natural history of allergy to such staples as fruits, vegetables, cereals and meat.
In food allergic children, tolerance must be tested by oral challenge at regular intervals. Often tolerance is not acquired suddenly, but there is a gradual increase of the doses tolerated at challenge. Even after years of apparent clinical tolerance, gastrointestinal symptoms of food allergy and reduced growth, . Epinephrine is the only medication that is effective for the treatment of anaphylaxis. have been reported (52).
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