Food allergy in adulthood

In the last decades, the results of studies involving controlled food challenges have provided a reliable scientific basis on the role of foods as a cause of hypersensitivity reactions. Most of these investigations have been focused on paediatric populations, highlighting the role of food allergy in the pathogenesis of atopic dermatitis, identifying foods that most commonly cause allergic reactions, and calling attention to the limited value of skin tests and in vitro assays in the diagnosis of clinical allergy (1). However, less evidence for specific features of adverse reactions to foods in adults has been available. Loveless (2) and Graham et al. (3) verified the association between the ingestion of food and development of symptoms in adults in the 1950s. Further, the remarkable studies conducted by Bernstein et al. (4) and Atkins et al. (5, 6) in the early and mid 1980s, definitely confirmed the role of foods as a cause of IgE-mediated allergic reactions in adults and evaluated the relationship between diagnostic procedures and reactivity to food on oral challenge. In 1987, Amlot et al. (7) coined the term, oral allergy syndrome (OAS) to describe the symptoms experienced by a subgroup of patients with positive skin tests to food, typically oral symptoms such as oral irritation and throat tightness, followed in a proportion of patients with systemic symptoms. The OAS was a 'new term' to describe an old featured clinical condition, the association between local oropharyngeal signs and symptoms with the ingestion of foods such as hazelnuts, apples, pears, carrots, celery, and potatoes with allergy to pollen, particularly birch. At that time, Ortolani et al. (8) published a large case series of adult patients who had oral symptoms after ingestion of fresh fruits and vegetables under the title 'The oral allergy syndrome'. From then on, this term has rapidly gained acceptance, although its exact meaning has not been kept out of some controversy (9, 10). For some years, however, most studies of food allergy in adults were anecdotal reports of anaphylactic reactions after ingestion of a specific food or based mainly on the clinical history supported by positive allergy skin testing and in vitro studies. In the last few years, a number of studies have evaluated adverse reactions to plant-derived foods in adults using DBPCFC models (11–17). Further, by identifying well-characterized clinically allergic patients, these studies have been the basis for detailed immunochemical analysis of allergenic components. The objective of the present review is to provide an overview of the complex nature of the relationship of foods and IgE-mediated allergic reactions in adults, focusing on distinctive features. Following the recommendations of the EAACI Nomenclature Task Force (18), the term food hypersensitivity (FH) will be used to designate an adverse reaction to food, food allergy (FA), when immunological mechanisms have been demonstrated, and IgE-mediated food allergy, if the role of IgE is highlighted. Recent population surveys have estimated rates of prevalence of perceived FH of 12% to 20% in adults (19–22). In a large multicentre study involving subjects aged 20–44 years of age from 15 countries, about 12% of adults reported adverse reactions following particular food ingestion (23). The rate of perceived adult FH varied largely across different countries (e.g. Spain, 4.6%; Australia, 19.1%) despite a common standardized methodology. By performing skin prick tests for five food allergens, after a postal questionnaire, Woods et al. (24) found that 1.3% of adults in Australia were consistently sensitized and perceived adverse food reactions to the same allergen. It is generally considered that true FH is less common in adults than in children. In two population studies performed in the mid 1990, which used DBPCFCs in a selected subgroup of the study population, the prevalence was estimated at 2.4% for FH in Dutch adults (19) and 1.4–1.8% for IgE-mediated FA to eight everyday foods in the UK (20). A slightly higher prevalence was found in a study conducted in a selected population; Bischoff et al. (25) found that 3.2% of 375 adult patients with inflammatory and functional gastrointestinal disease had FA, confirmed by endoscopic allergen provocation and/or elimination diet and re-challenge. However, the prevalence of FA confirmed by DBPCFC in patients infected with HIV seems to be similar to that found in the general adult population (26). Moreover, a recent epidemiological survey performed in France estimated the prevalence of perceived FA to be 4.2% in patients aged from 1 to 3 years and approximately 4% in adults (27). This study was performed only by questionnaire, but it included specific symptoms consistent with FA. Perceived hypersensitivity reactions to milk were estimated to occur in 3–6% of Finnish young adults (28), to peanut and tree nut in 1.1% of the general population of the USA (29) and to peanut in 0.5% of adults in the UK (30). Gender differences, with a female predominance of FH, have been noted in several studies performed on adults. In subjects aged 25–74 years, women (27.5%) were found to report significantly more allergic reactions to foods than men (14.0%) (22). The rate of near-fatal and fatal reactions to food in adults is unknown. However, fatalities have been described (31,32) and 91% of 32 casualties reported to a national registry established by the American Academy of Allergy Asthma, and Immunology occurred in adolescents and young adults (10–19 years of age, 17 subjects; 20–30 years, 10; and 30–33 years, 2) (33). After 6 years of age, peanut and tree nut caused all the fatalities; all but one of the subjects were known to have food allergy, most of them were known to have asthma, and only four subjects received epinephrine shortly after the reaction. In addition, foods were identified as the major causative agent of severe anaphylaxis with loss of consciousness (42% of 12 cases) and anaphylaxis (38.5% of 127 patients) treated in the emergency department of a general hospital (34) and in 42% of 142 cases of anaphylaxis (35). The foods most likely to cause proved FH in adults have not been identified through specifically designed community-based studies. Peanuts, fish, shellfish, and tree nuts are frequently listed in textbooks as the most relevant offenders in adult food allergy. Nonetheless, the increasing frequency of pollen allergy, which is found in approximately 15–20% of the general population in developed countries (36), and its relationship with allergy to fruits, suggest that these foods might be a leading cause of FH in adults. Clinical studies have verified clinical allergy to fresh fruits in approximately 20% of pollen-allergic adult patients, therefore more than 2% of the adolescents and young adults might be affected by fruit hypersensitivity (37). This is consistent with findings in the French population, where fruits and vegetables were identified as the most frequent cause of perceived FA from 7 to 30 years of age (27). Likewise, fruits (particularly Rosaceae) and tree nuts were the most common foods perceived as offenders in German adults (22). Also, fruit and vegetables were identified, by case history and positive skin testing, as the main cause of food allergy in patients with onset after 10 years of age in Israel, whereas milk and eggs were the least common (38). In Spain, two case series featured fresh fruits, shellfish, and nuts as the most common causes in adult patients, as diagnosed by case history and allergy testing (39, 40). The immunochemistry and molecular aspects of food allergens have been recently reviewed elsewhere (41, 42). There is scarce information on qualitative differences of IgE-binding to allergenic components in foods by children and adults. Paediatric and adult fish-allergic patients were shown to have a similar in vitro IgE binding to a 12.5- kDa protein from fish extracts, immunochemically similar to Gad c 1 (43). However, in other foods the primary route of sensitization and phenomena of cross-allergy may influence the antigenic recognition. As demonstrated by Pastorello et al. (44) two models of sensitization to apples seem to exist, one depending on sensitization to birch pollen, particularly Bet v 1, causing reactions on subsequent oral contact with the homologous allergen Mal d 1, and the other arising directly from ingestion of apples, in which the allergen Mal d 3 (LTP) is particularly relevant. Tropomyosin has been well characterized as the major allergen in shrimp-allergic patients through ingestion, however, an airborne heat-labile 94/97- kDa shrimp allergen was identified as relevant in patients having IgE-mediated respiratory symptoms through inhalation (45, 46). The major allergens from egg white are ovomucoid (Gal d 1), ovalbumin (Gal d 2), conalbumin (Gal d 3), and lysozyme (Gal d 4), but egg-yolk alpha livetin (chicken serum albumin) was identified as an important allergen in adults allergic to eggs in the context of bird-associated egg allergy (47). Food allergy found in adult subjects could represent a persistence of reactions starting early in childhood and children or be primarily initiated in adulthood. Food allergy is characteristically one of the first manifestations of the atopic syndrome and affects young children. The most important allergens are cow's milk, hen's egg, fish, and legumes. However, a number of studies have documented the adult onset of food-induced anaphylactic reactions through ingestion, particularly caused by shellfish, nuts, fruits and vegetables. Although more common in the developing gut-associated lymphoid tissue of young children, it is clear that sensitizing processes through the gastrointestinal tract and both cellular and IgE-mediated hypersensitivity responses to ingested foods could operate at any age. In addition, recently evidence has been presented to suggest the presence of localized IgE-mediated responses (duodenal presence of IgE-bearing cells, activated eosinophils, and T cells in patients) in adult patients with food allergy-related gastrointestinal symptoms confirmed by DBPCFC, but negative results of skin and in vitro testing (48). Furthermore, food allergy in adulthood seems to be commonly associated with sensitization to other allergens, particularly inhalants. This condition has had been the subject of special attention during the last decade. Several terms have been used to define this situation, such as OAS and wide variety of 'syndromes', which associated food allergy to other allergies (i.e., pollen, house-dust mite, bird, cat, latex). The immunological basis for these food allergies is IgE cross-reactivity, which might be clinically manifest or irrelevant. Experimental evidence suggests that inhalant allergens could represent the primary sensitizing agents for some patients, particularly with pollen-associated food sensitivity, which has been designated recently as class 2-food allergy. In most studies, these associations are mentioned as syndromes (e.g. pollen–food allergy syndrome, egg–bird syndrome), although they hardly fit the classical definition of syndrome as just a set of symptoms that occur together. Immunological and molecular aspects of birch pollen-associated food allergies have been studied intensively. A number of studies have shown that between 50 and 93% of birch pollen-allergic patients have immunological reactivity to plant-derived foods. In addition, homologues of the birch pollen allergens Bet v 1, Bet v 2, and Bet v 6, as well as glycoproteins carrying cross-reactive carbohydrate determinants, have been identified as important cross-reactive families in foods of vegetable origin (49). About 50% (30–80% depending on patients, clinical data, and test method; e.g. case history, IgE quantification, skin tests) of birch pollen allergic-patients has been claimed to be 'allergic' to apple (50–53). However, the frequency of clinical reactivity to apple confirmed by oral provocations in large case series of birch pollen-allergic patients remains unidentified, even though a slight increase in reactivity during the birch pollen season has been confirmed by oral challenge tests (54). In a birch pollen-free area, Cuesta-Herranz et al. (37) found that 37% of 95 adult pollen-allergic patients (mainly to grass and olive) had positive skin tests to plant-derived foods; but clinical reactivity confirmed by open provocation ranged from 10% (plum) to 50% (melon, peach) of sensitized individuals. Hence, clinically insignificant cross-reactivity is a common finding in pollen-associated food allergy, a fact that greatly limits the value of skin testing and specific IgE determinations on the diagnosis of true clinical fruit and vegetable allergy. Kazemi-Shirazi et al. (55) using sera from patients reporting isolated oral symptoms verified that pollen allergens (rBet v 1, rBet v 2, birch, and timothy grass) produced an almost complete inhibition of IgE binding to plant food allergens (apple, peach, hazelnut, celery, and carrot). In contrast, recombinant plant food allergens (Bet v 1-homologous) poorly inhibited IgE binding to Bet v 1. Thus, pollen allergens could represent the primary sensitizing agents in some patients, further reacting to fruits with OAS. However, although oral manifestations are very common in patients allergic to fresh fruits co-sensitized to pollen allergens, constraining the concept of fruit allergy to a pollen-related model causing mild or moderate symptoms could underestimate its potential to elicit severe anaphylactic reactions. Life-threatening allergic reactions induced by fresh fruits have been reported in patients with and without associated pollen allergy. The rate of systemic symptoms, following or not oral symptoms, was slightly higher in peach-allergic subjects without than with pollen allergy, but differences were not significant (25% vs. 46%), in a series of 61 adult peach-allergic patients having positive allergy testing and open food challenges (56). Therefore, sensitization to fresh fruit and vegetables is probably a complex event, since individuals are not only exposed to cross-reactive pollen allergens through the respiratory tract, but also to primary fruit allergens by ingestion. De Maat-Bleeker et al. (57) first reported the association of sensitivity to ingested egg yolk with rhinitis and asthma caused by exposure to a parrot in an older woman. By RAST-inhibition, Mandallaz et al. (58) demonstrated that livetin, the water-soluble fraction of egg-yolk proteins, is the major cross-reacting antigen found in bird dander and hen's egg proteins. They coined the term bird-egg syndrome to designate this association of inhalant and food allergy and suggested that egg allergy in adults could be mainly due to sensitization to egg-yolk livetins and provoked by inhalation of pet bird dander. Further, IgE from patients with bird-related egg allergy was shown to recognize alpha-livetin (chicken serum albumin) in egg yolk and some major allergens in bird feather extract (47, 59). A conclusive clinical explanation for this syndrome has been provided recently by Quirce et al. (60), who demonstrated by specific bronchial and oral challenges that chicken albumin may cause both respiratory and food-allergy symptoms in patients with the bird-egg syndrome. Case reports have described patients with combined shrimp and HDM allergy in adults. In a study of 48 patients allergic to shellfish (various species, but mainly shrimp), 82% appeared to be sensitized to HDM as well (61). Tropomyosin seems to be the protein involved in shrimp–HDM cross-reactivity, and it may be the only allergen involved. In a study of 17 HDM patients receiving immunotherapy, three had IgE against shrimp, and two of these having IgE against tropomyosin had oral allergy symptoms after ingesting shrimp (62). In addition, cross-reactivity between shrimp and German cockroach has been demonstrated by IgE-inhibition experiments (63). However, the primary sensitizing route and the clinical significance of cross-allergy among HDM, cockroach, and shrimp remains undefined. Some patients with HDM have been reported to experience severe anaphylactic symptoms when ingesting snails (64, 65). In a study (66), 31% of the allergic subjects to HDM were sensitized to snails, and cross-reactivity has been demonstrated by IgE-inhibition studies, which identified HDM as the primary sensitizing agent (67). In addition, several reports suggested that allergen immunotherapy with mite extract can worsen snail-induced allergy (68). Immunological reactivity to foods (skin test, food-specific IgE determinations) in natural rubber latex-allergic adult patients has been found to be common in several studies. Based on the clinical history, Blanco et al. (69) diagnosed 42 food allergies in 52% of 25 latex-allergic patients, and over half (55%) of these consisted of systemic anaphylaxis. The foods most commonly involved were avocado, chestnut, banana, kiwi, and papaya. Beezhold et al. (70) demonstrated that immunological reactivity to foods was more common in latex-allergic individuals than in controls. In this study, a total of 100 out of 376 food skin-prick tests were positive in 33 latex-allergic subjects. Twenty-seven percent of 100 positive food skin tests were associated with clinical symptoms. Thirty-seven percent of patients manifested a clinical allergy to at least one food including 11 with anaphylaxis, and 14 with local sensitivity reactions. Positive food skin tests occurred most frequently with avocado (53%), potato (40%), banana (38%), tomato (28%), chestnut (28%), and kiwi (17%). Brehler et al. (71) found that 42.5% of 136 patients with well-documented, clinically relevant, immediate-type hypersensitivity against latex proteins reported allergic symptoms after ingestion of fruits (papaya, avocado, banana, chestnut, passion fruit, fig, melon, mango, kiwi, pineapple, peach, and tomato). The potential severity of allergic reactions to ingested allergens in adults was illustrated long ago by Golbert et al. (72), who in 1969 depicted the clinical characteristics of the reactions in six adults, including most commonly dyspnoea, angioedema, abdominal distress, urticaria, cyanosis, and, less frequently, chest pain and syncope. Atkins et al. (5, 6) offered a detailed analysis of the reaction patterns during double-blind food challenges in a series of adult patients with a history of immediate allergic-like reactions after specific food ingestion. A number of clinical studies have provided evidence of adult onset of allergic reactions to a large group of foods, however, some particular features in adulthood deserve to be mentioned. Adult onset of cow's (73–75), mare's (76) and goat's (77) milk allergy has been objectively confirmed in several studies. In a retrospective study of 34 adult milk-allergic patients, the main organ manifestations of cow's milk allergy in adults were the respiratory tract and the skin, with gastrointestinal and cardiovascular symptoms occurring less often than in children (78). Only 28% of cow's milk-allergic adults were symptom-free when ingesting milk products after 4 years of disease. Compared with the existing studies on children, the results suggest that allergies to cow milk proteins in adults are less frequent but tend to persist longer. In addition, anecdotal reports have illustrated the adult onset of asthma induced by occupational exposure to aerosolized cow's milk proteins (79–81). Although egg allergy has been confirmed in adults by DBPCFC studies (82), most reports on egg-allergic adult patients have been focused on the bird-associated egg allergy. It has been suggested that the occurrence of a bird-egg syndrome is typical in adulthood, with a predominance of the female and in most patients the onset of symptoms of allergy to the clinical reaction to egg ingestion. In a study to IgE-binding components in bird feather and egg extracts, et al. found that the age in subjects with the bird-associated egg allergy was years, whereas the age in the subjects was 11 In a recent case series of eight patients who reported respiratory symptoms exposure to bird as well as allergy symptoms after ingestion of egg the age between and years, the onset of respiratory symptoms with egg allergy in half of patients, with a onset in the subjects patients were reported to experience followed in most cases by and less frequently by Most patients could eggs and ingestion or of chicken produced symptoms in any A DBPCFC with chicken albumin provoked and systemic allergic symptoms in two patients In addition, exposure to egg proteins among in egg has been verified as a cause of occupational respiratory allergy to airborne egg proteins with IgE-mediated egg allergy, which has been recently designed as is a major of but is limited information on allergic reactions to or the main allergens in these reactions. A case of anaphylaxis was confirmed in a who this clinical only when performing mild after and Also, allergy to chicken and has been reported in adults without sensitization to egg proteins caused by was reported long ago cross-reactivity among and and have been demonstrated in a to between and due to serum was described by et al. who coined the term syndrome. However, the clinical significance of immunological cross-reactivity has not been despite a case of fatal anaphylaxis that was recently reported in a with syndrome who had and established a relationship between and clinical allergy in adults. Further, et al. confirmed clinically relevant cross-reactivity among in fish-allergic adults evaluated using However, allergy to a fish species, such as probably due to the presence of allergens has been described The diagnosis of fish allergy since which is caused by ingestion of during fish an allergic reaction Moreover, an increasing number of reports have in the last few years, the role of fish as a cause of anaphylactic reactions after ingesting fish fish have been in the the of fish to responses in exposed skin contact has been reported as a cause of occupational protein contact in food as well as immunological contact Bernstein et al. (4) confirmed the clinical reactivity to shrimp in adults by double-blind food challenge. studies that serum of IgE are significantly in subjects who positive food challenges et al. studied a case series of adult patients with shellfish The most frequent causes of symptoms were shrimp and The most commonly found symptoms were asthma, and Tropomyosin has been identified as a cross-reactive allergen between and of the However, sera from patients were to recognize different allergens in different shrimp extracts, the that are shrimp allergens In addition, et al. have also hypersensitivity to a series of adults having symptoms of IgE-mediated reactions after ingesting or from most of them also after shrimp ingestion. Although and products have been primarily in IgE-mediated occupational asthma only anecdotal reports have illustrated to allergic reactions ingestion in adults. anaphylactic reactions in adults have been reported after ingestion of and Pastorello et al. evaluated patients with systemic symptoms after ingestion and identified a protein (LTP) as the major allergen. allergy in adults seems to be and described as anaphylactic for the most induced by et al. first verified a of in after ingestion of which was confirmed using challenge tests in two patients with anaphylaxis In a further study performed on 12 patients with the ingestion of and without provoked symptoms in two provoked symptoms even with a of and in one Only the of and provoked anaphylaxis in one and/or the test with were positive in most patients with A number of case reports of reactions induced by have been generally as contact and systemic reactions due to and protein were identified as the main allergens in from In addition, several reactions have been reported occurring after ingestion of but caused by Allergy due to ingestion to of has been reported in adults with the of in a clinical study performed in et al. confirmed by DBPCFC clinical allergy in of patients of adverse reactions to patients results with other legumes. symptoms such as and were in the of the DBPCFC in of patients, of patients only reactions such as and angioedema, and anaphylactic reactions occurred in of et al. have demonstrated allergy in approximately of patients allergic to In addition, the inhalation of has been demonstrated as a cause of allergic sensitization in exposed that might to occupational asthma and food allergy In adults, sensitization to mainly by inhalation of which has been identified as the causative agent of occupational asthma and asthma have been as one of the leading causes of severe allergic reactions in adults. However, most epidemiological and clinical established on nut allergy were based on studies including both children and adults. In an epidemiological survey in peanut and tree nut were found to only for 4% of the reported reactions to foods (27). of nut allergy seems to be most common in children, as illustrated in a clinical study from in which onset in or older was found only in of patients diagnosed with nut allergy by skin testing and clinical However, in this study the most severe reactions occurred in adults, who were of allergy and had ingested The frequency of reactivity to or of nuts has not been specifically in adults. However, in a study the of specific IgE to and nut in patients of all with a history of nut allergy, of sera were found to have specific IgE to more than one nut The of a with nut allergy having specific IgE to a particular of and nut was found to be age or In a than study of patients and allergic to peanut and approximately of patients had a reaction. severe reactions occurred only in 0.5% of patients, aged years a multicentre food challenge study has allergy in adults the symptoms during positive were cases of OAS localized to the oral three cases of oral and gastrointestinal symptoms, and five cases of oral and systemic symptoms. all patients were found to be sensitized to pollen, particularly birch and Further, sera from clinically patients were used to allergens, that the most important allergen of is the protein homologous to Bet v 1 In addition, three major allergens were in as proteins of and and a was identified as an allergen associated