Food allergy in adulthood
Authors: J. F. Crespo, J. Rodriguez
Journal: Allergy (2003)

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 sex, and in most patients the onset of symptoms of allergy to birds preceded the clinical reaction to egg ingestion. In a study to compare IgE-binding components in bird feather and egg extracts, Szepfalusi et al. (47) found that the median age in subjects with the bird-associated egg allergy was 46 years, whereas the median age in the egg-white-allergic subjects was 11 years. In a recent case series of eight patients who reported respiratory symptoms upon exposure to bird feathers, as well as allergy symptoms after ingestion of egg yolk, the age range being between 21 and 41 years, the onset of respiratory symptoms with birds preceded egg allergy in half of patients, with a simultaneous onset in the remaining subjects (60). All patients were reported to experience OAS, followed in most cases by facial angioedema and less frequently by acute asthma. Most patients could tolerate well-cooked eggs and ingestion or manipulation of well-cooked chicken produced no symptoms in any patient. A DBPCFC with chicken albumin provoked digestive and systemic allergic symptoms in two patients challenged. In addition, exposure to inhaled egg proteins among workers in egg processing facilities has been verified as a cause of occupational respiratory allergy to airborne egg proteins with consecutive ingestive IgE-mediated egg allergy, which has been recently designed as 'egg–egg syndrome' (83–86). Beef is a major source of protein, but there is limited information on allergic reactions to beef or the main allergens implicated in these reactions. A case of exercise-induced anaphylaxis was confirmed in a 72-year-old woman who suffered this clinical manifestation only when performing mild physical activity after eating pork and beef (87). Also, allergy to chicken and turkey meat has been reported in adults without sensitization to egg proteins (88, 89). Anaphylactic shock caused by pork was reported long ago (90). Interestingly, cross-reactivity among pork kidney and pork and lamb gut have been demonstrated in a patient able to tolerate pork meat (91). Crossed IgE-reactivity between pork and cat epithelia, due to serum albumin, was described by Drouet et al. (92), who coined the term pork–cat syndrome. However, the clinical significance of immunological cross-reactivity has not been extensively evaluated, despite a case of fatal anaphylaxis that was recently reported in a patient with pork–cat syndrome who had eaten wild boar meat (93). Hansen and Bindslev-Jensen (94) established a definite relationship between codfish and clinical allergy in adults. Further, Helbling et al. (95) confirmed clinically relevant cross-reactivity among various species in fish-allergic adults evaluated using DBPCFC. However, allergy to a single fish species, such as swordfish, probably due to the presence of species-specific allergens has been described (96). The diagnosis of fish allergy covers additional difficulties since scombroid poisoning, which is caused by ingestion of scombrotoxin accumulated during fish spoilage, closely resembles an acute allergic reaction (97). Moreover, an increasing number of reports have documented, in the last few years, the role of anisakis parasitizing fish as a cause of recurrent anaphylactic reactions after ingesting fish (98, 99). Airborne fish allergenic-components have been detected in the environment (100), explaining the capacity of fish to induce reproducible asthmatic responses in exposed workers (101–104). Fish skin contact has been reported as a cause of occupational protein contact dermatitis in food handlers (105, 106), as well as immunological contact urticaria (107–109). Bernstein et al. (4) confirmed the clinical reactivity to shrimp in adults by double-blind food challenge. Further studies indicated that serum levels of shrimp-specific IgE are significantly elevated in shrimp-hypersensitive subjects who exhibit positive food challenges (110). Castillo et al. (61) studied a case series of adult patients with shellfish hypersensitivity. The most frequent causes of symptoms were shrimp and squid. The most commonly found symptoms were urticaria/angioedema, asthma, and rhinitis. Tropomyosin has been identified as a cross-reactive allergen between crustaceans, molluscs and members of the phylum Arthropoda. However, sera from shrimp-sensitive patients were able to recognize qualitatively different allergens in different shrimp species extracts, supporting the hypothesis that there are species-specific shrimp allergens (111). In addition, Castillo et al. (112) have also investigated hypersensitivity to squid, describing a series of adults having symptoms highly suggestive of IgE-mediated reactions after ingesting squid or inhaling vapours from cooking squid, most of them also after shrimp ingestion. Although grains and grain products have been primarily implicated in IgE-mediated occupational asthma (113), only anecdotal reports have illustrated their ability to induce allergic reactions upon ingestion in adults. Severe anaphylactic reactions in adults have been reported after ingestion of millet seeds (114–116), buckwheat (117), and corn (118). Recently, Pastorello et al. (119) evaluated 22 patients with systemic symptoms after maize ingestion and identified a lipid transfer protein (LTP) as the major allergen. Wheat flour allergy in adults seems to be infrequent and especially described as anaphylactic shock for the most part induced by exercise (120, 121). Harada et al. (122) first verified a synergistic effect of aspirin in inducing urticaria/anaphylaxis after ingestion of wheat, which was confirmed using challenge tests in two patients with food-dependent exercise-induced anaphylaxis (FDEIA). In a further study (123) performed on 12 patients with FDEIA, the ingestion of wheat and aspirin without exercise provoked symptoms in two patients. Aspirin provoked symptoms even with a small amount of wheat and exercise in one patient. Only the combination of aspirin, wheat and exercise provoked anaphylaxis in one patient. Specific IgE, SPT and/or the histamine release test with gluten were positive in most patients with wheat-dependent FDEIA. A small number of case reports of reactions induced by barley have been published, generally as contact urticaria (124) and systemic reactions (125–127) due to barley malt. Recently, barley LTP and protein Z were identified as the main allergens in beer from barley malt (128, 129). In addition, several reactions have been reported occurring after ingestion of grain products, but caused by contaminating mites (130, 131). Allergy due to ingestion to edible seeds of legumes has been rarely reported in adults (132, 133), with the exception of peanut. Recently, in a clinical study performed in India, Patil et al. (16) confirmed by DBPCFC clinical allergy in 54% of 59 patients complaining of adverse reactions to chickpea. Of these, seven patients showed DBPCFC-positive results with other legumes. Respiratory symptoms alone such as breathlessness, wheezing, and coughing were observed in the course of the DBPCFC in 32.3% of patients, 38.7% of patients showed only cutaneous reactions such as urticaria and angioedema, and anaphylactic reactions occurred in 3.3% of patients. Moneret-Vautrin et al. (134) have demonstrated crossed lupine allergy in approximately 30% of 24 patients allergic to peanuts. In addition, the inhalation of lupine flour has been demonstrated as a cause of allergic sensitization in exposed workers that might give rise to occupational asthma and food allergy (135). In adults, sensitization to soybean occurs mainly by inhalation of soybean dust, which has been identified as the causative agent of occupational asthma and asthma epidemics (136). Nuts have been traditionally enunciated as one of the leading causes of severe allergic reactions in adults. However, most epidemiological and clinical established facts on nut allergy were based on studies including both children and adults. In an epidemiological survey in France, peanut and tree nut were found to account only for 4% of the reported reactions to foods (27). Onset of nut allergy seems to be most common in children, as illustrated in a clinical study from Ewan (137), in which onset in teens or older was found only in 8% of 62 patients diagnosed with nut allergy by skin testing and clinical history. However, in this study the most severe reactions occurred in adults, who were aware of their allergy and had inadvertently ingested nuts. The frequency of reactivity to individual or combinations of nuts has not been addressed specifically in adults. However, in a study exploring the pattern of specific IgE to peanut, hazelnut and Brazil nut in patients of all ages with a history of possible nut allergy, 61% of 731 sera were found to have specific IgE antibodies to more than one nut (138). The probability of a patient with nut allergy having specific IgE to a particular combination of peanut, hazelnut and brazil nut was found to be similar, whatever their age or sex. In a follow-up (more than 13 610 patient months) study of patients (adults and children) allergic to peanut and nut, approximately 15% of 567 patients had a follow-up reaction. Interestingly, severe follow-up reactions occurred only in 0.5% of patients, aged 27–40 years (139). Recently, a rigorous, multicentre double blind, placebo-controlled, food challenge study has extensively investigated hazelnut allergy in adults (11). Of the symptoms observed during positive DBPCFs, there were 59 cases of OAS localized to the oral cavity, three cases of oral and gastrointestinal symptoms, and five cases of oral and systemic symptoms. Almost all patients were found to be sensitized to pollen, particularly birch and hazel. Further, sera from clinically reactive patients were used to identify hazelnut allergens, confirming that the most important allergen of hazelnut is the 18-kd protein homologous to Bet v 1 (140). In addition, three new major allergens were recognized in hazelnut as proteins of 32, 35, and 47 kd and a 9-kd LTP was identified as an allergen associated