Current reviews of allergy and clinical immunology

(Supported by a grant from Glaxo Wellcome, Inc, Research Triangle Park, NC) Series editor: Harold S. Nelson, MD

Clinical implications of cross-reactive food allergens

Scott H. Sicherer, MD New York, NY
As a consequence of the general increase in allergic sensitization, the prevalence of hypersensitivity reactions to multiple foods that share homologous proteins has become a significant clinical problem. A variety of these allergens conserved among plants (eg, profilin and lipid transfer proteins) and animals (eg, tropomyosin and caseins) have been characterized. Although studies with molecular biologic techniques have elucidated the nature of these ubiquitous allergens, clinical studies have lagged behind. The physician is called on to determine the risk of reaction to related foods among legumes, tree nuts, fish, shellfish, cereal grains, mammalian and avian food products, and a variety of other plant-derived foods that may share proteins with pollens, latex, and each other. Clinical evaluations require a careful history, laboratory evaluation, and in some cases oral food challenges. The pitfalls in the evaluation of food allergyunreliable histories and limitations in laboratory assessment primarily caused by false-positive skin prick test responses/RAST results are magnified when dealing with cross-reactive proteins. This review focuses on the clinical data regarding cross-reacting food allergens with the goal of providing a background for improved risk assessment and a framework on which to approach these difficult clinical questions. (J Allergy Clin Immunol 2001;108:881-90.) Key words: Food allergy, cross-reactivity

Abbreviations used CMA: Cows milk allergy DBPCFC: Double-blind, placebo-controlled, oral food challenge IT: Allergen-specific immunotherapy LTP: Lipid transfer protein OAS: Oral allergy syndrome SPT: Skin prick test

various plant and animal proteins. Exposure to homologous proteins can trigger reactions or may be clinically silent while provoking positive test responses for foodspecific IgE antibody. Is the patient with peanut, fish, or apple allergy likely to react to related foods? The molecular basis of cross-reactivity was recently reviewed3,4 and will not be highlighted in this article. Rather, this review will focus on the clinical data regarding cross-reacting food allergens with the goal of providing a framework on which to approach these difficult clinical questions.

GENERAL CONCEPTS
Plant-derived proteins responsible for allergy include various families of pathogenesis-related proteins, protease and -amylase inhibitors, peroxidases, profilins, seed-storage proteins, thiol proteases, and lectins,4 whereas homologous animal proteins include muscle proteins, enzymes, and various serum proteins. The conservation of these proteins across biologic substances affects cross-reactivity in several ways. Certain foods (eg, peanut) are able to sensitize and elicit reactions after oral exposure (type 1 allergy) and could trigger responses that generalize to related foods (legumes). Other foods (eg, apple) with labile proteins are not strong oral sensitizers. In this latter group of foods, however, sensitization to homologous proteins encountered through respiratory exposure (eg, birch pollen) may mediate reactions to cross-reacting proteins in the food (type 2 allergy) with generally mild clinical manifestations. Factors that determine the clinical appearance of allergy in the face of sensitization are complex and relate to the host (immune response and target-organ hyperreactivity) and the allergen (lability and digestibility).5 Similar factors determine the clinical relevance of cross-reacting food proteins (Table I). Over 70% identity in primary
881

The diagnosis of clinical hypersensitivity to a particular food allergen is attained through careful history, physical examination, a priori reasoning concerning clinical and epidemiologic features of food allergy, and judicious selection and interpretation of tests, including skin tests, RASTs, elimination diets, and oral food challenges.1,2 Allergists are painfully familiar with the pitfalls of these evaluations, some of which are related to the limitations of tests for food-specific IgE antibody. Compounding the clinical challenge of identifying particular causal food allergens is the phenomenon of cross-reactivity among

From the Elliot and Roslyn Jaffe Food Allergy Institute, Division of Allergy and Immunology, Department of Pediatrics, Mount Sinai School of Medicine, New York. SHS is supported in part by HD28822-08 and K23 AI 01709-01. Received for publication May 30, 2001; accepted for publication July 2, 2001. Reprint requests: Scott H. Sicherer, MD, Division of Allergy/Immunology, Mount Sinai Hospital, Box 1198, One Gustave L. Levy Place, New York, NY 10029-6574. Copyright 2001 by Mosby, Inc. 0091-6749/2001 $35.00 + 0 1/10/118515 doi:10.1067/mai.2001.118515

882 Sicherer

J ALLERGY CLIN IMMUNOL DECEMBER 2001

TABLE I. Features that affect clinical relevance in cross-reactions

Immune responses Protein characteristics Exposure

Affinity of IgE antibody Degree of response (concentration of IgE)

Homology Solubility Stability-digestibility

Concentration Route (oral and respiratory) Cofactors (exercise and ethanol)

sequence is generally needed for cross-reactivity.3 Poorly soluble proteins are less likely to elicit reactions unless cofactors, such as exercise or ethanol ingestion, increase absorption (eg, food-dependent, exercise-induced anaphylaxis to wheat gamma-gliadin6). Resistance to digestive enzymes is associated with an increased risk of systemic reactions and oral sensitization.7,8 Additional factors influencing clinical correlation are allergen concentration, differential expression of allergens during ripening,9 and cooking.10 Host immune responses are also important: the risk of reaction rises with increasing concentration of serum food-specific IgE antibody,11 and antibody affinity is also likely to be influential.3

CROSS-REACTIONS AMONG VARIOUS FOODS Legumes

It is common to find positive test responses for IgE antibody to several beans in individuals who are clinically reactive to one type. Using RASTs, Barnett et al12 screened sera from 40 patients with peanut allergy against 10 other legumes and demonstrated IgE binding to multiple legumes for 38% of patients. BernhiselBroadbent and Sampson13 studied 62 children with allergy to at least 1 legume and found that 79% had serologic evidence of IgE binding to more than 1 legume, and 37% bound all 6 legumes. Despite the high rate of cross-sensitization, clinical cross-reactions are uncommon, as demonstrated by studies of allergenic legumes, such as peanut and soy. Among 113 children with atopic dermatitis evaluated with double-blind, placebo-controlled, oral food challenges (DBPCFCs), only 1 (0.8%) had clinical allergy to both foods, despite 19% reacting to peanut and 5% to soy.14 Bock and Atkins15 studied 32 children with peanut allergy confirmed by DBPCFCs and found that 10 (31%) had a positive skin test response to soy, but only 1 (3% of those with peanut allergy) had a clinical reaction to soy. In recent reviews of children with peanut allergy in which DBPCFCs were not routinely performed, higher estimates of reactions are reported: 14% of 10216 and 15% of 223 children.17 In considering a wider variety of legumes, only 3 (1.8%) of 165 children with atopic dermatitis evaluated with DBPCFCs reacted to more than 1 legume, despite 19% reacting to at least 1 legume.18 Bernhisel-Broadbent and Sampson13 specifically addressed the issue of legume cross-reactivity by performing open tests or DBPCFCs in 69 highly atopic children, with at least 1 positive skin test response to a legume. Oral challenges

to the 5 legumes (peanut, soybean, pea, lima bean, and green bean) resulted in 43 reactions in 41 patients (59%). Only 2 (5%) of 41 with any 1 positive challenge reacted to more than 1 legume. The authors concluded that elimination of all legumes in individuals with clinical reactions to 1 legume was unwarranted, despite the high prevalence of patients with multiple legume-positive skin prick test (SPT) responses. These studies did not include large batteries of legumes, and it may be that particular types are more allergenic or cross-reactive.19-21 In an evaluation of children with peanut allergy in France,21 11 (44%) of 24 had positive skin test responses to lupine, and of 8 subjects who underwent DBPCFCs (6 children) or labial challenges (2 children) to lupine, 7 reacted. In vitro studies showed the potential causal protein to be an allergen (43 kd) common to both legumes but not a major peanut allergen. Regional dietary habits and pollen exposure may influence the epidemiology of legume allergy. In Spain, for example, allergy to lentil was more common than allergy to peanut,22 and of 22 children with lentil allergy evaluated for reactions to other legumes,23 6 had a history of reacting to chickpea, 2 to pea, and 1 to green bean. These findings raise suspicion for multiple legume allergy on those reacting to lentil, lupine, and chickpea, but more studies in a variety of geographic settings are needed to quantify the risks.

Tree nuts
Assessment of cross-reactivity among tree nuts is complicated by shared allergens among the nuts and between nuts and other plant-derived foods and pollens. Clinical reactions to tree nuts can be severe,24 potentially fatal, and can occur from a first exposure to a nut in patients allergic to other nuts.25 Serologic studies have indicated a high degree of IgE binding to multiple tree nuts.16,26,27 In our studies of children with tree nut allergy,16 92% of 111 patients with peanut allergy, tree nut allergy, or both had IgE antibody to more than 1 tree nut, and 37% of 54 had experienced convincing reactions and had specific IgE antibody to more than 1 nut. Because of the frequency of severe reactions, there are no comprehensive studies on cross-reactivity to tree nuts. Bock and Atkins15 performed challenges to 1 or more nuts in 14 children, and at least 2 reacted to multiple nuts (as many as 5 types). Similar to our studies,16 Ewan24 has reported coallergy to multiple tree nuts in over a third of 34 patients evaluated for tree nut allergy. Considering the potential severity of the allergy and issues with accurate identification of particular nuts in prepared foods, caution would seem prudent, and total elimination of the nut

J ALLERGY CLIN IMMUNOL VOLUME 108, NUMBER 6

Sicherer 883

family (perhaps with the exception of previously tolerated nuts eaten in isolation) is suggested.16,28 These recommendations are potentially overrestrictive. Some nut allergens may be homologous and cause reactions (eg, in pistacchio-cashew29), whereas others may be homologous but rarely elicit clinical cross-reactivity (eg, proteins in coconut and walnut30).

Legumes, tree nuts, and seeds

Cosensitization to allergenic foods, such as peanut, tree nuts, and seeds (sesame, poppy, and mustard) is common. In a study of 731 subjects in the United Kingdom, 59% sensitized to peanut were also sensitized to hazelnut, Brazil nut, or both.26 Although clinically significant cross-reacting proteins have not yet been described, coallergy to peanut and tree nut has been reported between 23% and 50% in referral populations of atopic patients.16,24,31,32 The rate of coallergy is much lower in unselected populations (2.5%).33 The clinician must consider the age of the patient, history, and perhaps sensitization in considering categoric elimination of these allergenic foods.34 Reactions to seeds, such as sesame, mustard, and poppy, are reported,27,35,36 and cross-reactivity with foods (hazel, kiwi, and other seeds) and pollens is potentially important, but the full clinical implications are far from established.

plaice, herring, and mackerel was nearly 100%, and among patients exposed to each (6, 5, and 6 patients, respectively), all had a history of clinical reactions. In a study of 6 adults from Denmark with a positive DBPCFC result to at least 1 of 3 fish (catfish, codfish, and snapper) and challenged to at least 2 types, 4 reacted to more than 1 species.40 In summary, a patient with fish allergy is at high risk for reactions to other fish but may tolerate some fish species and may deserve further evaluation with supervised oral challenges if desirous of ingesting other fish. The fact that fish allergy can be severe and that cooking-canning and other processing can alter allergenicity must be considered during these evaluations.10

Shellfish
Invertebrate tropomyosin is a panallergen with significant sequence homology identified in Crustacea, such as shrimp,45 crab,46 and lobster47; mollusks, such as oyster, scallop, and squid48; parasites, such as anisakis49; and insects, such as cockroach, grasshopper, and dust mite,48,50,51 with less homology to vertebrate tropomyosin.52 Although the clinical impression is that reactions to multiple crustaceans are fairly common, there are few clinical studies addressing this issue. In 16 atopic patients with shrimp allergy, greater than 80% had positive SPT responses to crab, crayfish, and lobster.53 In 11 patients with immediate reactions to shrimp ingestion, the reaction rate to lobster, crab, and crayfish was 50% to 100% per species.54 On the other end of the spectrum is a report of several individuals with reactions to only particular species of shrimp.55 Overall, Crustaceae represent an increased risk of cross-reactivity, with a potential for severe reactions. Even less well defined is the risk for mollusk allergy for individuals with allergy to Crustaceae or mollusk. Lehrer and McCants56 reported a study of 6 oyster-sensitive, 7 oyster- and Crustacea-sensitive, and 12 Crustacea-sensitive patients in whom serologies were evaluated. Most of the reactions to oyster were isolated to the gastrointestinal tract and not associated with oyster-specific IgE antibody. Although oyster-specific IgE antibody did not correlate with clinical reactions to oyster, 9 of 19 Crustacea-sensitive subjects had positive RASTs to oyster, indicating crossreactive proteins. In another study evaluating 9 patients with shrimp anaphylaxis, binding to tropomyosin of 13 crustaceans and mollusks was universal.48 These studies lacked systematic clinical evaluations, and therefore, the risk of mollusk reactivity is unclear (although the overall impression is that it is not common). Tropomyosin is found in several common aeroallergens, which raises the possibility of sensitization by the respiratory route. Interestingly, there is a case report of a seafood-restaurant worker who had IgE to tropomyosin and occupational asthma to both mollusk (scallop) and crustacean (shrimp).57 In a report of asthma induced by snail consumption in 28 patients, RAST inhibition studies indicated that house dust mite sensitization was the likely initial sensitizing event.51 There are several reports linking allergen immunotherapy (IT) with Der-

Fish
Several reports demonstrate that isolated allergy to a single species of fish (eg, tropical sole37 and swordfish38) occurs and usually does so in the relative absence of IgE antibody to common fish allergens (Gad c 1). However, positive skin test responses to multiple fish in subjects with fish allergy is almost the rule,39-41 and clinical crossreactivity is also common. In 61 children with a history of fish allergy exposed to 2 to 8 species, 34 (56%) reacted to all, and 27 (44%) tolerated some types.41 In a study of 20 Italian children with codfish allergy,42 a high frequency of positive skin test responses (from 5% to 100% per each of 9 species tested) was documented. For those who ingested the fish to which antibody was detected, the clinical reaction rate per fish on the basis of history was 25% to 100%. In these children with cod allergy, eel, bass, sole, and tuna most frequently provoked reactions, and salmon, sardine, and dogfish were least likely to induce symptoms. Regional exposure patterns are relevant. Pascual et al43 from Spain evaluated the relevance of cross-reactivity among 6 regionally important species in 79 children with fish allergy in whom codfish is not a common food. Although all subjects had positive skin test responses to multiple species, only 31 (39%) of 79 had clinical reactions; hake and whiff had the highest and albacore the lowest reaction rate. A few studies have used challenges to evaluate fish allergy. In 10 US children evaluated with DBPCFCs to 4 to 6 species of fish and in whom reactions were confirmed to at least 1 species, 3 reacted to more than 1 type.39 Hansen et al44 evaluated 8 adults with codfish allergy proven by DBPCFC results. Sensitization to

884 Sicherer

J ALLERGY CLIN IMMUNOL DECEMBER 2001

matophagoides pteronyssinus to development of severe reactions to mollusks and Crustacea. Five of 6 patients from the Canary Islands with anaphylaxis to limpet, a mollusk, had received IT with dust mite.58 In a prospective study, 2 of 17 patients receiving dust mite IT had cross-reactive IgE antibodies to tropomyosin and oral symptoms to shrimp.59 It appears that there is a high, but not absolute, clinically relevant cross-reactivity among crustaceans, and reactions can be severe. Allergy to mollusks is less well established and appears less common. Allergy to and IT with dust mite may be an additional risk factor, but determination of the precise risks requires further investigation.

FRUIT, POLLENS, AND LATEX Pollen-food allergy syndrome (oral allergy syndrome)
Oral allergy syndrome (OAS) is classically described as isolated oral symptoms caused by labile proteins in fresh fruits and vegetables that share homology with proteins in pollens (the initial source of sensitization75,76). Several clinical associations have been described (eg, birch pollen with Rosaceae fruits, ragweed with melons, and mugwort with celery). The number of foods reported to be involved in the syndrome is ever expanding,77-79 and the molecular basis for the reactions is continually being elaborated.4 Cooked forms of the foods (eg, apple sauce) are typically tolerated. The epidemiology varies by the exposure to pollens. Among those with allergic rhinitis, 23% to 76% experience OAS to at least 1 food.80-82 Among those with OAS, upward of 70% react to more than 2 foods.83 Considering the almost doubling of sensitization to aeroallergens over the past 2 decades in the United States,84 an epidemic is brewing. Several studies have selected patients on the basis of particular fruit allergies rather than pollen allergies and evaluated for reactions to related fruits. Rodriguez et al85 evaluated 34 adults in Madrid with reported allergy to Rosaceae foods (peach, apple, apricot, almond, plum, pear, and strawberry). Eighty-two percent had positive SPT responses, RAST results, or both to at least 1 of the foods with a median of 5 positive foods per patient. Clinical reactivity determined by DBPCFCs was less than 10% for pear and up to 90% for peach (overall, 35% with a positive skin test response reacted to a given food). Multiple fruit allergy was common in the 22 (46%) who reacted to at least 1 fruit. Peach was the dominant allergenic fruit; 46% reactive to peach reacted to another Rosaceae fruit. Pastorello et al86 studied patients selected for a history of reactions to peach confirmed through open oral food challenges; among 19 evaluated, 63% reacted to at least 1 other fruit among cherry, apricot, and plum. Worse, of 19 patients with melon allergy confirmed by DBPCFC (of 54 patients suspected), 94% reacted to at least 1 of the following related fruits: watermelon, avocado, kiwi, chestnut, banana, and peach.87 Severity of reactions to these foods is an important issue. In a review of several studies with a total of 1,361 patients allergic to food pollen with OAS, 88 8.7% experienced associated systemic symptoms outside of the gastrointestinal tract, 3% at some time experienced systemic symptoms without oral symptoms, and 1.7% experienced anaphylactic shock. Hence the term pollen-food syndrome may be more appropriate than OAS. What distinguishes those at risk for severe reactions? There is evidence that when fruit allergy develops in the absence of pollen allergy, reactions are directed not only to Bet v 1 or profilins but also to lipid transfer proteins (LTPs). Reactions involving fruits with homologous LTPs are more likely to be severe.89,90 Fernndez-Rivas et al91 compared patients with Rosaceae fruit allergy with and without pollinosis

Cereal grains
Cereal grains (eg, wheat, rye, barley, and oat) share homologous proteins with grass pollens and each other.60,61 This may account for the high rate of cosensitization to these foods,60 but among 145 children with positive SPT responses to cereal grains, only 21% exhibited clinical reactivity during challenges. In addition, among those with reactions to 1 grain, 80% were tolerant of all other grains. Caution is warranted, but clinical reactivity to multiple grains appears uncommon.

Mammalian and avian food products

Cross-sensitization is more common within than between avian and mammalian meats, but clinical correlation with sensitization is generally under 50%.52 For avian foods, sensitization has been described to -livetin found in feathers, egg, and meat and associated with reactions to chicken meat in 22% to 32%.62,63 Although avian meat allergy is uncommon,64 when chicken meat allergy is present without egg allergy, the risk of reaction to multiple species of avian meats (turkey, pheasant, and quail) may be increased.65,66 Cross-reactive proteins among various avian eggs is also common,67 but the clinical implications have not been systematically studied. Reactions to duck and goose egg in the absence of hens egg allergy has been described.68 Homologous proteins influence reactions to mammalian meats and milks. A study with oral challenges showed that 9.7% of 62 children with cows milk allergy (CMA) reacted to beef.69 Heating and other cooking processes can reduce the allergenicity of beef,70 and therefore, well-cooked beef is less likely to cause a problem for those with CMA. The allergic relevance of crossreactivity among a variety of mammalian milks has recently been beautifully elucidated. In vitro studies showed extensive cross-reactivity among sheeps, cows, and goats milk71 and among cows, ewes, goats, and buffalos milk, with no significant binding to camels milk.72 Oral challenge studies of goats milk unequivocally showed this to be unsafe for patients with CMA: 92% of 26 patients reacted.73 However, only 4% of 25 children with CMA allergy reacted to mares milk.74 Unfortunately, most of the readily available animal milks are problematic for those with CMA.

J ALLERGY CLIN IMMUNOL VOLUME 108, NUMBER 6

Sicherer 885

FIG 1. Approximate rate of clinical reactivity to at least 1 other related food. The probability of reacting to related foods varies, depending on numerous factors (see text). *Data derived from studies with DBPCFCs.

886 Sicherer

J ALLERGY CLIN IMMUNOL DECEMBER 2001

and found that systemic reactions occurred in 82% without compared with 45% with pollinosis. Anaphylactic shock was also more common in the former (36% vs 9%, respectively). A similar theme was noted for hazelnut, in which patients without pollinosis experienced severe reactions and had IgE binding to hazelnut proteins that were heat stable.92 Asero93 found that individuals with positive skin test responses to commercial Rosaceae food extracts (presumably enriched for stable allergens) were more likely to experience systemic reactions than those with responses positive only to fresh extracts (64% vs 6%, P < .001).

Latex-food syndrome
Evaluation of natural rubber latex-food cross-reactivity is complicated by cross-reacting pollens and foods and coallergy to various substances with potential allergenic relationships. Commonly reported cross-reactive foods include banana, avocado, kiwi, chestnut, potato, and papaya, and numerous latex allergens cross-react with food and pollen proteins.94,95 In a study of 136 patients with latex allergy evaluated by means of RAST to 12 foods reported to be involved in latex-food reactions, 69% of responses were positive to at least 1 food, and 49% were positive to more than 1 food.96 Challenges were not performed, but only one third of the 42% of patients who reported reactions to the particular fruit had a positive RAST result. In another study of 47 patients with latex allergy, 100 of 376 food skin test responses were positive, but only 27 (7.2%) were associated with clinical reactions.97 In evaluating the converse situation of patients with fruit allergy (excluded if there was a well-known risk factor for latex allergy) for sensitization to latex, 86% of 57 patients had serum latex-specific IgE antibody, and 11% experienced clinical reactions to latex.98 There may be clinical value in differentiating individuals with isolated food, pollen, or latex sensitization. Levy et al99 evaluated adults with latex allergy with (n = 24) and without (n = 20) pollinosis and a group without latex allergy and with pollinosis (n = 25) for allergies to 12 foods (by convincing history) classically associated with latex and pollen allergy. In those with isolated latex allergy, reactions were reported to banana (n = 4), avocado (n = 4), kiwi (n = 2), and melon and peach (n = 1 each), whereas those with pollinosis were more likely to react to Rosaceae foods and celery. In the groups with pollen allergy, positive skin test responses to the foods were found in 45%, but for isolated latex allergy, only 24% of responses were positive. The numbers of reactions among those with positive test responses were generally less than 25%, except for reactions to banana, avocado, and kiwi, which approached 50% in those with isolated latex allergy.

DIAGNOSIS AND MANAGEMENT

The typical diagnostic routine for classical food allergy has recently been reviewed.1,2 The limitations and difficulties of the food allergy evaluation are compounded

when dealing with issues of cross-reactive proteinspanallergens. Evaluation of food-specific IgE antibody is particularly confusing because the risk of false-positive test results is great. Performing batteries of tests for screening is likely to result in confusion. Still, a negative test response is valuable to conclude that clinical reactivity is unlikely. For many of the cross-reactive proteins, lability of proteins in commercial extracts is an issue. SPTs with the prick-prick method with fresh fruits and vegetables may increase sensitivity when evaluating these labile allergens100; however, they carry additional concerns about reproducibility, triggering systemic reactions, and increased false-positive results. The oral food challenge remains the only modality to identify true clinical reactions. Unfortunately, the clinician could be facing an enormous number of oral challenges with potentially severe reactions. In practical terms many patients will not undergo oral challenges but may maintain diets arrived at through their clinical history, reasoning on the basis of the available literature, and the results of tests for specific IgE antibodies. The importance of obtaining a definitive diagnosis to allow the broadest diet depends on nutritional needs, food preferences, social issues, and other factors. It is easy to develop a pattern of unnecessarily avoiding multiple related foods. As outlined above, the rather low rate of clinical allergy within some food families (legumes and grains) begs for more thorough evaluations. As a guide, the epidemiologic likelihood of reacting to a related food is depicted in Fig 1. The clinical history of tolerance should be paid attention to because it is essentially a free oral food challenge indicating that the food is safe (at least for that point in time). Except perhaps for fish and shellfish allergy (with an appropriately suspicious history and positive skin test response), all of the studies indicate that oral challenges confirm nonreactivity for a majority of specific foods tested. This encouraging feature should be emphasized. A number of considerations come into play once a decision to perform oral food challenges is made. Risk assessments are based on the history, food involved, and test results to determine the rate and quantity of administration and precautions (eg, office vs hospital setting). Because many of the cross-reactive foods have labile proteins (fruits, vegetables, meat, and fish), additional care is needed in preparing food for blinded challenges. Freezedrying, heating, and other processing methods could reduce allergenicity, leading to a false-negative result.10,87,101 When evaluating pollen-related allergy, additional problems arise. Ripening102 and localization of allergen (peel of Rosaceae fruits103) may influence challenge results. An open challenge with the food in its natural form should always follow a negative blinded challenge result. Some of the salient features derived from the literature that may be helpful in these assessments are summarized in Table II. Unfortunately, there are no certainties. Uncertainty increases when a potentially cross-reactive food has never been ingested (anaphylaxis can occur on a first ingestion of a food with cross-reactive proteins104) or

J ALLERGY CLIN IMMUNOL VOLUME 108, NUMBER 6

Sicherer 887

TABLE II. Special risk factors

Food family-relationship Severity* Special considerations

Legumes

High, peanut; variable, others

Tree nuts

High

Fish

High

Crustaceae

High

Mollusks

Variable

Grains Pollen-related food allergy

Variable Low-Variable

Rosaceae family foods

Variable

Melon allergy Latex allergy

Variable Variable

Meats

Variable

Milks

Variable

Allergy to lentil, lupine, or chickpea may represent a higher likelihood for legume cross-reactions. Established allergy to more than 1 indicates higher risk for multiple allergies High rate of coallergy, cosensitization, severity, and difficulty in avoiding particular nuts may warrant class restriction. Some patients may have pollen-associated reactions Canned fish are less allergenic. High rate of cross-reactivity may warrant class restriction; importance of food may warrant individualized challenges. Isolated species allergy has been reported. Risk of multiple reactions may warrant class restriction, but importance of food may warrant individualized challenges. Allergy to isolated species is reported. Sensitization or immunotherapy with dust mite may increase risks. No comprehensive studies, but risk appears lower between Crustaceae and mollusk than within Crustaceae. Sensitization or immunotherapy with dust mite may increase risks. Importance of food group and low risk of clinical cross-reactivity warrants individualization. Finite but low risk of systemic reactions. Risks increased if history of systemic reactions to 1 of the related foods, reactions to cooked forms, or positive commercial SPT results. Variations by type of pollen exposure. Allergy to related foods without sensitization to related pollen or pollens may indicate increased severity and cross-reactions within food family. Established allergy to any one Rosaceae family food increases risks. Some members are less problematic (eg, pear), and others are more problematic (eg, peach); also as above for pollenrelated foods. Established allergy carries high risk of reaction to other gourds. If isolated latex allergy, then primary foods involved include banana, kiwi, avocado, and chestnut, but associated pollen allergy broadens scope. Rare allergy but potential for avian-avian and mammalianmammalian cross-reactions is greater than between types. Chicken allergy without egg increases likelihood of reacting to multiple avian meats. Except perhaps for mare and camel, mammalian milks cause cross-reactions.

In most cases oral food challenges prove that most related foods are tolerated, even when SPT responses, RAST results, or both are positive. *General impression.

when an individual is presenting a history of reacting to increasing numbers of related foods.19 A question arises also for those with food-pollen syndrome: Should they avoid the food or food family if they do not mind the mild oral symptoms? There are no definitive answers, but the results mentioned above caution that there is a finite risk for reactions beyond the mouth and even anaphylaxis, which can occur even to previously tolerated or unsuspected foods.87,90,91 The natural progression of these allergies has not been elucidated. Clearly, an open discussion with the patient is mandatory in deciding on an approach, and consideration for prescribing self-injectable epinephrine should be made with each evaluation. More specific in vitro diagnostic methods may be on the horizon because the causal cross-reacting allergens are being characterized.3,105 Testing directed to panallergens, such as tropomyosin or LTPs, may prove helpful, but more studies with DBPCFCs in a variety of settings

will be needed. In addition to numerous novel therapeutic approaches being investigated in allergy, the approach to treating pollen-related food allergy with pollen IT has had some success.106-109 Future therapies with anti IgE, specific panallergen IT, and others may prove helpful for these panallergic patients.

SUMMARY
The prevalence and magnitude of clinical allergy caused by cross-reacting proteins and panallergens appears to be increasing and reflects an increase in atopy and allergen sensitization. The limitations that have plagued the evaluation of classical food allergens (egg, milk, wheat, soy, peanut, and seafood), such as the high false-positive rate of SPTs and RASTs, failure of oral challenges to confirm most clinical suspicions of reactivity, and inconsistent reaction rates to related foods, are

888 Sicherer

J ALLERGY CLIN IMMUNOL DECEMBER 2001

magnified when dealing with cross-reactive proteins. Future studies are needed to address the clinical relevance, diagnosis, management, natural history, and treatment of these allergies. Such information can only be obtained from careful clinical studies that use blinded oral challenges.

REFERENCES 1. Sampson HA. Food allergy. Part 2: diagnosis and management. J Allergy Clin Immunol 1999;103:981-9. 2. Sicherer SH. Food allergy: when and how to perform oral food challenges. Pediatr Allergy Immunol 1999;10:226-34. 3. Aalberse RC. Structural biology of allergens. J Allergy Clin Immunol 2000;106:228-38. 4. Breiteneder H, Ebner C. Molecular and biochemical classification of plant-derived food allergens. J Allergy Clin Immunol 2000;106:27-36. 5. Sicherer SH. Determinants of systemic manifestations of food allergy. J Allergy Clin Immunol 2000;106:S251-7. 6. Morita E, Yamamura Y, Mihara S, Kameyoshi Y, Yamamoto S. Fooddependent exercise-induced anaphylaxis: a report of two cases and determination of wheat-gamma-gliadin as the presumptive allergen. Br J Dermatol 2000;143:1059-63. 7. Astwood JD, Leach JN, Fuchs RL. Stability of food allergens to digestion in vitro. Nat Biotechnol 1996;14:1269-73. 8. Yagami T, Haishima Y, Nakamura A, Osuna H, Ikezawa Z. Digestibility of allergens extracted from natural rubber latex and vegetable foods. J Allergy Clin Immunol 2000;106:752-62. 9. Hanninen AR, Mikkola JH, Kalkkinen N, Turjanmaa K, Ylitalo L, Reunala T, et al. Increased allergen production in turnip (Brassica rapa) by treatments activating defense mechanisms. J Allergy Clin Immunol 1999;104:194-201. 10. Bernhisel-Broadbent J, Strause D, Sampson HA. Fish hypersensitivity. II: Clinical relevance of altered fish allergenicity caused by various preparation methods. J Allergy Clin Immunol 1992;90:622-9. 11. Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 2001;107:891-6. 12. Barnett D, Bonham B, Howden ME. Allergenic cross-reactions among legume foodsan in vitro study. J Allergy Clin Immunol 1987;79:433-8. 13. Bernhisel-Broadbent J, Sampson HA. Cross-allergenicity in the legume botanical family in children with food hypersensitivity. J Allergy Clin Immunol 1989;83:435-40. 14. Sampson HA, McCaskill CC. Food hypersensitivity and atopic dermatitis: evaluation of 113 patients. J Pediatr 1985;107:669-75. 15. Bock SA, Atkins FM. The natural history of peanut allergy. J Allergy Clin Immunol 1989;83:900-4. 16. Sicherer SH, Burks AW, Sampson HA. Clinical features of acute allergic reactions to peanut and tree nuts in children. Pediatrics 1998;102:e6. 17. Skolnick HS, Conover Walker MK, Barnes Koerner C, Sampson HA, Burks AW, Wood RA. The natural history of peanut allergy. J Allergy Clin Immunol 2001;107:367-74. 18. Burks AW, James JM, Hiegel A, Wilson G, Wheeler JG, Jones SM, et al. Atopic dermatitis and food hypersensitivity reactions. J Pediatr 1998; 132:132-6. 19. Matheu V, de Barrio M, Sierra Z, Gracia-Bara MT, Tornero P, Baeza ML. Lupine-induced anaphylaxis. Ann Allergy Asthma Immunol 1999; 83:406-8. 20. Hefle SL, Lemanske RFJ, Bush RK. Adverse reaction to lupine-fortified pasta. J Allergy Clin Immunol 1994;94:167-72. 21. Moneret-Vautrin DA, Guerin L, Kanny G, Flabbee J, Fremont S, Morisset M. Cross-allergenicity of peanut and lupine: the risk of lupine allergy in patients allergic to peanuts. J Allergy Clin Immunol 1999;104:883-8. 22. Crespo JF, Pascual C, Burks AW, Helm RM, Esteban MM. Frequency of food allergy in a pediatric population from Spain. Pediatr Allergy Immunol 1995;6:39-43. 23. Pascual CY, Fernandez-Crespo J, Sanchez-Pastor S, Padial MA, DiazPena JM, Martin-Munoz F, et al. Allergy to lentils in Mediterranean pediatric patients. J Allergy Clin Immunol 1999;103:154-8. 24. Ewan PW. Clinical study of peanut and nut allergy in 62 consecutive patients: new features and associations. BMJ 1996;312:1074-8.

25. Bock SA, Munoz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions to foods. J Allergy Clin Immunol 2001;107:191-3. 26. Pumphrey RS, Wilson PB, Faragher EB, Edwards SR. Specific immunoglobulin E to peanut, hazelnut and brazil nut in 731 patients: similar patterns found at all ages. Clin Exp Allergy 1999;29:1256-9. 27. Vocks E, Borga A, Szliska C, Seifert HU, Burow G, Borelli S. Common allergenic structures in hazelnut, rye grain, sesame seeds, kiwi, and poppy seeds. Allergy 1993;48:168-72. 28. Hourihane JO, Dean TP, Warner JO. Peanut allergy in relation to heredity, maternal diet, and other atopic diseases: results of a questionnaire survey, skin prick testing, and food challenges. BMJ 1996;313:518-21. 29. Garcia F, Moneo I, Fernandez B, Garcia-Menaya JM, Blanco J, Juste S, et al. Allergy to Anacardiaceae: description of cashew and pistachio nut allergens. J Investig Allergol Clin Immunol 2000;10:173-7. 30. Teuber SS, Peterson WR. Systemic allergic reaction to coconut (Cocos nucifera) in 2 subjects with hypersensitivity to tree nut and demonstration of cross-reactivity to legumin-like seed storage proteins: new coconut and walnut food allergens. J Allergy Clin Immunol 1999;103:1180-5. 31. Hourihane JOB, Kilburn SA, Dean P, Warner JO. Clinical characteristics of peanut allergy. Clin Exp Allergy 1997;27:634-9. 32. Sicherer SH, Furlong TJ, Muoz-Furlong A, Burks AW, Sampson HA. A voluntary registry for peanut and tree nut allergy: characteristics of the first 5,149 registrants. J Allergy Clin Immunol 2001;108:128-32. 33. Sicherer SH, Muoz-Furlong A, Burks AW, Sampson HA. Prevalence of peanut and tree nut allergy in the US determined by a random digit dial telephone survey. J Allergy Clin Immunol 1999;103:559-62. 34. Committee on Nutrition, American Academy of Pediatrics. Hypoallergenic infant formulas. Pediatrics 2000;106:346-9. 35. Asero R, Mistrello G, Roncarolo D, Antoniotti PL, Falagiani P. A case of sesame seed-induced anaphylaxis. Allergy 1999;54:526-7. 36. Rance F, Dutau G, Abbal M. Mustard allergy in children. Allergy 2000;55:496-500. 37. Asero R, Mistrello G, Roncarolo D, Casarini M, Falagiani P. True monosensitivity to a tropical sole. Allergy 1999;54:1228-9. 38. Kelso JM, Jones RT, Yunginger JW. Monospecific allergy to swordfish. Ann Allergy Asthma Immunol 1996;77:227-8. 39. Bernhisel-Broadbent J, Scanlon SM, Sampson HA. Fish hypersensitivity. I. In vitro and oral challenge results in fish-allergic patients. J Allergy Clin Immunol 1992;89:730-7. 40. Helbling A, Haydel R, McCants ML, Musmand JJ, El Dahr J, Lehrer SB. Fish allergy: is cross-reactivity among fish species relevant? Doubleblind placebo-controlled food challenge studies of fish allergic adults. Ann Allergy Asthma Immunol 1999;83:517-23. 41. Aas K. Studies of hypersensitivity to fish. A clinical study. Int Arch Allergy Clin Immunol 1966;29:346-63. 42. de Martino M, Novembre E, Galli L, de Marco A, Botarelli P, Marano E, et al. Allergy to different fish species in cod-allergic children: in vivo and in vitro studies. J Allergy Clin Immunol 1990;86:909-14. 43. Pascual C, Martin EM, Crespo JF. Fish allergy: evaluation of the importance of cross-reactivity. J Pediatr 1992;121:S29-34. 44. Hansen TK, Bindslev JC, Skov PS, Poulsen LK. Codfish allergy in adults: IgE cross-reactivity among fish species. Ann Allergy Asthma Immunol 1997;78:187-94. 45. Daul CB, Slattery M, Reese G, Lehrer SB. Identification of the major brown shrimp (Penaeus aztecus) allergen as the muscle protein tropomyosin. Int Arch Allergy Immunol 1994;105:49-55. 46. Leung PS, Chen YC, Gershwin ME, Wong SH, Kwan HS, Chu KH. Identification and molecular characterization of Charybdis feriatus tropomyosin, the major crab allergen. J Allergy Clin Immunol 1998;102:847-52. 47. Leung PS, Chen YC, Mykles DL, Chow WK, Li CP, Chu KH. Molecular identification of the lobster muscle protein tropomyosin as a seafood allergen. Mol Mar Biol Biotechnol 1998;7:12-20. 48. Leung PS, Chow WK, Duffey S, Kwan HS, Gershwin ME, Chu KH. IgE reactivity against a cross-reactive allergen in crustacea and mollusca: evidence for tropomyosin as the common allergen. J Allergy Clin Immunol 1996;98:954-61. 49. Asturias JA, Eraso E, Moneo I, Martinez A. Is tropomyosin an allergen in Anisakis? Allergy 2000;55:898-9. 50. Santos AB, Chapman MD, Aalberse RC, Vailes LD, Ferriani VP, Oliver C, et al. Cockroach allergens and asthma in Brazil: identification of tropomyosin as a major allergen with potential cross-reactivity with mite and shrimp allergens. J Allergy Clin Immunol 1999;104:329-37.

J ALLERGY CLIN IMMUNOL VOLUME 108, NUMBER 6

Sicherer 889

51. van Ree R, Antonicelli L, Akkerdaas JH, Pajno GB, Barberio G, Corbetta L, et al. Asthma after consumption of snails in house-dust-mite-allergic patients: a case of IgE cross-reactivity. Allergy 1996;51:387-93. 52. Ayuso R, Lehrer SB, Tanaka L, Ibanez MD, Pascual C, Burks AW, et al. IgE antibody response to vertebrate meat proteins including tropomyosin. Ann Allergy Asthma Immunol 1999;83:399-405. 53. Daul CB, Morgan JE, Waring NP, McCants ML, Hughes J, Lehrer SB. Immunologic evaluation of shrimp-allergic individuals. J Allergy Clin Immunol 1987;80:716-22. 54. Waring NP, Daul CB, deShazo RD, McCants ML, Lehrer SB. Hypersensitivity reactions to ingested crustacea: clinical evaluation and diagnostic studies in shrimp-sensitive individuals. J Allergy Clin Immunol 1985;76:440-5. 55. Morgan JE, ONeil CE, Daul CB, Lehrer SB. Species-specific shrimp allergens: RAST and RAST-inhibition studies. J Allergy Clin Immunol 1989;83:1112-7. 56. Lehrer SB, McCants ML. Reactivity of IgE antibodies with crustacea and oyster allergens: evidence for common antigenic structures. J Allergy Clin Immunol 1987;80:133-9. 57. Goetz DW, Whisman BA. Occupational asthma in a seafood restaurant worker: cross-reactivity of shrimp and scallops. Ann Allergy Asthma Immunol 2000;85:461-6. 58. Carrillo T, Rodriguez dC, Blanco C, Castillo R, Quiralte J, Cuevas M. Anaphylaxis due to limpet ingestion. Ann Allergy 1994;73:504-8. 59. van Ree R, Antonicelli L, Akkerdaas JH, Garritani MS, Aalberse RC, Bonifazi F. Possible induction of food allergy during mite immunotherapy. Allergy 1996;51:108-13. 60. Jones SM, Magnolfi CF, Cooke SK, Sampson HA. Immunologic crossreactivity among cereal grains and grasses in children with food hypersensitivity. J Allergy Clin Immunol 1995;96:341-51. 61. Donovan GR, Baldo BA. Crossreactivity of IgE antibodies from sera of subjects allergic to both ryegrass pollen and wheat endosperm proteins: evidence for common allergenic determinants. Clin Exp Allergy 1990;20:501-9. 62. Bausela BA, Garcia AM, Martin EM, Boyano MT, Diaz PJ, Ojeda CJ. Peculiarities of egg allergy in children with bird protein sensitization. Ann Allergy Asthma Immunol 1997;78:213-6. 63. Szepfalusi Z, Ebner C, Pandjaitan R, Orlicek F, Scheiner O, BoltzNitulescu G, et al. Egg yolk a-livetin (chicken serum albumin) is a crossreactive allergen in the bird-egg syndrome. J Allergy Clin Immunol 1994;93:932-42. 64. Bock SA, Sampson HA, Atkins FM, Zeiger RS, Lehrer S, Sachs M, et al. Double-blind, placebo-controlled food challenge (DBPCFC) as an office procedure: a manual. J Allergy Clin Immunol 1988;82:986-97. 65. Kelso JM, Cockrell GE, Helm RM, Burks AW. Common allergens in avian meats. J Allergy Clin Immunol 1999;104:202-4. 66. Cahen YD, Fritsch R, Wuthrich B. Food allergy with monovalent sensitivity to poultry meat. Clin Exp Allergy 1998;28:1026-30. 67. Langland T. A clinical and immunological study of allergy to hens egg white. VI. Occurrence of proteins cross-reacting with allergens in hens egg white as studied in egg white from turkey, duck, goose, seagull, and in hen egg yolk, and hen and chicken sera and flesh. Allergy 1983;38:399-412. 68. Anibarro B, Seoane FJ, Vila C, Lombardero M. Allergy to eggs from duck and goose without sensitization to hen egg proteins. J Allergy Clin Immunol 2000;105:834-6. 69. Werfel SJ, Cooke SK, Sampson HA. Clinical reactivity to beef in children allergic to cows milk. J Allergy Clin Immunol 1997;99:293-300. 70. Fiocchi A, Restani P, Riva E, Mirri GP, Santini I, Bernardo L, et al. Heat treatment modifies the allergenicity of beef and bovine serum albumin. Allergy 1998;53:798-802. 71. Spuergin P, Walter M, Schiltz E, Deichmann K, Forster J, Mueller H. Allergenicity of alpha-caseins from cow, sheep, and goat. Allergy 1997;52:293-8. 72. Restani P, Gaiaschi A, Plebani A, Beretta B, Cavagni G, Fiocchi A, et al. Cross-reactivity between milk proteins from different animal species. Clin Exp Allergy 1999;29:997-1004. 73. Bellioni-Businco B, Paganelli R, Lucenti P, Giampietro PG, Perborn H, Businco L. Allergenicity of goats milk in children with cows milk allergy. J Allergy Clin Immunol 1999;103:1191-4. 74. Businco L, Giampietro PG, Lucenti P, Lucaroni F, Pini C, Di Felice G, et al. Allergenicity of mares milk in children with cows milk allergy. J Allergy Clin Immunol 2000;105:1031-4. 75. Kazemi-Shirazi L, Pauli G, Purohit A, Spitzauer S, Oschl R, Hoffmann-

76.

77.

78.

79.

80. 81.

82.

83. 84.

85.

86.

87.

88. 89.

90.

91. 92.

93.

94.

95. 96. 97. 98. 99.

Sommergruber K, et al. Quantitative IgE inhibition experiments with purified recombinant allergens indicate pollen-derived allergens as the sensitizing agents responsible for many forms of plant food allergy. J Allergy Clin Immunol 2000;105:116-25. Valenta R, Kraft D. Type 1 allergic reactions to plant-derived food: a consequence of primary sensitization to pollen allergens. J Allergy Clin Immunol 1996;97:893-5. Jensen-Jarolim E, Leitner A, Hirschwehr R, Kraft D, Wuthrich B, Scheiner O, et al. Characterization of allergens in Apiaceae spices: anise, fennel, coriander and cumin. Clin Exp Allergy 1997;27:1299-306. Figueredo E, Cuesta-Herranz J, Minguez A, Vidarte L, Pastor C, de las HM, et al. Allergy to pumpkin and cross-reactivity to other Cucurbitaceae fruits. J Allergy Clin Immunol 2000;106:402-3. Reindl J, Anliker MD, Karamloo F, Vieths S, Wuthrich B. Allergy caused by ingestion of zucchini (Cucurbita pepo): characterization of allergens and cross-reactivity to pollen and other foods. J Allergy Clin Immunol 2000;106:379-85. Enberg RN, Leickly FE, McCullough J, Bailey J, Ownby DR. Watermelon and ragweed share allergens. J Allergy Clin Immunol 1987;79:867-75. Ebner C, Birkner T, Valenta R, Rumpold H, Breitenbach M, Scheiner O, et al. Common epitopes of birch pollen and applesstudies by western and northern blot. J Allergy Clin Immunol 1991;88:588-94. Bircher AJ, Van MG, Haller E, Curty B, Frei PC. IgE to food allergens are highly prevalent in patients allergic to pollens, with and without symptoms of food allergy. Clin Exp Allergy 1994;24:367-74. Ortolani C, Ispano M, Pastorello E, Bigi A, Ansaloni R. The oral allergy syndrome. Ann Allergy 1988;61:47-52. Chiu L, Sampson HA, Sicherer SH. Estimation of the sensitization rate to peanut by prick skin test in the general population: Results from the National Health and Nutrition Examination Survey 1988-94 (NHANES III). J Allergy Clin Immunol 2001;107:S192. Rodriguez J, Crespo JF, Lopez-Rubio A, Cruz-Bertolo J, Ferrando-Vivas P, Vives R, et al. Clinical cross-reactivity among foods of the Rosaceae family. J Allergy Clin Immunol 2000;106:183-9. Pastorello E, Ortolani C, Farioli L, Pravettoni V, Ispano M, Borga A, et al. Allergenic cross-reactivity among peach, apricot, plum, and cherry in patients with oral allergy syndrome: an in vivo and in vitro study. J Allergy Clin Immunol 1994;94:699-707. Rodriguez J, Crespo JF, Burks W, Rivas-Plata C, Fernandez-Anaya S, Vives R, et al. Randomized, double-blind, crossover challenge study in 53 subjects reporting adverse reactions to melon (Cucumis melo). J Allergy Clin Immunol 2000;106:968-72. Ortolani C, Pastorello EA, Farioli L, Ispano M, Pravettoni V, Berti C, et al. IgE-mediated allergy from vegetable allergens. Ann Allergy 1993;71:470-6. Pastorello EA, Farioli L, Pravettoni V, Ortolani C, Ispano M, Monza M, et al. The major allergen of peach (Prunus persica) is a lipid transfer protein. J Allergy Clin Immunol 1999;103:520-6. Cuesta-Herranz J, Lazaro M, Martinez A, Figueredo E, Palacios R, LasHeras M, et al. Pollen allergy in peach-allergic patients: sensitization and cross- reactivity to taxonomically unrelated pollens. J Allergy Clin Immunol 1999;104:688-94. Fernandez-Rivas M, van Ree R, Cuevas M. Allergy to Rosaceae fruits without related pollinosis. J Allergy Clin Immunol 1997;100:728-33. Schocker F, Luttkopf D, Muller U, Thomas P, Vieths S, Becker WM. IgE binding to unique hazelnut allergens: identification of non pollen- related and heat-stable hazelnut allergens eliciting severe allergic reactions. Eur J Nutr 2000;39:172-80. Asero R. Detection and clinical characterization of patients with oral allergy syndrome caused by stable allergens in Rosaceae and nuts. Ann Allergy Asthma Immunol 1999;83:377-83. Nel A, Gujuluva C. Latex antigens: identification and use in clinical and experimental studies, including crossreactivity with food and pollen allergens. Ann Allergy Asthma Immunol 1998;81:388-96. Blanco C, Carrillo T, Castillo R, Quiralte J, Cuevas M. Latex allergy: clinical features and cross-reactivity with fruits. Ann Allergy 1994;73:309-14. Brehler R, Theissen U, Mohr C, Luger T. Latex-fruit syndrome: frequency of cross-reacting IgE antibodies. Allergy 1997;52:404-10. Beezhold DH, Sussman GL, Liss GM, Chang NS. Latex allergy can induce clinical reactions to specific foods. Clin Exp Allergy 1996;26:416-22. Garcia Ortiz JC, Moyano JC, Alvarez M, Bellido J. Latex allergy in fruit-allergic patients. Allergy 1998;53:532-6. Levy DA, Mounedji N, Noirot C, Leynadier F. Allergic sensitization and

890 Sicherer

J ALLERGY CLIN IMMUNOL DECEMBER 2001

100.

101.

102.

103.

clinical reactions to latex, food and pollen in adult patients. Clin Exp Allergy 2000;30:270-5. Ortolani C, Ispano M, Pastorello EA, Ansaloni R, Magri GC. Comparison of results of skin prick tests (with fresh foods and commercial food extracts) and RAST in 100 patients with oral allergy syndrome. J Allergy Clin Immunol 1989;83:683-90. Sanchez-Monge R, Blanco C, Perales AD, Collada C, Carrillo T, Aragoncillo C, et al. Class I chitinases, the panallergens responsible for the latex-fruit syndrome, are induced by ethylene treatment and inactivated by heating. J Allergy Clin Immunol 2000;106:190-5. Diaz-Perales A, Collada C, Blanco C, Sanchez-Monge R, Carrillo T, Aragoncillo C, et al. Cross-reactions in the latex-fruit syndrome: a relevant role of chitinases but not of complex asparagine-linked glycans. J Allergy Clin Immunol 1999;104:681-7. Fernandez-Rivas M, Cuevas M. Peels of Rosaceae fruits have a higher allergenicity than pulps. Clin Exp Allergy 1999;29:1239-47.

104. Kelso JM, Jones RT, Yunginger JW. Anaphylaxis after initial ingestion of rambutan, a tropical fruit. J Allergy Clin Immunol 1998;102:145-6. 105. Scheurer S, Pastorello EA, Wangorsch A, Kastner M, Haustein D, Vieths S. Recombinant allergens Pru av 1 and Pru av 4 and a newly identified lipid transfer protein in the in vitro diagnosis of cherry allergy. J Allergy Clin Immunol 2001;107:724-31. 106. Asero R. Fennel, cucumber, and melon allergy successfully treated with pollen-specific injection immunotherapy. Ann Allergy Asthma Immunol 2000;84:460-2. 107. Asero R. Effects of birch pollen-specific immunotherapy on apple allergy in birch pollen-hypersensitive patients. Clin Exp Allergy 1998;28:1368-73. 108. Moller C. Effect of pollen immunotherapy on food hypersensitivity in children with birch pollinosis. Ann Allergy 1989;62:343-5. 109. Kelso JM, Jones RT, Tellez R, Yunginger JW. Oral allergy syndrome successfully treated with pollen immunotherapy. Ann Allergy Asthma Immunol 1995;74:391-6.