Role of Food Allergy in Atopic Eczema

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1 Chapter 41 Role of Food Allergy in Atopic Eczema 41 T. Werfel, K. Breuer 41.1 Introduction Atopic eczema (AE) is a chronic inflammatory skin disease that commonly begins in early infancy, runs a course of exacerbations and remissions, and is associated with a characteristic distribution and morphology of skin lesions. Furthermore, pruritus and subsequent sleeplessness are hallmarks of AE (Werfel and Kapp 2004). Numerous trigger factors have been identifiedforaeoverthelastfewdecades,suchasinhalative allergens, food allergens, irritative substances, and infectious microorganisms such as Staphylococcus aureus and Malasseziafurfur [6, 43] (Fig. 41.1). There issubstantialevidencethatfoodssuchascow smilk and hen s egg are major provocation factors for the flares of AE in infancy, while inhalant allergens and pollen-related foods are of greater importance in adults [8]. Superantigens Irrititating substances Psychological stress Inhalant allergens Climate Food allergens Infections Hormones Fig Trigger factors of atopic dermatitis According to Wüthrich et al., three patterns of cutaneous reactions to food may occur in patients with AE upon oral challenge [49]: 1. Immediate-type reactions such as urticaria, angioedema, and erythema, commonly occurring a few minutes after ingestion of food without an exacerbation of AE. Additionally, gastrointestinal, respiratory, and cardiovascular symptoms may evolve. 2. Pruritus occurring soon after the ingestion of food with subsequent scratching leading to an exacerbation of AE. 3. Exacerbations of AE occurring after 6 48 h, termed late reactions, which may also occur after an immediate-type response Prevalence of Food Allergy in Atopic Eczema TheprevalenceoffoodallergyininfantswithAEwas reported to range from 20% to 80% in various studies, and may be estimated at 30% [11, 29, 33]. Hen s egg, cow s milk, soy, and wheat account for about 90% of allergenic foods in children with AE [11, 22]. About one-third of children will outgrow their food allergy after 1 2 years under allergen avoidance, dependent on the kind of food [36]. Atherton et al. observed a significant improvement in dermatitis in more than 50% of children during a period of a placebo-controlled diet [1]. Several open studies also describe some benefit in various sites in subpopulations of patients with AE, but a major problem of these studies is their open design, which does not exclude placebo effects [2]. Immediate-type responses to foods are well characterized in studies using oral provocation tests with children with atopic eczema, but there are only very few trials studying true late eczematous responses, which need 6 48 h to develop and may occur only after repetitive ingestion of food.

2 Role of Food Allergy in Atopic Eczema In a recent study, we found that 46% of all doubleblind placebo-controlled oral challenge tests (DBPCFC) resultedinanimmediateand/orlateeczematousreactioninchildrenintheagerangeof1 10years[8]. Based on these results, food allergy was diagnosed in 64% of the children studied. These high numbers may have resulted from the preselection of the children investigated in our study, who were suspected of having food allergy by their history or positive food-specific IgE or positive atopy patch tests (APT). Similarly, in a study by Niggemann et al. [23], 51% of all challenge tests resulted in an allergic reaction, and81%ofallpatientsreactedtoatleastoneallergen. Sampson et al. found a frequency of food allergy of more than 60% in children with AE [31, 35]. The frequency of food allergy in children with AE was estimated at 30% in a study by Burks and co-workers who investigated infants who were not specifically referred for the evaluation of food allergy [10]. Children included in this study were older than children investigated in other studies Late Eczematous Reactions to Foods in Atopic Eczema Whether eczematous lesions can be induced by the ingestion of food is still a matter of debate. The cutaneous inflammatory infiltrate in eczematous lesions of patients with AE consists mainly of CD4+ T cells, and food allergen-specific T cells have been shown to be involved in the late eczematous response to food [27, 46, 47]. There are few studies in the literature that differentiate food-induced eczema occurring after many hours clearly from immediate-type reactions, which may have been the result of most investigators not observing the patients for longer periods than 1 day upon challenge. Due to the pathophysiological mechanisms involved in food-induced eczema, eczematous lesions usually need at least 6 h to develop and therefore, late eczematous reactions should be defined as occurring later than 6 h after ingestion of food. In order to distinguish eczematous responses clearly from early cutaneous reactions, the suspected food should be given over a periodof2days.ideally,thenextfoodshouldbeintroduced after a challenge-free day. This provocation scheme is recommended for the detection of true eczematous late-phase reactions by the German Society of Allergology and Clinical Immunology [48] (Fig. 41.2). It is different from the current proposals, which mainly address immediate reactions to food [4]. Differences in the proportion of AE patients reacting to food challenge in different studies may therefore not only be due to preselection, but also to the method used for DBPCFC. In the studies by Niggemann [23], Burks [10], and Sampson [31, 35], the food was not given repetitively over 2 days. Each day, two challenges (verum/placebo) were administered within 4 h in the trials by Sampson and Burks, and thus the patients were not observable for longer periods than 1 day. Similar to our study [9], cow s milk, wheat powder, and soy milk were administered by Niggemann et al. [23]. Instead of egg powder consisting of egg white and yolk as was administered in our study, they used raw egg. Dehydrated food mixed with juice was used in the studies by Burks and Sampson Rate of Late Reactions to Challenges with Foods More than 50% of all positive oral challenges in children sufferingfromaewereassociatedwithanexacerbation of eczema in our study (Breuer 2004). Isolated eczematous reactions were seen in 12% of all positive challenges (Fig. 41.3); 50% of these reactions occurred after challenge with wheat, but the limited number of patients reacting in this way might have biased these results. Niggemann et al. observed late reactions in 25% of positive provocation tests [23]. Late reactions were e.g., placebo e.g., milk e.g., hen s egg Fig Repetitive oral provocation tests for the detection of true eczematous reactions in atopic eczema. Each column represents 1 day. The food or placebo is titrated on the 1st day. In case of a negative reaction, an-age adapted fulldoseisgivenonthesubsequentday

3 41.5 Predictive Values of Diagnostic Tools % 43% Immediate reactions Delayed 12% reactions Combined reactions Fig Investigation of food-responsive atopic dermatitis in children: pattern of clinical reactions definedassymptomsoccurringaftermorethan2hin their study, thus including probably not only eczematous reactions. Other investigators did not observe true eczematous reactions upon DBPCFC [10, 35], which maybeduetothechallengemethoddescribedabove.in these studies, cutaneous symptoms such as pruritus andrashoccurredwithin2huponchallenge.such immediate-type symptoms may be induced by mast cell degranulation with subsequent release of pro-inflammatory mediators such as histamine. Interestingly, 19% of all immediate reactions occurred on the 2nd challenge day after the highest dose had been tolerated on the 1st day in our study. The pathophysiologic mechanism of this phenomenon is not clear, but repetitive doses may boost the food-specific allergic response and may therefore reflect the normal situation in a more sensitive way. Delayed immediate reactions occurring in 16% of our patients after 2 6 h are thought to be induced by mediators derived from mast cell like leukotrienes and cytokines, leading to an influx of eosinophils, basophils, and neutrophils [16, 32] Predictive Values of Diagnostic Tools Reliable markers for the identification of patients with food-responsive eczema are still lacking. Anamnestic data given by the parents often do not correlate with the findings of an oral challenge, particularly with regard to eczematous reactions [1, 17]. We found a low predictive accuracy of the personal history, particularly for eczematous reactions, which require several hours to develop [9]. Specific IgE levels associated with a positive challenge test have been described as significantly higher than specific IgE levels associated with a negative challenge [8, 23]. The fact that sensitivity, specificity, and positive predictive value (PPV) of food-specific IgE are higher for immediate than for eczematous reactions underlines the importance of food-specific IgE, particularly for immediate reactions. From a physician s point of view, the PPV are of greatest interest, because they indicate how likely the patient will develop a clinical reaction to a certain food. The PPV of food-specific IgE was only 33% for eczematous reactions, which means that only one-third of all challenges associated with food-specific IgE resulted in exacerbation of AE. The PPV of food-specific IgE was 57% for immediate reactions. This result is consistent with a previous study by Sampson et al., who found the PPV ranging from 18% to 57% for different kinds of food. The diagnostic accuracy of food-specific IgE has been described to be lower in children who were older than 2 years compared to younger children, which is most likely explained by the fact that many children outgrow their food allergy, while food-specific IgE remains detectable [36]. The probability of a positive immediate reaction to food has been shown to depend on the level of food-specific IgE and for foods such as cow s milk and hen s egg it is possible to determine IgE levels which predict clinical reactivity with 95% certainty in children with AE [34, 37]. Of all positive challenges, 25% were associated with negative food-specific IgE in our trial, and food-specific T cells may play a predominant role in the pathogenesis of these reactions. A relatively high number of patients without food-specific IgE, who had a history suggestive of food allergy or a positive APT were included in our analysis, which might have resulted in therelativelyhighnumberofpositivechallengesassociated with negative food-specific IgE. Thus the suspicion of food allergy rather than the detection of foodspecific IgE should be the indication for DBPCFC in children with moderate and severe atopic dermatitis. Similarly as Niggemann et al., who found that 10% of positive DBPCFC were not associated with food specific IgE [24], there were no differences in terms of age and total IgE levels as compared to children with food specific IgE. Since the atopy patch test (APT) lesions resemble spontaneous lesions both clinically and histologically, APTs are likely to mimic the mechanisms involved in food/aeroallergen-responsive atopic dermatitis [12]. Of our patients with an isolated eczematous reaction, 75% had a positive APT (Breuer 2004). In five patients with a positive challenge who had no food-specific IgE, an APT was performed and resulted in a positive reac-

4 Role of Food Allergy in Atopic Eczema tion, suggesting a major role of food-specific T cells. However, we calculated a low specificity and PPV for the APT in our study. A high rate of false-positive APT reactions was seen, particularly after application of wheat proteins and was possibly caused by irritation. In contrast, the atopy patch test with cow s milk allergy hadappvof95%inastudybyroehretal.[30].the combination with positive food-specific IgE of any level resulted in a PPV of 100% for early and late reactions. Isolauri et al. also found a very good correlation between positive patch test results and late reactions to cow s milk [20]. Other investigators, however, found a markedly lower PPV of 40% for immediate reactions to cow s milk, but did not investigate late reactions [42]. In another study focusing on wheat allergy, the PPV was63%[22].todate,theaptisnotwellstandardized, and different methods in preparing the test solutions are likely to cause controversial results. Therefore further studies are needed before the APT can be used as a routine tool for the diagnosis of food allergy. Taken together, the personal history, food-specific IgE,andtheAPTarenotreliableenoughfortheidentification of clinically relevant foods, particularly when eczematous reactions are concerned. Therefore, food challenges are still necessary for the appropriate diagnosis of food allergy in patients with AE. Elimination diets based solely on in vitro or skin tests are inadequate, if the history is not convincing. A negative open challenge may confirm the absence of food allergy, in positive cases, a DBPCFC is recommended Allergen-Specific T Cell Responses in Atopic Eczema Early studies on passively sensitized individuals demonstrated that immunologically active food proteins can enter the circulation and are distributed throughout the body, including skin sites. Such resorbed food antigens can directly interact with specific IgE that is bound to Fc receptors on Langerhans cells, mast cells, monocytes, and basophilic granulocytes, but also skininfiltrating T lymphocytes. Since eczematous lesions are probably triggered by T lymphocytes, new diagnostic approaches may come from the characterization of allergen-specific T cell parameters. We found significant differences in the proliferative response of blood lymphocytes between patients who reacted to milk with worsening of atopic eczema and control groups and were able to generate casein-specific T cell clones from the blood of these patients [27, 46, 47]. Higher proliferative responses to LPS-depleted casein the major protein fraction in cow s milk and thus the main protein source in the nutrition of many humans were observed both in atopic children and in adults reacting with worsening of eczema to oral provocation. Although this method cannot be recommended for routine purposes, so far it can be the basis for novel T cell-based specific tests. As mentioned above, specific IgE to food antigens is detectable in most children with atopic eczema investigated who reacted with clinical symptoms (Reekers 1996). In contrast, we found food-specific IgE in less than 50% of adult patients who reacted to oral provocation with cow s milk. A type 1 cytokine pattern (i.e., production of IFN * but not of IL-4) was detectable in the majority of food-specific T cell clones from these latter patients. Moreover, no correlation between specific lymphocyte proliferation and specific IgE was found [47]. This indicates that IgE independent mechanisms may be involved in the eczematous reaction to food in some patients, stressing the potential pathophysiological role of allergen-specific T lymphocytes in atopic eczema Pollen-Associated FoodAllergy in Atopic Eczema Patients sensitized to pollen allergens often develop an IgE response to cross-reactive food allergens. Of adolescent or adult patients with birch pollen reactive pollinosis, 50% 70% also show immediate symptoms upon ingestion of birch pollen-related foodstuff [15]. An abundance of food has been identified as birch pollen-related over the last few years, including a multitude of plant families such as rosaceae, solanaceae, and umbelliferae (Fig. 41.4). Among these apple, hazelnut, carrot, and celery most often induce allergic symptoms such as the oral allergy syndrome, urticaria, angioedema, rhinoconjunctivitis, asthma, or even anaphylactic shock [25, 26]. Most patients avoid these foods when they become aware of their allergenic character. The major allergen of birch pollen, Bet v1, is mainly involved in the development of cross-reactive IgE antibodies to apple, celery, and hazelnut [5, 14, 19]. Furthermore, the highly conserved protein profilin Bet v2

5 References 403 Betulacea Alder Hazel Hazelnut Solanacea Tomato Potatoe Paprika Birch Umbellifera Celery Carrot Rosacea Apple Peach Cherry Fig Cross-reactive plant families to birch pollen allergens [41], a 60-kD plant panallergen [18] and the isoflavone reductase-related protein Bet v5 [21, 41] have been identified as cross-reactive minor birch pollen allergens. Relatively high levels of specific IgE to birch pollenandbetv1/betv2areoftendetectedintheseraof patients suffering from AE in Northern England, whereas lower levels of food-specific IgE are found in most patients at the same time. While cow s milk, hen s egg, wheat, and soy are frequent food allergens in children with AE, pollen-related foods are of greater importance in adults. No established model exists for oral challenge with birch pollen-related food, and various studies using different methods are published [3, 28, 39]. In a pilot study, we were able to show that birch pollen-related food may lead to an exacerbation of eczema in a subpopulation of adult patients with AE [28]: 37 patients with a sensitization to birch pollen who had no history of immediate reactions to birch pollen-related foods were investigated. These patients were challenged with birch pollen-related food in a doubleblind, placebo-controlled setting after a 4-week elimination diet. Nearly half of the patients showed late eczematous reactions following oral provocation after 24 h, and most of them had not been aware that this kind of food played a role in their skin disease. Interestingly, a birch pollen-specific T cell response was detected in lesional skin of the responding patients. Thepresenceofserum-IgEantibodiestoinhalant allergens increases with age. A sensitization to inhalant allergens commonly develops at about 3 4 years of age [38], and some children become sensitized to pollen as earlyasinthefirstmonthsoflife[40].childrenwith respiratory allergy sensitized to birch pollen allergens often suffer from immediate symptoms to pollen-related food [13]. In a recent study, we showed that birch pollen-related foodmightinduceallergicsymptomsinasubgroupof childrenwithaesensitizedtobirchpollen,eveninthe absence of a history suggestive of food allergy (Breuer et al. 2004b). Four of 12 (33%) patients with moderate to severe AE aged 3 9 years who were sensitized to birch pollen reacted with late eczematous reactions upon oral challenge with birch pollen-related food. Moreover, in another three children, worsening of AE might have been suppressed by systemic corticosteroids, which had to be administered due to immediate symptoms. These data show for the first time that children with AE who are sensitized to birch pollen may also develop late eczematous responses upon ingestion of birch pollen-relatedfood.bothinadultsandinchildren,the deterioration of dermatitis presented as a flare-up of preexisting lesions 24 h after ingestion of food. Patients who experienced a worsening of dermatitis upon oral challenge did not differ significantly from the other patients in terms of total IgE, birch pollen-specific IgE, history of respiratory allergy, age, or severity of AE. However, in order to select patients who may react with a deterioration of dermatitis to birch pollen-related food, a history of seasonal respiratory atopy and immediate reactions to this kind of food and furthermore the determination of birch pollen-specific IgE might be helpful. References 1. Atherton DJ, Sewell M, Soothill JF, Wells RS 1978) A doubleblind controlled crossover trial of an antigen-avoidance diet in atopic eczema. Lancet 1: Atherton DJ (1988) Role of diet in treating atopic eczema: elimination diets can be beneficial. BMJ 297: Ballmer-Weber BK, Hoffmann A, Wüthrich B, Lüttkopf D, Pompei C, Wangorsch A et al (2002) Influence of food processing on the allergenicity of celery: DBPCFC with celery spice and cooked celery in patients with celery allergy. Allergy 57: Bindslev-Jensen C, Ballmer-Weber BK, Bengtsson U, Blanco C, Ebner C, Hourihane J, Knulst AC, Moneret-Vautrin DA, Nekam K, Niggemann B, Osterballe M, Ortolani C, Ring J, Schnopp C, Werfel T (2004) Standardization of food challenges in patients with immediate reactions to foods position paper from the European Academy of Allergology and Clinical Immunology. Allergy 59:

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