REVIEW URRENT C OPINION

The association between atopic dermatitis and food allergy in adults Seshi Manam a, Teresa Tsakok b, Stephen Till c, and Carsten Flohr a

Purpose of review We conducted a systematic literature search for studies investigating the link between atopic dermatitis and food sensitization or clinically significant allergy (FA) in adults, to assess the strength of the association between the two diseases in both general and selected populations. Recent findings Around 10% of adults with FA have concomitant atopic dermatitis at the population level. Adult atopic dermatitis patients show much higher rates of sensitization to foods than healthy individuals, in particular to food proteins cross-reactive with airborne allergens, rather than the food allergens that typically predominate amongst children with atopic dermatitis. When food challenges have been performed, rather than relying on questionnaire information and specific IgE testing alone, they often do not confirm eczematous reactions. Only half of patients who have challenge-proven FA improve on a strict elimination diet. Summary Challenge-proven FA in adults with atopic dermatitis is uncommon. The incidence of new-onset FA in adult atopic dermatitis patients is currently unknown, as are the main routes of sensitization. There is increasing evidence from studies in infants that sensitization to food protein can occur across the skin barrier, in particular in the presence of eczematous skin inflammation. Carefully conducted large longitudinal studies amongst adults that take into account skin barrier function and genetics are required. Keywords adults, atopic dermatitis, atopic eczema, food allergy

INTRODUCTION Atopic dermatitis (synonym ‘atopic eczema’) is the commonest inflammatory skin disease and affects around 20% of children in industrialized countries [1 ]. It commonly starts before 2 years of age, and the majority of patients grow out of their disease by early teenage years [1 ]. Compared with our detailed knowledge of pediatric atopic dermatitis, far less is known about the burden of atopic dermatitis in adults and its comorbidities. Atopic dermatitis during adulthood may occur as new-onset disease or as a consequence of childhood atopic dermatitis persisting into adulthood, more often seen in patients with severe childhood atopic dermatitis and respiratory allergies [2]. Prevalence estimates for atopic dermatitis in adults mostly range between 1 and 3%, depending on the population studied [2,3 ,4,5]. As in children, clear associations with other atopic diseases have been described, including allergic rhinitis and asthma [2]. Whereas &

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IgE-mediated FA, for instance to egg, cow’s milk and peanut, is a well recognized association and flare factor in pediatric atopic dermatitis [6], the interplay between food sensitization, clinical FA and atopic dermatitis in adults remains poorly understood. This review focuses on studies investigating the association between adult atopic dermatitis and FA in general and selected populations. To inform this review, we conducted a systematic

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St John’s Institute of Dermatology, bGuy’s and St Thomas’ Hospital NHS Foundation Trust and King’s College and cDepartment of Adult Allergy, Guy’s and St Thomas’ Hospital NHS Foundation Trust and King’s College London, London, UK Correspondence to Dr Carsten Flohr, St John’s Institute of Dermatology, Guy’s and St Thomas’ Hospital NHS Foundation Trust, Westminster Bridge Road, London SE1 7EH, UK. Tel: +44 20 7188 7188 x51601; e-mail: [email protected] Curr Opin Allergy Clin Immunol 2014, 14:423–429 DOI:10.1097/ACI.0000000000000095

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KEY POINTS  Around 10% of adults with FA have concomitant atopic dermatitis at the population level.  Adult atopic dermatitis patients have a significantly higher risk of food sensitization than adults without atopic dermatitis, with different culprit foods to those classically seen in children.  As there are only cross-sectional studies to date, longitudinal studies are needed to further elucidate the nature of the association between food allergy and atopic dermatitis in adults, and to shed light on the relative importance of transcutaneous and gastrointestinal routes of sensitization.

search of the literature, using Medline from inception until May 2014.

CLINICAL REACTION PATTERNS TO FOODS IN PATIENTS WITH ATOPIC DERMATITIS Patients with established atopic dermatitis who are sensitized to a food protein can show three distinct reaction patterns: noneczematous reactions, isolated atopic dermatitis flares or a combination of both [6,7]. Noneczematous reactions typically include urticaria, gastrointestinal and respiratory symptoms; if severe, this can evolve into anaphylaxis. They are usually seen within minutes or at least a couple of hours postexposure. Atopic dermatitis flares can also occur within this time window, either in combination with noneczematous symptoms, or as a standalone phenomenon with more delayed onset up to 48 h postexposure. The latter form the focus of this review.

IMMUNOLOGICAL LINKS BETWEEN FOOD ALLERGY AND ATOPIC DERMATITIS Previously, the above reaction patterns were classified by timing of exposure to food allergens into early, late and combined. Immune-mediated exacerbation of atopic dermatitis caused by food ingestion may involve IgE-mediated mast cell activation (type 1 hypersensitivity), particularly when symptoms occur within minutes or a few hours of exposure. More delayed or eczematous reactions are believed to be cell-mediated, occurring as a result of mediators produced by CD4þ Th2 cells activated by food antigens presented by dendritic cells [7]. Such mechanisms may coexist, but when delayed hypersensitivity to food occurs without early IgE-mediated symptoms, the identity of the provoking food may 424

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not be clear. In this scenario, time-consuming double-blind placebo-controlled food challenges (DBPCFC) are required to elicit whether food sensitization is clinically relevant. In adults, chronic atopic dermatitis may occasionally be associated with ongoing consumption of food allergens, particularly when sensitization is presumed to have occurred in early life, for instance to milk, egg or wheat. Allergen-specific T-cell responses have been demonstrated in such patients [6]. For example, patients aged over 16 years who experienced atopic dermatitis exacerbations due to cow’s milk were found to generate casein-specific CD4þ T cells [8]. Although early IgE-mediated symptoms are often not apparent in such patients, IgEspecific responses to individual foods may still be detectable on skin prick or in-vitro testing. Food allergies that develop later in life, such as to tree nuts, seeds, fish, crustacea, fruit and vegetables, are more typically associated with clear-cut IgE-mediated reactions. Since ensuing cell-mediated inflammation may cause an atopic dermatitis flare, these foods tend to be avoided by susceptible individuals. Birch pollen allergy may present a different clinical scenario, as cross-reactive T cells have been linked with delayed eczematous reactions in the absence of immediate reactivity [4,9,10]. An important route of food sensitization in early life is via antigen-presenting cells in the epidermis [11 ]. There is evidence from murine models that early life epicutaneous exposure to peanut or cow’s milk protein induces food-specific Th2 responses and clinical allergy. More importantly, this may prevent oral tolerance induction and amplify the Th2 response [12,13], even when the skin barrier has not been artificially disrupted. In humans, the use of topical preparations containing oat [14] and peanut [15] has also been associated with the development of sensitization in atopic dermatitis patients. Skin barrier dysfunction and severe atopic dermatitis of early onset are important risk factors for food sensitization in exclusively breastfed infants [11 ]. Furthermore, allergic reactions to egg and peanut often occur on first gut exposure, suggesting that initial food sensitization may have already occurred across the skin [11 ]. Conversely, the gut mucosal interface is likely to be important in the development of tolerance to food protein in early life. Murine models suggest that early gastrointestinal tract exposure commonly induces tolerance to food proteins and makes subsequent transcutaneous sensitization less likely [13]. Several randomized controlled trials in infants are currently underway to test whether the introduction of allergenic foods in &

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Atopic dermatitis and fo od allergy in adults Manam et al.

early life alongside breastfeeding is able to reduce FA risk. If this is correct, exclusively breastfed infants with early-onset atopic dermatitis are at the highest risk of food sensitization through the skin [16]. It is currently unknown whether de-novo food sensitization in adults occurs primarily through the gut or skin interface and whether eczematous skin inflammation is an important mediator in this process.

POPULATION-BASED STUDIES ON THE ASSOCIATION BETWEEN FOOD ALLERGY AND ATOPIC DERMATITIS Four studies recruited participants from the general population, two from Germany [4,5], one from Finland [17] and one from Australia [18] (Table 1) [4,5,9,10,17–21]. Worm et al.’s [4] cross-sectional survey of 1739 German adults aged 18–65 years stands out because of its careful design. Questionnaires were used to screen for atopic dermatitis symptoms, then detailed telephone interviews were conducted and consequently 146 participants with likely atopic dermatitis were invited for further assessment, including skin examination. Twenty-eight participants were diagnosed with current atopic dermatitis. Amongst these, only 7.4% were sensitized to the classical food allergens (egg, cow’s milk and wheat). Hazelnut and carrot were the commonest food sensitizations detected (37.0%), followed by sesame (25.9%). However, only one out of nine patients who underwent DBPCFC experienced worsening of their atopic dermatitis during the challenge. Some of these findings were echoed in the study from Finland, conducted in 286 1st year university students. This suggested that sensitization to the foods known to play a major role during childhood is less important in adults with atopic dermatitis. Kiwi sensitization was commonest (17.1%), followed by peanut (14.6%). Foodrelated atopic dermatitis flares were frequently reported by patients (16.6% with current atopic dermatitis vs. 13.6% with past history of atopic dermatitis), but it is important to note that this study did not perform food challenges. Scha¨fer et al. [5] assessed the frequency of atopic dermatitis amongst patients with FA (defined as a history of immediate hypersensitivity symptoms and skin sensitization) in 1537 German adults aged 25–74 years. 10.1% of participants with FA had atopic dermatitis compared with 1.8% in healthy controls (odds ratio 5.19, 95% confidence interval 2.21–12.19) [5]. Woods et al.’s [18] cross-sectional survey of 1141 Australians aged 20–45 years also used questionnaires and skin prick testing as assessment tools, suggesting that 1.1% of all participants who

reported adverse reactions to foods had a history of atopic dermatitis, similar to the atopic dermatitis frequency reported in the general population in other settings. Only 1.3% of all individuals had a history suggesting FA and skin sensitization to the same allergen. The commonest positive skin prick testing sensitization was to peanut (3.8%), and this was significantly associated with a history of atopic dermatitis (P ¼ 0.02). However, these figures are low and need to be treated with caution, because of the lack of stringent diagnostic criteria used for either FA and atopic dermatitis.

STUDIES IN SELECTED POPULATIONS ON THE ASSOCIATION BETWEEN FOOD ALLERGY AND ATOPIC DERMATITIS A number of studies have examined the association between food sensitization and atopic dermatitis in selected populations. For instance, Celakovska et al. [19–21] reported on wheat, egg and cow’s milk allergy in 179 well phenotyped Czech patients with atopic dermatitis who were aged 14–63 years and recruited from a hospital’s dermatology outpatient department. All patients underwent skin prick and serum-specific IgE testing, as well as open food challenges. In addition, DBPCFCs were performed to confirm FA to wheat and cow’s milk where open challenges were positive. All patients were followed up for a year, recording improvements in atopic dermatitis with and without elimination diets. Overall, DBPCFC-proven food allergy was rare (wheat 4.5%, egg 6.1% and cow’s milk 0.6%), whereas 11.2% showed allergic sensitization to wheat, 28% to egg and 9.5% to cow’s milk. Elimination diets only improved symptoms in around 50% of challenge-positive cases. A less rigorously conducted study was performed in Japan by Uenishi et al. [22] on 195 dermatology outpatients with atopic dermatitis aged 16–53 years. 44.1% (86/195) had a positive unstandardized open challenge to foods containing cow’s milk (chocolate, cheese and yoghurt) as well as to coffee and soya. Although the authors state that 89.5% of patients improved during an exclusion diet, 84% were not sensitized to the food in question. These results should be treated with caution in view of the uncontrolled and unblinded nature of the food challenges. Finally, Werfel et al. [8] looked at a group of 88 German atopic dermatitis outpatients aged 16–66 years who reported that their disease was exacerbated by cow’s milk exposure. The investigators showed that those who experienced worsening of atopic dermatitis during DBPCFC with cow’s milk had a higher incidence of casein-specific T-cell

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Study type Country

Cross-sectional Nested case– control study Germany

Cross-sectional Australia

Cross-sectional Nested case– control study Finland

Cross-sectional Germany

Scha ¨ fer 2001 [5]

Woods 2002 [18]

Mattila 2003 [17]

Worm 2006 [4]

Population-based studies

First author Year

www.co-allergy.com 1739 18–65 years

286 students: current atopic dermatitis þ/– current hay fever or asthma, past atopic dermatitis þ/– current hay fever or asthma, hay fever or asthma, healthy controls (identified from 14 202) 18–26 years

1141 20–45 years

1537 25–74 years

Number of participants Age

SPT ( 3 mm) sIgE (cut-off unspecified) DBPCFC

Questionnaire SPT ( 3 mm) sIgE (0.7 kU/l)

Questionnaire Skin examination (Hanifin and Rajka)

Questionnaire Telephone interview (Hanifin and Rajka) Skin examination (Hanifin and Rajka, SCORAD)

SPT (3 mm) Questionnaire (symptoms)

SPT ( 2 mm ) sIgE (unspecified cut-off) Questionnaire (symptoms)

Measures of food sensitization and/or food allergy

Questionnaire

Questionnaire (physician diagnosis)

Atopic dermatitis diagnostic criteria

Table 1. Summary of studies on the association between food allergy and atopic dermatitis in adults

146/1739 (8.4%) had atopic dermatitis based on telephone interview, but current atopic dermatitis confirmed on skin examination in only 28 (1.6%). 27 further evaluated for food sensitization: Potato 10/27 (37.0%) – SPT Hazelnut, carrot both 8/27 (37.0%) – SPT Sesame 7/27 (25.9%) – SPT Apple, celery both 6/27 (22.2%) – SPT Oatmeal, barley flour both 4/27 (14.8%) – SPT Hen’s egg, cow’s milk, wheat flour all 2/27 (7.4%) – SPT and sIgE DBPCFC in 9/27: 1/9 provocation tests showed a worsening of atopic dermatitis, 3/9 had oral symptoms and 5/9 were negative

Rate of food sensitization in patients with atopic dermatitis on examination vs. healthy controls: Kiwi 17.1% (adjusted OR¼17.4, 95% CI 2.0–147.7) – SPT Wheat 9.8% (adjusted OR¼10.8, 95% CI 1.1–104.3) – SPT Peanut 14.6% (adjusted OR¼8.5, 95% CI 1.6–45.4) – sIgE 16.6% with current atopic dermatitis reported adverse reaction to food vs. 13.6% with past history of atopic dermatitis 11.4% of atopic dermatitis patients reported food-induced flares

1.1% (2/187) of adults with reported adverse food reactions had a history of atopic dermatitis Significant association between ‘probably IgE-mediated peanut allergy’ and a history of atopic dermatitis ( p ¼ 0.02). However, no association with ’current eczema’

10.1% of adults with FA (history of FA and positive SPT to corresponding allergen) had atopic dermatitis vs. 1.8% in healthy controls, OR¼5.19 (95% CI 2.21–12.19)

Results

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Cross-sectional Czech Republic

Cross-sectional Czech Republic

Cross-sectional Germany

Cross-sectional Japan

Cross-sectional Germany

Celakovska 2011 [19]

Celakovska 2012 [21]

Reekers 1999 [10]

Uenishi 2003 [22]

Werfel et al. 1997 [9]

88 outpatients with atopic dermatitis and a history of cow’s milk-induced flares 16–66 years

195 outpatients with atopic dermatitis 16–53 years

37 outpatients sensitized to birch pollen but no history of hypersensitivity to birch pollen-related foods Birch pollen-sIgE >17.5 kU/l 17–64 years

179 outpatients with atopic dermatitis 14–63 years

179 outpatients with atopic dermatitis 14–63 years

179 outpatients with atopic dermatitis 14–63 years

Hanifin and Rajka SCORAD

Hanifin and Rajka

Hanifin and Rajka SCORAD

Hanifin and Rajka SCORAD

Hanifin and Rajka SCORAD

Hanifin and Rajka SCORAD

DBPCFC

RAST (grade 2) Open food challenge Exclusion diet

DBPCFC with a mixture of birch pollen-related foods Lymphocyte proliferation assays Skin punch biopsy in 14 patients

SPT ( 3 mm) sIgE (>0.35 kU/l) Open food challenges DBPCFC (those positive to open challenge)

SPT ( 3 mm) sIgE (>0.35 kU/l) Open food challenges

SPT ( 3 mm) sIgE (>0.35 kU/l) Open food challenges DBPCFC (those positive to open challenge)

All participants were put on 4-week milk exclusion diet, followed by a DBPCFC. ! Two groups: patients whose atopic dermatitis remained unchanged with regard to severity and those who experienced a significant flare (SCORAD 30 points from baseline). Non-atopic controls were also examined 66/88 (75%) of patients did not react during DBPCFC Individuals who experienced worsening of atopic dermatitis caused by oral provocation with milk showed a higher incidence of casein-specific T-cell reactions when compared with control subjects

86/195 (44.1%) had positive open food challenge: Chocolate 34/86 (39.5%) Cheese 21/86 (24.4%) Coffee 18/86 (20.9%) Yoghurt 15/86 (17.4%) Soya 11/86 (12.8%) RAST negative in 84% of patients with positive open challenges 77/86 (89.5%) patients followed up for 3 months improved on an exclusion diet

All 37 patients underwent elimination diet, avoiding all birch pollen related foods 17 patients experienced flare during on DBPCFC (rise in SCORAD 15 points from baseline) Higher sIgE levels in food challenge-positive patients The proliferative response of skin-derived T-cell lines from reactive patients to birch pollen extract was significantly higher than that of nonreactive patients

17/179 (9.5%) patients with positive sIgE to cow’s milk 5/179 (2.8%) SPT positive to cow’s milk 8/179 (4.5%) open challenge positive to cow’s milk, confirmed by DBPCFC in one case

11/179 (6.1%) patients had egg allergy on open food challenge. Of these, six had a clear improvement in atopic dermatitis severity on an egg elimination diet 28% of atopic dermatitis patients were sensitized to egg on SPT and IgE with no clinical symptoms

8/179 (4.5%) of atopic dermatitis patients had DBPCFC confirmed allergy to wheat Positive SPT to wheat in 20/179 (11.2%), confirmed by DBPCFC in 2/20 Positive sIgE testing to wheat in 8/179 (4.5%), confirmed by DBPCFC in 4/8

CI, confidence interval; DBPCFC, double-blind placebo-controlled food challenges; OR, odds ratio; RAST, radioallergosorbent test; SCORAD, Scoring of Atopic Dermatitis; sIgE, specific IgE; SPT, skin prick testing.

Cross-sectional Czech Republic

Celakovska 2011 [20]

Selected populations

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reactions when compared with control subjects. The same group also examined the role of birch pollen-related foods (carrot, celery, hazelnut and apple) in strongly birch pollen-sensitized adults aged 17–64 years (specific IgE>17.5 kU/l) without a history of FA [10]. All 37 were hospital outpatients and underwent an elimination diet to avoid all birch pollen-related foods, before being challenged with a mixture of carrot, celery, hazelnut and apple. Seventeen of 37 (45.9%) experienced an atopic dermatitis flare during DBPCFC, with a rise in Scoring of Atopic Dermatitis of at least 15 points from baseline. In addition, significantly higher specific IgE levels to the birch pollen-related foods were found in those who reacted upon challenge. Interestingly, the proliferative response of skinderived T-cell lines from reactive patients to birch pollen extract was significantly higher than that of nonreactive patients. This may provide a mechanistic explanation as to why foods that cross-react with birch pollen may be implicated in atopic dermatitis flares and chronicity.

DISCUSSION Overall, the body of literature on the association between FA and atopic dermatitis in adults is small. Population-based studies show a significantly higher risk of food sensitization in atopic dermatitis patients compared with healthy controls, and up to 10% of adults with FA have concomitant atopic dermatitis. However, food hypersensitivity reported by patients is often not confirmed by formal challenges. Unlike in children, common culprit foods such as carrot, celery and hazelnut, can cross-react with aeroallergens, whereas the food allergens classically implicated in childhood atopic dermatitis appear to be less important. Even in selected atopic dermatitis populations with moderate-to-severe disease, challenge-proven cow’s milk, egg and wheat allergy only affects around 5% of individuals. Interestingly, birch pollen-specific skin-homing T cells may be implicated in atopic dermatitis flares following exposure to birch pollen-related foods, whilst casein-specific T-cell immune responses have been found in the systemic circulation of atopic dermatitis sufferers who react to cow’s milk during DBPCFC. This offers insight on the molecular level as to how foods may cause non-IgE-mediated flares in atopic dermatitis. The current body of evidence is hampered by suboptimal study quality and a lack of methodological standardization, making it difficult to make direct comparisons between studies. For instance, all studies used different allergen panels, and most primarily relied on questionnaire-derived 428

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information and patient-reported food reactions, rather than performing skin examinations with validated diagnostic criteria for atopic dermatitis and gold standard DBPCFCs. Furthermore, participant numbers were small, in particular in the studies looking at selected populations. Most importantly, all studies to date were cross-sectional in nature and conducted in a limited number of countries. None measured filaggrin loss-of-function skin barrier gene mutation carriage.

CONCLUSION Although the rise in atopic dermatitis and FA amongst children over the past decades is well established and likely to result in an increased burden amongst adults, both diseases remain underresearched in adult populations. Further well conducted longitudinal studies utilizing skin examination for atopic dermatitis and specific IgE testing to food allergens as well as DBPCFC are needed, for instance to examine how food sensitization and allergy impact on atopic dermatitis chronicity and severity. In addition, it remains unclear whether adults who develop de-novo FA become sensitized through the transcutaneous route or the gut interface. That food proteins can induce sensitization through the skin has already been reported amongst adults using hydrolyzed wheat-containing cosmetics [23,24]. Now the question is whether such a mechanism may be involved and amplified in patients with skin barrier dysfunction, such as seen in atopic dermatitis. Finally, although it is an increasingly recognized phenomenon, the loss of previous food tolerance over time in adults is poorly understood, and there are a multitude of factors potentially at play, including food additives, broad-spectrum antibiotic exposure and related effects on the gut microbiome and indeed that of the skin [25,26]. It will be essential for future studies examining the link between FA and atopic dermatitis to look at both the skin and gut interface together. Let the cohort studies begin. Acknowledgements C.F. holds a National Institute for Health Research (NIHR) Clinician Scientist Award (NIHRCS/01/2008/ 009). The views expressed in this publication are those of the authors and not necessarily those of the United Kingdom National Health Service, the NIHR, or the United Kingdom Department of Health. Conflicts of interest S.T. has unrestricted research funding from ALK Abello. All other authors have no conflicts of interest. Volume 14  Number 5  October 2014

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REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest

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The association between atopic dermatitis and food allergy in adults.

We conducted a systematic literature search for studies investigating the link between atopic dermatitis and food sensitization or clinically signific...
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