Skin‐centered strategies in food allergy prevention

While the early introduction of food allergens in the infant diet has been shown to be effective at preventing the development of food allergy (FA), its implementation in real life has been associated with various challenges. Interventions aimed at correcting skin barrier dysfunction have been explored in recent decades as a distinct or complementary mean to prevent allergic sensitization through the skin and subsequent development of FA. Studies assessing the application of emollient from birth have yielded conflicting results, and meta‐analyses have demonstrated either no effect or only a slight positive effect on FA prevention. However, a careful review of the clinical trials reveals that different emollients were used, which may have explained some of the discrepancies between study results. Emollient application protocols also varied widely between studies. While firm conclusions cannot be drawn with regard to their overall efficacy at preventing FA, the available data provide valuable insight into the characteristics that could be associated with a more effective intervention. Namely, successful trials tended to use emollients with an acidic pH of 5.5, applied over the entire body, and combined with topical corticosteroids in affected areas. Consensus on the optimal strategy to restore skin barrier function could help improve the homogeneity and clinical relevance of future trials on this topic. In the meantime, clinicians should avoid products associated with worse outcomes.

sensitization through the skin while waiting for the development of oral tolerance.The dysfunctional epithelial barrier is easily accessible, making an obvious target for interventions aimed at modulating its interaction with the environment.In the last decade, several studies have explored the hypothesis that interventions aimed at restoring skin barrier function early in life could prevent FA.
In the present review, we question the role of the skin in the prevention and treatment of FAs and the place of such strategies in pediatrics.

| WHATARETHELIMITATI ON SOF CURRENTS TR ATEG IE SFORPRE VENTING FOODALLERG IE S?
After over a decade of recommendations for the delayed introduction of food allergens, randomized controlled trials (RCTs) demonstrated that early introduction before 12 months of age was in fact effective at preventing FA.Several authors then proposed the concept of a window of opportunity for allergen introduction, a short period early in life during which food allergens should be introduced to promote tolerance instead of allergy.Recent systematic reviews including the above-mentioned studies concluded that early food introduction (4-12 months) is safe and may prevent food allergies, 5,6 whereas a recent study has determined that within the window of opportunity, the introduction of peanut at 4-6 months was more efficient to prevent peanut allergy than introduction at 12 months. 7wever, the heterogeneity of included studies limited the statistical power, since most RCTs have been performed with peanut and egg.
If the early introduction of cow's milk, that is, as a complement to breastfeeding, could prevent cow's milk allergy, is also debated, 8,9 suggesting that the window of opportunity may vary depending on the allergen.
Nevertheless, recognizing the lack of biological plausibility for a distinction between foods and how unrealistic it would be to conduct a distinct individual trial for each potential allergenic food, like hazelnut, tree nut, and soy, national and international societies have progressively adapted their guidelines by recommending not delaying the introduction of any allergenic foods, and conversely promoting their early introduction from 4 to 6 months, especially for children at risk of FA.

| Earlyfoodintroductionisonlyefficientto preventallergytothisspecificfood
Clinical trials show that early introduction of food allergens only works for the specific foods that were introduced.In the Learning Early About Peanut Allergy (LEAP) study, patients who were early introduced peanut showed a reduced prevalence peanut allergy at 60 months compared with patients who avoided peanut (4.8% vs.
18.6%, respectively, p < .001) 10 but similar rates of IgE sensitization to other foods than peanut. 11In other words, early introduction of peanut may prevent only peanut allergy, but will not prevent the development of almond or hazelnut allergy.One consequence is the theoretical need to introduce all possible food allergens as early as possible in infants, which is not physically feasible.Even focusing only on the main allergens can lead to large amounts of different foods and be an additional source of stress for parents, who are already dealing with the transition from breastfeeding to solid food. 12rticipants from the Enquiring About Tolerance (EAT) study, a RCT that evaluated the impact of early introduction of six allergens on FA, reported the difficulties they experienced with the study diet. 13Three main issues emerged, illustrating the practical difficulties met in the early introduction of solid foods: (1) infant refusal, (2)   concerns about allergic reaction, and (3) practical problems (related to lifestyle and food preparations). 13These difficulties are reflected in the poor adherence to the study protocol in the early-introduction group, compared with the standard-introduction group (42.8% vs. 92.9% of the participants, respectively). 14As a consequence, in the intention-to-treat analysis, there was no difference in the frequency of FA to one or more of the six intervention foods between the standard-introduction group and the early-introduction group (p = .32). 14 Conversely, in the per-protocol analysis, the prevalence of any FA was significantly lower in the early-introduction group than in the standard-introduction group (2.4% vs. 7.3%, p = .01). 14

| Earlyoralintroductionoffoodallergensisnot enough,regularintakeisalsorequired
Recent guidelines for the early introduction of solid foods had an impact on parental behavior, but recent data question their effectiveness in real life.As an illustration, a study showed that the incidence of peanut allergy in Australia was similar before and after the modification of guidelines regarding the time of peanut introduction in children (3.1% to 2.6%, respectively; difference: −0.5% [95% CI: −1.4% to 0.4%]; p = .26). 15 This suggests that the age of introduction of food allergens may not be the only relevant factor affecting the effectiveness of the intervention.The same team showed that the frequency of peanut consumption greatly varied between children, from once to more than four times a week. 16is suggests that a regular intake is needed once a food allergen is introduced to maintain an immune tolerance.This concept has also been described in patients who spontaneously outgrew food allergies 17 or after food immunotherapy, where regular consumption

Keymessage
It is reasonable to consider using emollients and treating atopic dermatitis as strategies to prevent food allergy, although evidence is currently lacking due to concerns about study methodologies.appeared needed to maintain the tolerance state. 18[21] Despite the lack of RCT-based evidence, this concept is largely supported by clinical experience and the Canadian Society of Allergy and Clinical Immunology (CSACI) published a statement highlighting the importance of a regular ingestion of food allergens to prevent FAs. 22That being said, the minimal frequency of consumption to maintain oral tolerance, as well as the time window during which this exposition must be maintained, is unknown.Furthermore, if regular consumption appears feasible for certain foods such as cow's milk, others could be more problematic in young children, including nuts or shellfish.

| Evidencethatskinisarouteofsensitization tofoodallergens
At the time of solid food introduction, a significant part of children is already sensitized to food allergens.That has been illustrated in clinical trials exploring the role of early introduction of food allergen in preventing FA, in which participants were tested by skin prick tests (SPT) and/or food-specific IgE (sIgE).For instance, among the 834 patients aged 3-11 months screened to participate in the LEAP study, 76 (9.1%) had a SPT to peanut ≥4 mm without ever having consumed orally peanuts. 23Of the 163 atopic children aged 3-4 months and exclusively breastfed who were included in a study from Nishimura et al., 56.3% in the "food introduction" group and 61.4% in the "avoidance group" were sensitized to at least one food allergen, defined by sIgE > 0.1 kU/L. 24Other studies reported similar findings, 14,25 including in non-atopic cohort. 14ese data challenge the concept of a window of opportunity for the oral introduction of food allergen, or at least highlight the limit of the concept and the need for complementary strategies in preventing FAs.
The hypothesis of skin as a possible route of sensitization to food allergens has emerged many years ago.That was strongly supported by the fact that atopic dermatitis (AD), a chronic inflammatory skin disease, is a major risk factor for FA and is a major determinant of atopic trajectories. 26As an illustration, a recent meta-analysis found that 49.8% (95% CI: 44.4-55.1) of children with AD had an IgE sensitization to at least one food allergen and that 31.4% (26.9-36.1)an IgE-mediated FA, 27 while a systematic review determined that having AD is a strong predictor of food sensitization at 3 months (odds ratio [OR]: 6.18, 95% CI: 2.94-12.98). 28 ex vivo experiment also demonstrated that the stimulation of circulating memory T cells isolated from peanut-allergic children with peanut extract induced the predominant proliferation of peanut-specific CD4 + T cells expressing the skin-homing marker CLA (cutaneous lymphocyte antigen), whereas similar stimulation of memory T cells from non-allergic controls induced the predominant proliferation of memory T cells expressing the intestine-homing marker α4β7 integrin. 29Another study demonstrated that peanutsensitized children had a greater percentage of CLA-expressing effector T cells than non-sensitized children. 30These results suggest that in sensitized children, the initial immune response to peanut occurred in the skin whereas in tolerant children, it occurred in the gastrointestinal tract.That supports the dual allergen exposure hypothesis, according to which oral exposure to food promotes immune tolerance, whereas exposure through other epithelium such as skin promotes allergies.
Sensitization through the skin requires the presence of food allergens in the environment.3][34] The risk of sensitization is also correlated with the concentration of peanut protein found in the home environment. 35In consequence, even in the absence of consumption by children, food allergens are found in bedding and play areas. 34Skincare products are other possible sources of food allergens, especially those labeled "natural" or "ecological" that may contain food-derived proteins. 36The use of such skincare products has been shown to be associated with an increased risk of FA, [37][38][39] and children with AD should avoid such type of products.

| Theskinbarrierdysfunctionpromotes sensitizationtofoodallergens
One important role of the skin is to serve as a barrier to limit the penetration of environmental allergen into the organism. 40The barrier function of the skin involves chemical, physical, mechanical, immune, and microbial aspects that can be disturbed in diseases, such as in AD. 40 Neonates and infants have a more permeable skin barrier than adults. 41Transepidermal water loss (TEWL), an indirect measure of skin barrier function, has been shown to improve progressively in the first years of life, reaching adult values by 5 years of age. 41An increased TEWL at birth or during infancy, suggestive of skin barrier dysfunction, has been shown to be predictive of AD onset. 42,43wborns also have a higher skin pH than adults (>6.6 vs. <5, respectively). 44Acidic skin pH, which is an important determinant of a competent skin barrier function by maintaining the commensal microbiota, regulating epidermal differentiation and lipidic barrier stabilization and other mechanisms, is obtained after several weeks. 45e epidermis of both children and adults with AD has a higher pH compared with healthy individuals. 46ese observations support a place for an early emollient-based intervention to optimize the skin barrier function in newborns.The use of emollients was historically aimed at preventing the occurrence of AD flare-ups.Recently, it has been proposed that application of emollients on newborn skin rapidly after birth could help to prevent not only AD but also the atopic comorbidities.[49]

| EmollientsmaypreventADoccurrence
Recent RCTs have evaluated the impact of early application of emollient to prevent the occurrence of AD. 50These studies had heterogeneous methods, with several assessing the cumulative incidence of AD while on emollient treatment (meaning that participants were preventively treated for AD, without a wash-out period) 51 and others the point prevalence of AD several months after emollient treatment (reflecting a real preventive effect of emollient application). 52Despite this limitation, there was a trend toward a preventive effect of emollient application from the first weeks of life on AD, and considering AD as an important risk factor of FA, 53 one can assume that preventing AD may subsequently prevent FA.

| WHATDOCLINI C ALTRIAL SSAYON EMOLLIENTEFFEC TIVENE SSTOPRE VENT FOODS EN S ITIZ ATI ON?
RCTs testing the efficacy of skin emollients at preventing food sensitization and/or allergy during infancy are listed in Table 1.Except for the PreventADALL study, 54 efficacy of emollient application on food sensitization and/or allergy was only a secondary outcome in these RCTs.A common concern in many of these RCTs is that completely forbidding the use of skincare in the control groups is impossible for ethical reasons, since it is part of standard care for AD.In fact, one publication reports the ethics committee's request to prescribe a standard emollient (Vaseline) in the control group, 55 and another one reports that a gentle soap used for atopic skin was provided to both intervention and control groups. 52Conversely, observance may have varied in the intervention group, as regular emollient use is challenging even for motivated parents with proper support.Moreover, recommendations concerning the introduction of food allergens during the studies were not systematically clarified in the protocols and the definition of food sensitization and/or allergy varied between the studies.Taken together, these limitations could have contributed to decreased power to detect significant preventive effect of emollient on food sensitization/allergy in some studies.
Different pair-wise meta-analyses took into account all these studies and finally did not find that emollient application prevents either sensitization to food allergen or FA. 50,56,57The heterogeneity of the studies that have been included in these meta-analyses (I 2 = 41%, 57 40%, 56 and 66% 50 ) forces to consider them with precaution.

| Thenatureofemollientiscrucial
A retrospective study from Perkin et al. 58 reported results from a survey completed by participants of the EAT study and questioning their habits on emollient use during the first 3 months of their babies' life.Based on this questionnaire, this study suggested that the risk of FA increased dramatically with the frequency of emollient use. 58 this study cohort of 3-month infants, the use of emollient during the first months of life was associated with the development of FA, in infants without eczema with an adjusted OR of 1.18 (95% CI: 1.07-1.30)for developing FA, and in infants with eczema with an adjusted OR of 1.20 (95% CI: 1.11-1.31). 58However, emollients used by participants were various and not comparable.Many of them were also known to increase the penetration of exogenous chemical into the skin, such as olive oil and other plant oils, 59 which were the products the most frequently used as emollients in the study. 58reover, several skincare products, whose some of which are considered as emollients, are also known to induce or aggravate skin barrier defects.In mouse models with normal skin, commercial products claimed to benefit from "dry and damaged skin" or "hypersensitive skin" increased TEWL and skin pH, and decreased the skin hydration after 4 days of twice-daily applications. 60A clinical study performed in volunteers with a previous history of AD demonstrated that an emollient commonly used (including in the Perkin et al. study 58 ), the Aqueous cream BP, induced significant damage to the skin barrier as demonstrated by the TEWL increase and a concomitant alteration in the stratum corneum integrity. 61That could be explained by the fact that the Aqueous cream BP contains a surfactant, the sodium lauryl sulfate (SLS), to create an oil-in-water emulsion that is known to enhance the skin penetration of exogenous chemical and to be an irritant. 62,63assuringly, some emollients obviously improve barrier functions, but the ability to reduce TEWL can vary between products even when following comparable application protocols. 64,65The emollient that has been shown to have the best effect on the skin barrier is a ceramide-based emollient 66 that had been shown to reduce TEWL more drastically than other emollients 64 and, consistently, was shown to have an important preventive effect on FA occurrence. 67

| Emollientsshouldbeappliedatleastoncea day,ontheentirebody,topreventfoodallergies
Barrier defect affects the entire skin in atopic babies and children, including both lesional and nonlesional skin, as demonstrated in patients with AD. 68,69 This is why it is usually recommended to apply emollient on the entire body to prevent AD flare-ups and not only on TA B L E 1 Randomized clinical trials that assessed the efficiency of skin-centered strategies to prevent sensitization to food allergens.

Effectofskininterventiononfood IgEsensitization
Intervention: emollient application using an appropriate protocol (ceramide-based emollient, at least twice daily, on the whole body) (Continues) specific sites.Moreover, studies exploring the effect of emollients on the skin barrier usually required at least one application per day 65,70 and a recent study even showed that an emollient applied twice daily may have a stronger impact on AD prevention than applied once a day. 71However, some protocols deviate from these practices without any evaluation of their equivalence in terms of skin barrier repair.For instance, the protocol used in the PreventADALL study was bathing infants for a maximum of 10 min with the addition of emulsified oil (paraffinum liquidum and trilaureth-4-phosphate) and application of an emollient only on the entire face, at least 4 days per week. 54In addition, it was previously described that emulsification of lipids with water reduces their moisturizing effect. 70In the study from Dissanayake et al., the protocol consisted in the application of an emollient "particularly on the cheeks and the peri-oral area," not on the entire body (this was allowed, but not recommended). 72In contrast, in the Lowe et al. study as well as in the STOP-AD trial, the ceramide-based emollients were applied twice a day, all over the children's body. 52,67e discrepancies between the interventions used in the various trials (Table 1) may offer plausible explanations for the different

TA B L E 1 (Continued)
conclusions.Future trials should ensure the use of emollient-based strategies with demonstrated ability to restore and maintain the barrier function and avoid recourse to skincare products that aggravate skin damage.This may include emollient reducing the skin pH 46 and delivering ceramide, free fatty acids, and cholesterol. 73fortunately, few emollients currently offer these features and those that do are generally expensive, which is a major limitation in the context of prevention.

| APPROPRIATELYTRE ATINGATOPI C DERMATITISTOPRE VENTFOODALLERGY
In addition to the skin barrier defect, atopic skin is a site of a type-2 inflammation, even in the absence of visible lesions.1). 75The study protocol was considered not feasible in real-life practice, because of the adverse effects of the enhanced treatment. 75However, it proves the concept that more aggressive treatment of AD skin inflammation is effective at preventing allergic sensitization.It also confirmed the importance of the cutaneous microenvironment in the process of sensitization to food allergens, since the topical corticoids have only a localized action. 76A novel generation of emollients, called "emollient plus," may have some anti-inflammatory properties 77 that could improve their preventive effects on FAs, without the risk of disproportionate systemic exposure to corticosteroids.
At a larger scale than skin alone, in patients with moderate-tosevere AD, the use of biologic therapy such as dupilumab, which is now indicated from 6 months of age, could potentially contribute to reducing allergic sensitization.A meta-analysis of previous RCTs found that patients reported less allergic events while on treatment, 78 but there are no data on whether this translates to a real change in disease-modifying effect or simply a suppression of allergic symptoms while on therapy.This will need to be tested prospectively in properly designed RCTs.

| CON CLUS ION
Many evidences support the concept of skin sensitization to foods, and skin-centered strategies may play a key role in FA prevention, in association with the early oral introduction of allergens.However, there is currently too much heterogeneity in the emollients and protocols used in the literature to draw firm conclusions.Further studies including rigorous skin barrier analyses to validate the emollient-based protocol should be carried out to better determine the weight of such strategies.Actually, it appears that the best emollients would be those that at least maintain an acidic pH, and if possible provide ceramides, free fatty acids, and cholesterol, but these products are generally expensive.In any case, one can suggest avoiding any skincare products that may promote skin barrier

CO N FLI C TO FI NTE R E S TS TATE M E NT
None.

PE E RR E V I E W
The peer review history for this article is available at https:// www.webof scien ce.com/ api/ gatew ay/ wos/ peer-review/ 10. 1111/ pai.

R E FE R E N C E S
defects and increase the sensitization to food allergens.AUTH O RCO NTR I B UTI O N S Camille Braun: Conceptualization; writing -review and editing; writing -original draft; validation.Laurianne Coutier: Writingreview and editing.Philippe Bégin: Writing -review and editing; supervision; validation.Audrey Nosbaum: Writing -review and editing; supervision; validation.FU N D I N GI N FO R M ATI O N Camille Braun was supported by the French Society of Pediatrics, the French Society of Allergy, the Hospices Civils de Lyon, ANAFORCAL (Association de formation continue en allergologie) and the Réseau Mère-Enfant de la Francophonie.Philippe Bégin was supported by the Fonds de Recherche du Québec en Santé (281662).
69,74While there has been a longstanding hypothesis that proactive treatment of AD could help prevent the development of FA, this is challenging to test in a clinical trial since it would be unethical to purposefully not offer proper AD treatment in a control group.Recently, an RCT compared the incidence of egg allergy in children with AD after 15-21 weeks of a conventional (i.e., topical corticoids only on lesional skin) or an enhanced treatment (i.e., topical corticoids on the entire body except scalp, 2 days per week, twice a day).At 28 weeks of age, the rate of egg allergy, determined by an oral food challenge, was significantly lower in the group treated with the enhanced protocol than in the control group (31.4% vs. 41.9%respectively, p < .001;Table