There is a clear association between atopic dermatitis (AD) and food allergy (FA), yet substantial controversy remains over the role of food allergens as causative or aggravating stimuli.1 Many patients and families seeking a root cause for AD focus on dietary triggers. The prevalent belief among patients, parents, and providers that FA is a causative factor for AD symptoms can lead to confusion, unnecessary elimination diets, excessive specialist consultation and testing, and disregard for the cornerstones of AD treatment. Additionally, recent evidence suggests that the inflammatory state and disrupted skin barrier seen in AD may actually lead to FA, instead of the other way around. In this review, we aim to identify the different types of adverse food reactions and evaluate the relationship between FA and AD.
Types of Adverse Food Reactions
Adverse food reactions cover a wide range of immune-mediated and non-immune mediated conditions, leading to a diverse array of clinical symptoms depending on the mechanism and the affected target organ.2 While “food allergy” is a term frequently used by the public and media as well as in health care settings, the exact definition is very narrow and specific. Many patients, families, and alternative practitioners have co-opted this term, conflating a number of food-related phenomena.
The term “allergic sensitization” indicates the development of immunoglobulin-E (IgE) antibodies to allergens that are ingested, inhaled, or absorbed.3 Sensitization occurs when there is an exposure to an allergen and a subsequent immune response, consisting of antigen presenting cells, T-cells, B-cells, and mast cells/basophils, to that allergen. This process usually occurs early in childhood and is a necessary first step in the development of allergic diseases.3,4 The process of sensitization occurs in the gastrointestinal tract for class I food antigens (i.e., milk, egg, peanut).5 However, evidence from both animal and human studies suggests that epicutaneous sensitization of food antigens is also possible.6,7 Epicutaneous sensitization may offer a potential explanation of how the disrupted skin barrier seen in AD may lead to increased rates of FA. This concept will be discussed in detail later.
When a sensitized individual experiences an IgE-mediated reaction to food, such as urticaria, angioedema, or anaphylaxis, this indicates a true FA. True FAs are typically instantaneous reactions, which can be life-threatening and require immediate attention.4 Milk, eggs, wheat, peanuts, nuts, sesame, fish, fruits, and vegetables are common causes of IgE-mediated FA.4 On the other end of the food reaction spectrum, delayed-type reactions describe a T-cell mediated process that can be activated via IgE-dependent or IgE-independent pathways.4 These reactions are less severe and typically occurs 24-48 hours after allergen ingestion.4 Delayed-type reactions may represent food-induced AD in some cases. Irritant contact dermatitis describes a nonspecific response of the skin to direct chemical damage and does not involve antigen/allergen-specific T cells.8,9 Irritant contact dermatitis to foods can occur in those with food-related occupations, such as bakers, butchers, and cooks, who have repeated exposure to irritants.10 Since patients with AD have a disrupted epithelial barrier, they may have increased permeability to antigens and irritants.9
Other categories of immune-mediated adverse food reactions include Celiac disease and eosinophilic esophagitis (EoE). Celiac disease is an autoimmune condition that is triggered by gluten ingestion in genetically predisposed individuals.11 Dermatitis herpetiformis is a cutaneous manifestation of Celiac disease, which improves with dietary gluten avoidance. Although Celiac disease is immune-mediated, it is not categorized as a FA.2 EoE is a multifactorial inflammatory disorder characterized by a deficient mucosal barrier of the esophagus, more common in those with AD.12 EoE patients become sensitized to foods and experience symptom flares in response. Empirical elimination diets consisting of milk, wheat, soy, eggs, peanut/nuts, and fish/seafood restriction, can alleviate symptoms in EoE patients.12
Food intolerance is a broad term that describes non-immune mediated food reactions. This encompasses enzymatic, pharmacological, and undefined reactions. Enzymatic food intolerance is secondary to an enzymatic defect. The best example is lactase deficiency leading to lactose intolerance. Pharmacologic food intolerance can be due to food additives or vasoactive amines naturally found in foods, such as histamine, tyramine, phenylethylamine, and serotonin. Undefined food intolerances describe adverse reactions to food colorings, flavors, preservatives, and antioxidants.13,14 Additionally, adverse reactions to fermentable carbohydrates termed “FODMAPs” (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) in irritable bowel disease and non-Celiac disease adverse reactions to gluten, are sometimes categorized as food intolerances as well.14
A summary of adverse food reactions can be found in Table 1.
Testing Methods
Guidelines for diagnosing FA in patients with AD15,16 recommend that children with an immediate reaction to ingestion of a potential allergen, or those with persistent moderate to severe AD refractory to optimal skincare, should be considered for FA testing.17 Diagnosis is multifactorial, consisting of a thorough history, evidence of sensitization with a skin prick test (SPT) and/or specific IgE (sIgE) testing, and an elimination diet trial. An oral food challenge (OFC) may be required in some cases for confirmation.
The sIgE testing uses an immunoenzymatic assay (such as ImmunoCAP) to test for sIgE, a marker of sensitization, in the patient’s serum. Most people with IgE-mediated FAs have concurrent sensitization and corresponding detectable sIgE. However, sIgE alone is not sufficient to diagnose FA. Increasing concentrations of sIgE are associated with increased risks of allergy but cannot predict the severity of an allergic reaction to the tested allergen. Furthermore, AD patients tend to have elevated total and specific IgE levels that may be unrelated to foods, due to exposure to other environmental triggers and immune dysregulation.17 Component-resolved diagnostics (CRD) is a newer specialized form of IgE testing that increases specificity for clinically relevant IgE. CRD uses specific food antigens or epitopes, as opposed to the whole food extracts containing multiple proteins which are used in traditional sIgE testing.18 CRD currently has uncertain cutoff values and cost-effectiveness, although it is promising.
Simple, cost-effective SPTs have long been the optimal cutaneous allergy testing method to screen for food-specific IgE in the skin. Commercially available extracts of food-specific IgE antibodies are applied on the forearm with a subsequent small skin prick, then the wheal site is measured 10-15 minutes later for a reaction. Unfortunately, the preparation and evaluation of SPT lack standardization and vary between devices, which is important to consider in evaluation.
The sensitivity, specificity, and positive and negative predictive values for SPT vary by age, study design, testing techniques, cutoff values, and population prevalence of FA. These metrics also vary by individual foods for sIgE. Positive tests for both sIgE and SPT indicate food sensitization, not necessarily allergy, and must be interpreted in the context of patient history. In conjunction, they can be useful to detect sensitization and identify high-risk patients.19 SPT and sIgE results can be applied to determine potential foods to target in careful, focused elimination diets. If elimination of specific foods leads to significant AD improvement, this could indicate a possible food trigger, which can then be followed by an OFC for confirmation. As outlined previously, elimination diets carry significant risk. Consequently, these diets should be prescribed with caution, and consultation with nutritional experts is recommended to avoid adverse effects.
In any investigation of FA, the OFC—specifically a double-blind, placebo-controlled food challenge (DBPCFC)—is the diagnostic gold standard.19 Open or single-blinded challenges are often chosen as alternatives to lower time and costs. This outpatient, supervised procedure consists of giving increasing doses of the food allergen in question to the patient. Objective symptoms, such as urticaria, swelling, or wheezing, confirm an IgE-mediated allergy. However, this process, even when open or single-blinded, demands both time and resources, and is thus not always feasible or desired.
Many other FA tests are available. The aforementioned tests are limited to IgE-mediated allergy; delayed-type reactions present a greater testing challenge. One option for delayed-type reactions is the atopy patch test (APT), where food allergen protein extracts are topically applied and assessed after 48-72 hours for a Type IV hypersensitivity symptoms, such as erythema and infiltration. This test has limitations and lacks the consistency and standardization of SPT and sIgE but may be the best option for detecting delayed-type cutaneous sensitization.20
To further complicate matters, a plethora of unvalidated FA commercial tests abound, which are important to be aware of as they may target and appeal to patients. Tests such as IgG testing, kinesiology, and hair and gastric juice analysis have no proven benefit at this time.21
“Leaky” Skin
Studies increasingly support the idea that a maladaptive, inflamed skin barrier underlies the etiology of food sensitization and allergy.22 Skin exposure as a sensitizing pathway is even more likely in those with impaired cutaneous integrity, such as AD; loss-of-function mutations in skin barrier genes are associated with food sensitization or allergy.23,24 In the absence of cutaneous instability, epicutaneous sensitization leading to FA generally requires an inflammatory adjuvant.25
Many factors associated with FA relate to reduced skin barrier integrity, seemingly independent of AD, suggesting that epicutaneous and/or transcutaneous sensitization is the mechanism through which AD leads to FA.26 For example, increased neonatal transepidermal water loss (a non-invasive measure of skin barrier function) predicts later FA. This was noted even in infants without AD, bolstering the mechanism of epicutaneous sensitization and implicating barrier dysfunction as preceding AD and associated atopic conditions.27 Skin microbiome disruption, known to contribute to AD pathogenesis, also is implicated in FA by augmenting epicutaneous sensitization. While many AD patients are colonized with Staphylococcus aureus (S. aureus), FA is strongly correlated with S. aureus colonization independent of AD severity.28 Methicillin-resistant S. aureus is especially linked to higher rates of FA.29
As infants grow, their immune system encounters countless new potential antigens and must develop either tolerance or sensitization to each compound. The gut and skin are two major sites through which the immune system is exposed to environmental factors. The intriguing “dual-allergen exposure hypothesis” suggests that interaction of food allergen with these tissues triggers opposing immune responses: tolerance if ingested and exposed to the gut-associated lymphoid tissue (GALT) or sensitization if contact occurs cutaneously.30 For example, epicutaneous sensitization through chronic use of skin products containing wheat and peanut has been found to contribute to the development of corresponding clinical allergy.31
Loss of skin barrier integrity, with concurrent lack of oral tolerance development, progresses towards FA. Early cutaneous exposure may allow food allergens a pathway to avoid provoking GALT tolerance. Once it occurs, sensitization can later develop into a full-fledged allergy.32 Epicutaneous sensitization to foods in those with AD has been demonstrated in adults, as well,26 suggesting that the impaired skin barrier as a route for sensitization is not limited to infancy.
Preventing Food Allergies
In 2017, the National Institute of Allergy and Infectious Diseases published three new addendum guidelines for the prevention of peanut allergy in the US,33 based on the Learning Early about Peanut Allergy (LEAP) trial,34 the first randomized trial to study early allergen introduction as a preventive strategy. The study found that early introduction of peanuts significantly decreased the frequency of the development of peanut allergy among high-risk children, including infants with AD. These findings could potentially be extrapolated for other commonly allergenic foods.
For infants with severe AD, screening with peanut-specific IgE or SPT was recommended before dietary peanut introduction around four to six months of age, while those with mild to moderate AD did not need prior screening before introduction around six months of age.33 This represents a divergence from previous guidelines recommending the exclusion of allergenic foods from the diet in infants with a family history of atopy until three years of age.35,36
Moreover, elimination diets may be associated with an increased risk of developing completely new, IgE-mediated allergic reactions after reintroduction of a food.37 These reactions are generally cutaneous but can be anaphylactic.38 Therefore, not only can elimination diets for AD be ineffective and detract from mainstay therapies, they may actually prove to be dangerous and should thus be used thoughtfully.
Promoting dietary tolerance through early introduction of foods and avoidance of elimination diets promisingly tackles the gut side of the dual-allergen exposure hypothesis, while the skin facet can be targeted by preventing transcutaneous sensitization through reducing cutaneous allergen exposure and, presumably, by restoring and strengthening the skin barrier.39 Examples of this strategy include promoting emollient therapy in early infancy and reducing exposure to harmful substances, such as soaps or hard water.39
Conclusion
A strong connection exists between FA and AD, with cutaneous barrier impairment likely serving as a link and route of sensitization, yet much remains to be discovered about the exact mechanisms of this complex interplay. With more knowledge of biomarkers, risk factors, and pathophysiology, treatments and prevention strategies could ideally be devised with precise targets to change the course of these atopic conditions. Given the increasing prevalence of FA and the potential life-threatening complication of anaphylaxis, FA in those with AD warrants a strong research emphasis.
Options for testing, treatment, and prevention of FA should continue to be explored. Improving the consensus on guidelines for these three aspects will aid future and current parents, patients, and providers in better management of AD and FA. Clinicians should be aware of the consequences of inappropriate food avoidance and restriction when considering dietary changes.40 AD treatment is essential to improving skin barrier health, consequently lessening sensitization and FA impact. Treatment studies for AD should consider the potential of early moisturization and skin improvement as not only ameliorative for AD, but also as preventative or management tools for FA.
The authors received no funding for this article. Dr. Lio reports research grants/funding from Regeneron/Sanofi Genzyme, and Abbvie; is on the speaker’s bureau for Regeneron/Sanofi Genzyme, Lilly, and Pfizer; reports consulting/advisory boards for Dermavant, Regeneron/Sanofi Genzyme, Dermira, Pfizer, LEO Pharmaceuticals, Abbvie, Eli Lilly, Menlo Therapeutics, IntraDerm, Exeltis, Realm Therapeutics. The other authors report no conflicts of interest.
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