Role of allergy in atopic dermatitis (eczema)

INTRODUCTION — There is some controversy with regard to the role of allergy in atopic dermatitis (AD; eczema). Despite its name, AD itself is not a type I allergy, nor is it necessarily associated with allergic sensitization. However, overall, the data indicate that allergy plays a role in selected patients with AD.

The epidemiology, clinical manifestations, diagnosis, and treatment of AD, as well as the role of delayed-type hypersensitivity to chemicals in topical medications and skin care products in exacerbating AD, are discussed separately. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis" and "Treatment of atopic dermatitis (eczema)".)

ATOPIC ASSOCIATIONS

Rates of allergic disease in patients with AD — Patients with AD have higher rates of allergic diseases than the general population. Up to 80 percent of children with AD develop asthma and/or allergic rhinitis later in childhood [1]. This progression from AD in infancy to allergic rhinitis and asthma in childhood and young adulthood is referred to as the "allergic march" or "atopic march" [2-5]. (See "The relationship between IgE and allergic disease", section on 'The atopic march'.)

Rates of AD in patients with allergic disease — The converse is true as well. A higher rate of AD is seen in teenagers with asthma than those without asthma (risk ratio [RR] 4.5, 95% CI 3.1-6.5) [6]. Ten to 20 percent of patients with AD have food-induced urticaria/anaphylaxis [7,8] compared with 1 to 3 percent of the general population [9,10]. In infants with eczema, the prevalence of immunoglobulin E (IgE) mediated food allergy confirmed by double-blind, placebo-controlled food challenge (DBPCFC), except in patients with a history of anaphylaxis and positive specific IgE, ranges from 33 to 63 percent [7,11-15]. Earlier onset (less than three months of age) and more severe AD is associated with high hen's egg, cow's milk, and/or peanut-specific IgE [16]. Patients with AD and concomitant hen's egg, peanut, or dust mite allergy are more likely to have AD that persists beyond five years of age [17].

Association with elevated total IgE — AD is also associated with elevated serum IgE [18]. Inflammation of the skin in AD triggers release of interleukin (IL) 4, IL-13, and thymic stomal lymphopoietin (TSLP), which leads to T helper type 2 (Th2) inflammation, Ig class switching, and higher IgE levels. IgE levels are typically in the thousands but can be in the tens of thousands. The level can decrease as AD improves. IL-13 variants are associated with slightly higher total IgE levels and sensitization to food allergens, most commonly hen's egg, in young children with AD [19]. In adults, elevated total IgE is associated with persistent eczema with a wide distribution after 10 years of follow-up [20].

Risk factor for food allergies — AD is considered the major risk factor for development of food allergies. The current hypothesis is that cutaneous sensitization through disrupted skin barrier leads to food sensitization and food allergies. In particular, defects in serine peptidase inhibitor, Kazal type 5 (SPINK5) are associated with food challenge-proven food allergy [21,22]. In addition, skin barrier impairment at birth predicts food allergy at two years of age [23]. Thus, the concept of skin barrier for the prevention of food allergy is under study in multiple clinical trials.

ALLERGEN SENSITIZATION

Increased sensitization in AD — Numerous studies have demonstrated an increased rate of sensitization to both food and aeroallergens in patients with AD [24,25]. On average, 50 percent of children and 35 percent of adults with AD are sensitized to common allergens. However, these proportions vary widely (7 to 78 percent) [26,27]. Patients with AD commonly have elevated total IgE that can lead to nonspecific IgE binding on allergen-specific IgE assays, raising the risk of false-positive tests. One option to address this is to dilute the sample; this can be done in a research lab but is not a practical approach in routine clinical medicine.

Sensitization versus allergy — Evidence of allergen sensitization is not proof of clinically relevant allergy. Persons are considered to have clinically significant allergy or allergic disease when they have both allergen-specific IgE measured by blood or skin testing and symptoms upon exposure to substances containing that allergen. (See "The relationship between IgE and allergic disease", section on 'Sensitization' and "The relationship between IgE and allergic disease", section on 'Allergy'.)

Confirming clinical reactivity is especially important when food allergies are suspected in young children since avoidance of food allergens can put growing children at nutritional risk. (See "Management of food allergy: Nutritional issues" and 'Food allergies' below.)

Sensitization profile — Infants and young children with AD are more commonly sensitized to foods (wheat and hen's egg sensitization are most prevalent in the United States, Japan, Australia, and Europe) [27,28]. Children over five years and adults are more commonly sensitized to aeroallergens (dust mite sensitization is most prevalent in both children and adults) [29]. A higher rate of dust mite sensitization in patients with AD is also seen with atopy patch testing (APT) [30].

Factors that influence sensitization patterns — Several studies have compared allergic sensitization patterns in patients with AD from different countries. The findings demonstrate a wide variability in sensitization patterns between countries and confirm that allergic sensitization is associated with higher socioeconomic status and depends upon exposure patterns [25,31-33]. As an example, in an asthma prevention trial of 2184 infants from 12 different countries with AD and a family history of atopic disease, 53 percent overall had IgE ≥30 kU/L (range based on country, 35 to 67 percent) [32]. Over one-half of these infants were sensitized (specific IgE ≥0.70 kU/L), with 19 percent monosensitized and 37 percent polysensitized. Nearly one-half were sensitized to at least one food (hen's egg most common), and one-third were sensitized to one or more inhalant allergens (dust mites most common). Rates of specific allergen sensitization varied widely among countries. The rate of egg white sensitization, for example, was 54 percent in Australia and 23 percent in Belgium.

FOOD ALLERGIES

Patterns of clinical reactions — Two types of dermatologic manifestations are believed to be associated with food allergies: urticaria/anaphylaxis and food-exacerbated AD. Only the second type of reaction is examined here. (See "Food-induced anaphylaxis" and "New-onset urticaria".)

In food-exacerbated AD reactions, ingestion of the food acutely is thought to cause a flare of the patient's AD (increased erythema and pruritus of eczematous lesions) [34]. The flare occurs within minutes to a few hours if the reaction is IgE mediated but may take hours to days if the reaction is non-IgE mediated. The patient has persistent lesions if the food is eaten chronically. (See "Clinical manifestations of food allergy: An overview".)

Diagnosis

●Approach to diagnosis – The diagnosis of food allergy involves two steps: identification of the food sensitization and confirmation of clinical allergy [35]. Identification involves history taking and allergy testing. Patients are unlikely to have food allergies as a trigger of their severe AD if they have periods of clear skin on a regular diet without medication. Food allergy is a more likely trigger if the onset or worsening of AD correlates with exposure to the food. Infants with AD and food allergy may have additional findings that suggest the presence of food allergy, such as vomiting, diarrhea, and failure to thrive [36]. (See "History and physical examination in the patient with possible food allergy".)

●Types of testing – Food allergy can be evaluated by either skin prick testing or in vitro testing for food-specific IgE. Eosinophilia may be a predictor of food allergy in patients with AD [37]. The diagnostic utility of patch testing for foods in patients with AD is of limited utility and not generally recommended. (See "Diagnostic evaluation of IgE-mediated food allergy" and "Overview of skin testing for IgE-mediated allergic disease", section on 'Skin conditions' and "Overview of in vitro allergy tests" and "Future diagnostic tools for food allergy", section on 'Atopy patch testing'.)

●Rates of food allergen sensitization versus allergy – In patients with AD, the rate of sensitization to foods ranges from 30 to 80 percent, depending upon the population, but the actual rate of confirmed food allergy is much lower [7,11,27,38-44]. As an example, 52 percent of children in a birth cohort who developed AD during the first six years of life were sensitized to at least one food allergen, but only 15 percent had challenge-confirmed food allergy [27]. Wheat was the most common food to which patients were sensitized, but hen's egg was the most common food to which patients were allergic, as confirmed by food challenge.

●Rates of food allergy and severity of AD – The frequency of food-induced AD reactions varies in relation to the severity of AD. Both IgE- and non-IgE-mediated food allergies play a role in exacerbating AD in up to 33 percent of patients with severe AD, 10 to 20 percent with moderate AD, and 6 percent with mild AD [7,11,38,42].

●Food challenges – Most patients with food sensitization and AD fall into a gray area in which the test is neither negative nor above the 95 percent positive predictive value (PPV). Other patients may have suspected non-IgE-mediated food allergy, for which no standardized diagnostic tests are available. Food challenges need to be performed in these cases to confirm clinical reactivity to the food(s) in question and prevent malnutrition from inappropriate food avoidance [36]. (See 'Food elimination diets' below.)

Clinical reactivity can be confirmed by a medically supervised oral food challenge or a double-blind, placebo-controlled food challenge (DBPCFC) for suspected IgE-mediated allergy or reproducible findings upon elimination and reintroduction of the food for suspected non-IgE-mediated allergy. The rate of food-exacerbated AD varies with the severity of the eczema. Approximately 1 to 3 percent of children with mild AD, 5 to 10 percent with moderate AD, and 20 to 33 percent with severe AD have food-induced AD [41,45-47]. Food-exacerbated AD is rare in adults. (See "Oral food challenges for diagnosis and management of food allergies" and "Diagnostic evaluation of IgE-mediated food allergy".)

Food elimination diets — Elimination of food allergens in patients with AD and confirmed food allergy can lead to significant clinical improvement [44,48]. However, foods should not be eliminated from the diet randomly without firm clinical suspicion, especially since overall foods have a low rate of triggering AD [49]. Nor should foods be excluded from the diet long term (as opposed to short term for diagnostic purposes) based upon positive skin or in vitro tests or patient history alone (see 'Diagnosis' above). Test results should be correlated with the clinical history and clinical reactivity confirmed when necessary by DBPCFC or elimination/challenge test. In addition, patients on an elimination diet should be evaluated at regular intervals to determine if the food allergy has resolved. (See "Food allergy in children: Prevalence, natural history, and monitoring for resolution".)

Risks of dietary avoidance — The risks of dietary avoidance include nutritional deficiencies and poor growth, negative impacts on quality of life (QOL) and social activities, and the immunologic risk of transitioning from delayed allergic reactions (AD) to anaphylaxis with food reintroduction. Of particular concern is unnecessary avoidance of foods, either chosen empirically or because they were identified as suspected triggers based upon testing or history, that are not actually contributing to symptoms.

●Nutrition/growth – Removal of key nutritional foods can negatively affect growth in children with food allergy and AD [50,51]. As an example, children with cow's milk allergy are at increased for iron and vitamin D deficiencies [52]. (See "Management of food allergy: Nutritional issues".)

●QOL/social – Children with food allergy have a lower QOL [53] and can develop anxiety disorders related to the food [54]. (See "Food allergy: Impact on health-related quality of life".)

●Severe, acute reactions with reintroduction – There is a risk of a more severe reaction, including anaphylaxis, when foods are reintroduced after a period of avoidance [55,56].

ENVIRONMENTAL ALLERGIES — There are less data on the role of environmental allergies in AD compared with food allergies. The data available suggest that environmental allergens are a trigger of AD in a small subset of children and adults. Patients who have environmental allergies as a trigger of AD have persistent disease with chronic exposure to an allergen in the environment.

Aeroallergens — Exposure to aeroallergens may occur by inhalation or by direct skin contact.

There are several lines of evidence that support the concept that immune responses in AD skin can be elicited by aeroallergens in sensitized patients:

●In one study of schoolchildren, sensitization to aeroallergens, particularly cat and dust mite, correlated with disease severity [57]. These children had persistent AD on areas of exposure (eg, on areas of their arms not covered by a shirt).

●A small study of adults with AD demonstrated that exposure to grass pollen in an environmental challenge chamber for two consecutive days resulted in a significant worsening of AD (increased SCORing Atopic Dermatitis [SCORAD] scores and itch intensity) compared with exposure to clean air (placebo) [58].

●Atopy patch tests (APT) to aeroallergens elicit delayed-type eczematous reactions on uninvolved skin in 40 to 85 percent of patients with AD [29,59-63]. Rates of positive APT are generally lower in young children with mild AD and higher in older children and adults with moderate to severe AD. Positive APT reactions are also more frequent in patients that have AD in an air-exposed distribution pattern. However, APT results do not always correlate with disease extent, severity, or localization [63]. Dust mites are consistently the most common positive aeroallergen and also appear to be the most clinically relevant [29]. (See "Future diagnostic tools for food allergy".)

●Intranasal and bronchial challenges with aeroallergens cause pruritus and flare up of AD lesions in some patients with AD [64,65].

●Effective measures to reduce house dust mite allergen lead to modest improvement in AD in patients with sensitization to one or more aeroallergens [35,66].

●T cells that selectively respond to Dermatophagoides pteronyssinus (Der p 1) and other aeroallergens have been isolated from AD skin lesions and allergen patch test sites [67-69].

Malassezia — Malassezia yeast is part of the normal cutaneous microflora and is found predominantly in lipid-rich areas, such as the head and neck. Immune reactions, both IgE and T cell mediated, to Malassezia species can also worsen AD [70,71]. IgE specific to Malassezia has been found in adolescent and adult patients with refractory head and neck AD. These patients may respond to antifungal therapy (eg, a one- to two-month course of daily itraconazole or ketoconazole followed by long-term weekly treatment). In addition, topical calcineurin inhibitors may inhibit the growth of Malassezia.

EFFICACY OF THERAPIES USED FOR OTHER ATOPIC DISEASES — An additional line of evidence in support of the role of food and environmental allergies in AD is that therapies used for other atopic diseases are also effective in AD. Dust mite subcutaneous immunotherapy in adults with chronic moderate AD improved eczema severity scores and reduced use of topical corticosteroids [72,73]. Anti-IgE (omalizumab) therapy improved AD in patients with concomitant asthma [74-76]. Dupilumab, an interleukin (IL) 4 receptor antagonist originally used to treat AD, has also shown efficacy for other allergic diseases such as asthma and eosinophilic esophagitis [77]. (See "Treatment of atopic dermatitis (eczema)" and "Management of severe, refractory atopic dermatitis (eczema) in children" and "Anti-IgE therapy", section on 'Other allergic disorders'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atopic dermatitis".)

SUMMARY AND RECOMMENDATIONS

●Allergen sensitization in atopic dermatitis (AD) – Infants and young children with AD are more commonly sensitized to foods, whereas children over five years and adults are more commonly sensitized to aeroallergens. However, evidence of allergen sensitization is not proof of clinically relevant allergy. (See 'Allergen sensitization' above.)

●Food sensitization and allergy in AD – In patients with AD, the rate of sensitization to foods (positive skin or in vitro test) ranges from 30 to 80 percent, depending upon the population. The rate of confirmed food allergy is much lower. Food allergies play a role in exacerbating AD in up to 33 percent of patients with severe AD, 10 to 20 percent with moderate AD, and 6 percent with mild AD. Elimination of food allergens in patients with AD and confirmed food allergy can lead to significant clinical improvement. (See 'Food allergies' above.)

●Food allergy diagnosis and elimination diets – Foods should not be eliminated from the diet randomly without any clinical suspicion, nor should foods be excluded from the diet long term (as opposed to short term for diagnostic purposes) based upon positive skin or in vitro tests or patient history alone. Test results should be correlated with the clinical history and clinical reactivity confirmed when necessary by double-blind, placebo-controlled food challenge (DBPCFC) or elimination/challenge test. (See 'Diagnosis' above and 'Food elimination diets' above.)

●Risks of dietary avoidance – The risks of dietary avoidance include nutritional deficiencies and poor growth, negative impacts on quality of life (QOL) and social activities, and the immunologic risk of transitioning from delayed allergic reactions (AD) to anaphylaxis with food reintroduction. (See 'Risks of dietary avoidance' above.)

●Environmental allergies and AD – The data on the role of aeroallergens in exacerbating AD are less extensive. Dust mites are consistently the most common positive aeroallergen and also appear to be the most clinically relevant. Immune reactions, both immunoglobulin E (IgE) and T cell mediated, to Malassezia species can also worsen AD. (See 'Environmental allergies' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jonathan M Spergel, MD, PhD, FAAAAI, who contributed to earlier versions of this topic review.