**3. Clinical characteristics of food allergy in AD**

#### **3.1 Clinical features of AD**

The clinical phenotype of AD varies with age and course of the disease [10]. The eczematous lesions may present as acute (oozing, crusted, or eroded vesicles or papules on erythematous plaques), subacute (thick and excoriated plaques), or chronic (lichenified, slightly pigmented, or excoriated plaques) forms. Furthermore, xerosis and a lowered threshold for itching are usual hallmarks of AD. Pruritus attacks can occur throughout the day and worsen at the night, causing insomnia, exhaustion, and a substantial impairment in quality of life. To date, the symptoms and signs of AD have been listed horizontally. However, the primary clinical manifestations of AD include eczematous skin lesions and itching caused by allergen-specific Th2 immune responses. Some clinical manifestations of AD, including papule, plaque, and xerosis, are descriptions of skin manifestations; some manifestations, including excoriation, are related to the primary AD symptoms and signs; and some manifestations, including viral infection and impetigo, insomnia, and exhaustion, are secondary to the primary symptoms and signs.

#### **3.2 Clinical features of food allergy in AD**

The clinical manifestations of IgE-mediated food allergy (IFA) are uniform in AD and in the absence of AD; they include dermatologic manifestations, such as immediate urticaria and rashes, as well as other cardiovascular and respiratory symptoms and signs [2].

The clinical manifestations of non-IgE-mediated food allergy (NFA) are not uniform. Although IFA has been described as a central immunopathogenesis of atopic dermatitis, the symptoms and signs of IFA do not correspond to those of atopic dermatitis. Rather, the symptoms and signs of NFA are those of atopic dermatitis itself.

Food allergies have clinical manifestations on the skin as well as gastrointestinal and respiratory systems. Cutaneous reactions have been categorised as non-eczematous versus eczematous and early versus late [11]. Non-eczematous reactions tend to occur immediately after exposure to the food, usually immediately or within less than 1 hour. The typical reactions include pruritus, urticaria, angioedema, and diffuse morbilliform erythema. These reactions do not cause immediate exacerbations of AD, and they are commonly associated with gastrointestinal or respiratory symptoms. Acute urticaria and angioedema are among the most common symptoms, and acute contact urticaria or allergy can also occur. One-half of the reactions after the ingestion of milk are not mediated by specific IgE antibodies to

Food Allergy in Atopic Dermatitis 233

of AD with development of new eczematous outbreaks tends to occur as a late reaction and infrequently as an early reaction. However, in its clinical and immunopathogenic aspects, NFA is similar to AD. With the advent of successful treatments for food allergy, IFA is less so. In this chapter, AD are described, especially in the viewpoint of non-IgE-

Multiple sensitisation with foods has not been generally considered a possible cause of AD; this is another point that can easily confuse clinicians and patients. The prevalence of data describing multiple food allergies in published studies provides an estimate of multiple food allergy prevalence [7, 13]. In a study of food allergies in a highly atopic group of children, all of whom had atopic dermatitis and 50% of whom had concurrent asthma or allergic rhinitis, 57% reacted to two or three foods during double-blind, placebo-controlled food challenges [17]. Most children in this subset had positive skin prick tests (SPTs) to several foods, although only approximately one third of positive tests correlated with positive food challenge [13]. However, few children reacted to more than three foods [18]. Five foods (eggs, peanuts, milk, wheat, and soy) accounted for approximately 60% of the

More than 500 random serum samples were evaluated for specific IgE against six common food allergens (milk, eggs, wheat, soy, peanuts, and cod) [17]. They addressed that having evidence of IgE-mediated sensitisation to a food does not necessarily imply a true food allergy. This study found that 27% of children were sensitised to more than one of the six foods. The main limitation of this retrospective study was that information regarding clinical reactivity to foods was not available; therefore, it is not known how many of these

A recent study examining the prevalence of multiple food allergies found that most (>70%) food-allergic children were allergic to or were avoiding multiple foods [17]. On average, each child was avoiding three or four foods or food groups. These children were generally very atopic, with 56% showing atopic dermatitis, 47% having allergic rhinitis, and 38% having asthma. Thus, highly atopic children may be at greater risk for allergies

Although food allergies are not the only cause of AD, in many cases AD is caused by multiple food allergies. Over 50% of AD patients also exhibited NFA to a mean of 2.8 food items [18]. Moreover, IFA co-exists simultaneously with AD and NFA [7]. Interestingly, in most cases, patients with isolated IFA did not have AD. From these results, it seems clear that NFA is the major type of food allergy in AD, although IFA is

The diagnosis of food allergy should be made following the discrimination of IgE- and non-IgE-mediated allergies. Diagnostic protocols for IFA have been proposed by various researchers, institutes and academic societies; however, the concept of dosage

mediated food allergy.

to multiple foods.

**3.5 Multiple food allergies in AD Multiple sensitisation to foods in IFA** 

positive clinical responses in this study [19].

patients were truly allergic to more than one food.

**Sensitisation to multiple foods in AD** 

**4. Diagnosis of food allergy in AD** 

the aggravating cause of AD.

milk protein and are lost by the age of 3 years. Eczematous reactions has been regarded as occurring less frequently. They usually manifest as a late event, generally defined as occurring 2 to 6 hours or more after exposure to the food. As has already been shown, eczematous reactions can develop infrequently as an early event or in combination with non-eczematous reactions.

The symptoms and signs of NFA are not uniform; they vary according to subjects and foods [2]. In addition, in one subject, various symptoms and signs often develop according to the food ingested. The onset time of symptoms and signs of NFA ranges from 2 hours to several days, up to even a week, after intake [12]. Because it is very difficult to predict the onset time of NFA symptoms, physicians should observe patients long enough to cover the maximum onset time following challenge or intake during daily life. The clinical manifestations of NFA show patterns of their own with respect to onset time, the severity of clinical manifestations, and type of allergy.

It should be kept in mind that AD patients, as well as other food allergy patients, may be allergic to multiple food allergens [13]. These patients may also have multiple types of food allergy, such as IFA and NFA, together. However, when this is the case, patients will not necessarily have both IFA and NFA simultaneously to the same food. The diagnosis, management, and treatment of food allergy in AD should be approached keeping in mind that subjects may have food allergies to multiple foods and that they may exhibit multiple types of food allergies including both IFA and NFA.

### **3.3 Types of foods that cause atopic dermatitis**

Based on OFC outcomes, the most common food allergens in the United States, accounting for the vast majority of food allergies in patients, are known as cow's milk, hen's eggs, peanuts, soy, wheat, tree nuts, and shellfish [14]. Although some children prove to be truly allergic to meats, fruits, vegetables, or other grains, the vast majority have negative OFCs for these foods.

As confirmed in several studies, cow's milk, hen's eggs, wheat, soy, and peanuts are responsible for approximately 75% of food-associated AD [15,16] in IFA, whereas for NFA, meats as well as cow's milk, hen's eggs, soy and wheat were the major causes of AD [13].

In Western country, Hen's eggs and cow's milk are significantly more likely to result in IFA and are associated with elevated food-specific IgE [11]. Soy and wheat are more likely to cause late eczematous flares, but reactions to cow's milk were also observed. Although some of these reactions are observed in the context of elevated food-specific IgE, some also occur in the absence of food-specific IgE.

The same food can provoke IFA and NFA. In recent studies, foods were mapped according to the kinds of food allergy (IFA or NFA) and severity [7]. Such mapping is necessary for the proper management of food allergy in atopic dermatitis.

#### **3.4 Mixed-type allergy: The simultaneous presence of two different types of food allergy, IFA and NFA, in AD**

Because IFA and NFA are present together in atopic dermatitis, the characteristics of AD that result from each of these two types of food allergy should be clarified [7]. It is generally understood that IFA, rather than NFA, plays a central role in the immunopathogenesis of AD until recently [12]. Immediate reactions in IFA often lead to increased scratching and, eventually, secondary exacerbation of eczematous lesions [11], whereas direct exacerbation

milk protein and are lost by the age of 3 years. Eczematous reactions has been regarded as occurring less frequently. They usually manifest as a late event, generally defined as occurring 2 to 6 hours or more after exposure to the food. As has already been shown, eczematous reactions can develop infrequently as an early event or in combination with

The symptoms and signs of NFA are not uniform; they vary according to subjects and foods [2]. In addition, in one subject, various symptoms and signs often develop according to the food ingested. The onset time of symptoms and signs of NFA ranges from 2 hours to several days, up to even a week, after intake [12]. Because it is very difficult to predict the onset time of NFA symptoms, physicians should observe patients long enough to cover the maximum onset time following challenge or intake during daily life. The clinical manifestations of NFA show patterns of their own with respect to onset time, the severity of clinical

It should be kept in mind that AD patients, as well as other food allergy patients, may be allergic to multiple food allergens [13]. These patients may also have multiple types of food allergy, such as IFA and NFA, together. However, when this is the case, patients will not necessarily have both IFA and NFA simultaneously to the same food. The diagnosis, management, and treatment of food allergy in AD should be approached keeping in mind that subjects may have food allergies to multiple foods and that they may exhibit multiple

Based on OFC outcomes, the most common food allergens in the United States, accounting for the vast majority of food allergies in patients, are known as cow's milk, hen's eggs, peanuts, soy, wheat, tree nuts, and shellfish [14]. Although some children prove to be truly allergic to meats, fruits, vegetables, or other grains, the vast majority

As confirmed in several studies, cow's milk, hen's eggs, wheat, soy, and peanuts are responsible for approximately 75% of food-associated AD [15,16] in IFA, whereas for NFA, meats as well as cow's milk, hen's eggs, soy and wheat were the major causes of AD [13]. In Western country, Hen's eggs and cow's milk are significantly more likely to result in IFA and are associated with elevated food-specific IgE [11]. Soy and wheat are more likely to cause late eczematous flares, but reactions to cow's milk were also observed. Although some of these reactions are observed in the context of elevated food-specific IgE, some also occur

The same food can provoke IFA and NFA. In recent studies, foods were mapped according to the kinds of food allergy (IFA or NFA) and severity [7]. Such mapping is necessary for the

Because IFA and NFA are present together in atopic dermatitis, the characteristics of AD that result from each of these two types of food allergy should be clarified [7]. It is generally understood that IFA, rather than NFA, plays a central role in the immunopathogenesis of AD until recently [12]. Immediate reactions in IFA often lead to increased scratching and, eventually, secondary exacerbation of eczematous lesions [11], whereas direct exacerbation

**3.4 Mixed-type allergy: The simultaneous presence of two different types of food** 

non-eczematous reactions.

manifestations, and type of allergy.

have negative OFCs for these foods.

in the absence of food-specific IgE.

**allergy, IFA and NFA, in AD** 

types of food allergies including both IFA and NFA.

**3.3 Types of foods that cause atopic dermatitis** 

proper management of food allergy in atopic dermatitis.

of AD with development of new eczematous outbreaks tends to occur as a late reaction and infrequently as an early reaction. However, in its clinical and immunopathogenic aspects, NFA is similar to AD. With the advent of successful treatments for food allergy, IFA is less so. In this chapter, AD are described, especially in the viewpoint of non-IgEmediated food allergy.
