**4.3.5 Indications for an OFC**

Indications for an OFC in AD are listed below [2, 20, 32]; 1) Identify foods causing AD for the initial diagnosis of a food allergy and for monitoring resolution of the food allergy, 2) Discriminate between IFA and NFA, 3) Calibrate the provoking dose and determine the clinical severity of the reaction for therapeutic purposes in IFA and in order to monitor progress in IFA treatment, 4) Expand the diet in persons who have multiple dietary restrictions because of subjective complaints, such as headaches or hyperactive behaviour, 5) Assess the status of tolerance to cross-reactive foods, 6) Assess the effect of food processing on food tolerability, e.g., fruits and vegetables that may be tolerated in cooked form in the pollen-food allergy syndrome.

#### **4.3.6 OFC procedures for IFA and NFA**

The basic concept of OFC is the same for IFA and NFA. However, due to the different clinical characteristics of the two types of allergy, the OFC protocols for each differ significantly in principle and in dosage protocol [7]. OFC is conducted with relevant protocols for IFA or NFA. An OFC for IFA is relatively easy and simple, with higher risk, whereas an OFC for NFA is intricate and all aspects of this OFC should be carefully considered.


IFN- does not inhibit allergy provocation [19]; however, it does improve the pre-existing symptoms and signs of atopic dermatitis, including eczematous skin lesions and pruritus [19, 21]. The clinical characteristics of AD are of the non-IgE-mediated type, and the onset and duration of symptoms and signs are relatively longer [7]. It is difficult to handle or proceed to the next challenge when the patient shows a severe NFA reaction during the challenge. The use of steroids or antihistamines for symptomatic treatment can inhibit the allergic reaction caused by OFC or hide the symptoms of allergy provocation during an OFC.

#### **4.3.7 Clinical characteristics of OFC**

#### 1. IFA and NFA

Rapid onset and apparent clinical manifestations are typical of IFA [7]. During proceeding with the OFC for food allergy, the onset time following challenge, the duration of symptoms and signs, and the various clinical manifestations should be considered. Although the diagnosis of NFA is made based on the change of clinical severity scores, expertise is necessary in the OFC for NFA because the same food may provoke variable clinical manifestations with an unexpected onset time during the challenge.

2. Characteristics of OFC

The characteristics of food allergy are well described by Noh and Lee [7]. The clinical characteristics of food allergy to the same food may differ among patients and may differ in the same patient according to the type of food. Some foods, such as shrimp and mackerel, tend to provoke IgE-mediated food allergy, whereas other foods, such as milk, eggs,

Food Allergy in Atopic Dermatitis 241

Because of its nutritional purpose, this process is designed to identify completely safe foods rather than allergenic foods [2]. According to the OFC protocol for breast-fed babies, it is very important to list the foods that can be ingested by the mother that are completely safe for the baby. The primary purpose of the diagnosis of food allergy is to provide safe recipes for the infant and the mother. Subsequently, the test results will be applied to the infant during the phase of solid food introduction. Safe foods will be introduced with priority. An OFC is conducted on the mother using normal protocols; the sole difference is that the food

In formula-feeding babies, the OFC is simpler than in breast-feeding infants [2]. The primary purpose of treatment is to set up safe formula feeding with casein hydrolysate, soy formula or other foods. To rule out milk allergy, challenge with casein hydrolysate will be performed for the diagnosis of allergy, especially to casein. If the infant improves with casein hydrolysate, he

If the baby does not improve on casein hydrolysate formula, it is subsequently challenged with amino acid-based formula. If the baby improves, the baby is allergic to components other than casein in milk or together with allergic to casein. The baby can then be fed the amino acid-based formula or be tested on soy formula. If the baby cannot tolerate the amino acid-based formula and has an allergy to casein hydrolysate, or if the parents wish to feed the baby soy formula, a soy formula challenge can be performed. If the baby improves with the soy formula, the baby is allergic to milk and can be fed with soy formula until weaning. TIFA for any formula is indicated when the baby does not improve with either soy formula or casein hydrolysate or when the baby does not tolerate amino acid-based formula [2]. Parents can select the kinds of foods (milk or soy) to be tolerised. After tolerance induction

An initial elimination diet for the mother is conducted with simultaneous feeding of a safe formula, as described above [2]. After initially setting the baby up with safe formula feeding and diet restriction of the mother, an OFC of the mother for the diagnosis of food allergy in

The primary purpose of diagnosis is to set up a safe recipe for the infant to prevent nutritional deficiencies due to elimination diets or food allergies [2]. Transiently, an elimination diet should be conducted in the mother and all solid foods should be stopped in the infant (elimination diet of infant and mother). Due to nutritional considerations, elimination for the infant and the mother should not be conducted for more than 3 days. If the baby does not improve, IFN- therapy for the baby is indicated during subsequent OFCs of the baby. If the baby improves following an elimination diet of the mother and baby with or without IFN-, sequential introduction of solid foods may be performed according to the weaning schedule. However, the sequence of foods can be changed according to the circumstances of the infant and the mother. The mother and infant should be simultaneously fed with the same challenge foods. In case of formula feeding infants, stop all solid foods to the infant (elimination diet in the infant) and simultaneously set up a safe

or she is allergic to casein and casein hydrolysate formula is be used until weaning.

is given to the mother and reactions are observed in the infant.

for formula, the baby is fed the tolerised formula until weaning.

the infant should be performed as described above.

**4.4.3 Mixed-feeding baby (breast-feeding with formula feeding)** 

**4.4.4 Solid food introduction for baby (approximately 5-12 months)** 

**4.4.2 Formula-feeding infants** 

soybeans and wheat, tend to provoke both IgE- and non-IgE-mediated food allergies. Other foods, such as meats, tend to predominantly provoke non-IgE-mediated food allergy. According to the characteristics of the region, the kinds of foods that cause food allergy also differ. Patients who live near the sea tend to have allergies to seafood, whereas patients who live in land tend to have less frequent allergies to seafood. Allergy to rice is less frequent in Oriental countries than in Western countries, whereas wheat allergy is more frequent in Oriental countries than in Western countries.

The statistics on food allergy are very important in clinical practice. Basically, the foods that should be restricted in the initial elimination diet for the control of food allergy in atopic dermatitis have been identified based on the statistics on food allergy [12, 13, 18, 19, 21]. The necessary statistics should be based on challenge tests conducted at least with open OFC and not on laboratory results because IgE-based tests cannot predict the presence of food allergy, particularly for non-IgE-mediated food allergy in atopic dermatitis.

Interestingly, meat (beef, chicken, pork) has not been recognised as an important cause of food allergy in atopic dermatitis because meats induce predominantly non-IgE-mediated food allergies [12, 13, 18, 19, 33]. From the statistics, fewer than 5% of patients have allergies to chicken and pork simultaneously. Therefore, if a patient shows an allergy to either chicken or pork, the physician can predict the possibility that the other may not provoke allergy in the patient. Approximately 10% of patients have allergies to both milk and eggs; thus, if a patient is allergic to either milk or eggs, the possibility that the patient has allergy to the other is less than 10%. Similar data are available for soybeans and wheat. The use of statistics is thus very helpful in managing food allergies related to atopic dermatitis.

Patients sometimes think that they may be allergic to beef if they are allergic to milk because milk comes from cows. However, this is not the case. Milk and beef have no statistical relationship as causes for food allergy in atopic dermatitis [12, 13, 18, 19, 33]. The same is the case for chicken and eggs. Physicians and dietitians should consider these points in the management of food allergy in atopic dermatitis.

#### **4.4 Diagnosis of food allergy in infants 4.4.1 Breast-feeding infants and children**

If an infant develops severe eczema while it is exclusively breast-fed, it is essential to consider a food allergy provoked by proteins in the breast milk. All food proteins can pass from the maternal diet into breast milk [31]. If an allergy due to exposure to a protein via maternal milk is diagnosed, it is necessary to modify the diet of the mother with professional dietetic support and supervision. Previously, in cases where multiple foods were implicated or there were concerns about maternal nutrition, it was appropriate to suggest the substitution of an appropriate milk formula. However, with the advent of tolerance induction, TIFA for allergenic foods is also available.

For the diagnosis of food allergy in the breast-feeding infant, OFC is performed through the mother [2]. Improvement of the baby following an elimination diet in the mother should occur before proceeding with an OFC. The mother ingests the challenge food and the baby consumes the breast milk. The baby is then evaluated following the same processes. The important point is that the baby should consume breast milk within a specified time (1-2 hours) after the mother ingests the challenge food. If the baby does not improve with the mother's elimination diet, IFN- therapy can be administered to the baby to elicit clinical improvement.

soybeans and wheat, tend to provoke both IgE- and non-IgE-mediated food allergies. Other foods, such as meats, tend to predominantly provoke non-IgE-mediated food allergy. According to the characteristics of the region, the kinds of foods that cause food allergy also differ. Patients who live near the sea tend to have allergies to seafood, whereas patients who live in land tend to have less frequent allergies to seafood. Allergy to rice is less frequent in Oriental countries than in Western countries, whereas wheat allergy is more frequent in

The statistics on food allergy are very important in clinical practice. Basically, the foods that should be restricted in the initial elimination diet for the control of food allergy in atopic dermatitis have been identified based on the statistics on food allergy [12, 13, 18, 19, 21]. The necessary statistics should be based on challenge tests conducted at least with open OFC and not on laboratory results because IgE-based tests cannot predict the presence of food allergy,

Interestingly, meat (beef, chicken, pork) has not been recognised as an important cause of food allergy in atopic dermatitis because meats induce predominantly non-IgE-mediated food allergies [12, 13, 18, 19, 33]. From the statistics, fewer than 5% of patients have allergies to chicken and pork simultaneously. Therefore, if a patient shows an allergy to either chicken or pork, the physician can predict the possibility that the other may not provoke allergy in the patient. Approximately 10% of patients have allergies to both milk and eggs; thus, if a patient is allergic to either milk or eggs, the possibility that the patient has allergy to the other is less than 10%. Similar data are available for soybeans and wheat. The use of

statistics is thus very helpful in managing food allergies related to atopic dermatitis.

Patients sometimes think that they may be allergic to beef if they are allergic to milk because milk comes from cows. However, this is not the case. Milk and beef have no statistical relationship as causes for food allergy in atopic dermatitis [12, 13, 18, 19, 33]. The same is the case for chicken and eggs. Physicians and dietitians should consider these points

If an infant develops severe eczema while it is exclusively breast-fed, it is essential to consider a food allergy provoked by proteins in the breast milk. All food proteins can pass from the maternal diet into breast milk [31]. If an allergy due to exposure to a protein via maternal milk is diagnosed, it is necessary to modify the diet of the mother with professional dietetic support and supervision. Previously, in cases where multiple foods were implicated or there were concerns about maternal nutrition, it was appropriate to suggest the substitution of an appropriate milk formula. However, with the advent of

For the diagnosis of food allergy in the breast-feeding infant, OFC is performed through the mother [2]. Improvement of the baby following an elimination diet in the mother should occur before proceeding with an OFC. The mother ingests the challenge food and the baby consumes the breast milk. The baby is then evaluated following the same processes. The important point is that the baby should consume breast milk within a specified time (1-2 hours) after the mother ingests the challenge food. If the baby does not improve with the mother's elimination diet, IFN- therapy can be administered to the

Oriental countries than in Western countries.

particularly for non-IgE-mediated food allergy in atopic dermatitis.

in the management of food allergy in atopic dermatitis.

tolerance induction, TIFA for allergenic foods is also available.

**4.4 Diagnosis of food allergy in infants 4.4.1 Breast-feeding infants and children** 

baby to elicit clinical improvement.

Because of its nutritional purpose, this process is designed to identify completely safe foods rather than allergenic foods [2]. According to the OFC protocol for breast-fed babies, it is very important to list the foods that can be ingested by the mother that are completely safe for the baby. The primary purpose of the diagnosis of food allergy is to provide safe recipes for the infant and the mother. Subsequently, the test results will be applied to the infant during the phase of solid food introduction. Safe foods will be introduced with priority. An OFC is conducted on the mother using normal protocols; the sole difference is that the food is given to the mother and reactions are observed in the infant.

#### **4.4.2 Formula-feeding infants**

In formula-feeding babies, the OFC is simpler than in breast-feeding infants [2]. The primary purpose of treatment is to set up safe formula feeding with casein hydrolysate, soy formula or other foods. To rule out milk allergy, challenge with casein hydrolysate will be performed for the diagnosis of allergy, especially to casein. If the infant improves with casein hydrolysate, he or she is allergic to casein and casein hydrolysate formula is be used until weaning.

If the baby does not improve on casein hydrolysate formula, it is subsequently challenged with amino acid-based formula. If the baby improves, the baby is allergic to components other than casein in milk or together with allergic to casein. The baby can then be fed the amino acid-based formula or be tested on soy formula. If the baby cannot tolerate the amino acid-based formula and has an allergy to casein hydrolysate, or if the parents wish to feed the baby soy formula, a soy formula challenge can be performed. If the baby improves with the soy formula, the baby is allergic to milk and can be fed with soy formula until weaning.

TIFA for any formula is indicated when the baby does not improve with either soy formula or casein hydrolysate or when the baby does not tolerate amino acid-based formula [2]. Parents can select the kinds of foods (milk or soy) to be tolerised. After tolerance induction for formula, the baby is fed the tolerised formula until weaning.

#### **4.4.3 Mixed-feeding baby (breast-feeding with formula feeding)**

An initial elimination diet for the mother is conducted with simultaneous feeding of a safe formula, as described above [2]. After initially setting the baby up with safe formula feeding and diet restriction of the mother, an OFC of the mother for the diagnosis of food allergy in the infant should be performed as described above.

#### **4.4.4 Solid food introduction for baby (approximately 5-12 months)**

The primary purpose of diagnosis is to set up a safe recipe for the infant to prevent nutritional deficiencies due to elimination diets or food allergies [2]. Transiently, an elimination diet should be conducted in the mother and all solid foods should be stopped in the infant (elimination diet of infant and mother). Due to nutritional considerations, elimination for the infant and the mother should not be conducted for more than 3 days. If the baby does not improve, IFN- therapy for the baby is indicated during subsequent OFCs of the baby. If the baby improves following an elimination diet of the mother and baby with or without IFN-, sequential introduction of solid foods may be performed according to the weaning schedule. However, the sequence of foods can be changed according to the circumstances of the infant and the mother. The mother and infant should be simultaneously fed with the same challenge foods. In case of formula feeding infants, stop all solid foods to the infant (elimination diet in the infant) and simultaneously set up a safe

Food Allergy in Atopic Dermatitis 243

anaphylaxis, Peptide immunotherapy has also been investigated using the immunodominant

**5.2 Oral immunotherapy for food allergy: Tolerance induction for food allergies (TIFA)** 

Oral immunotherapy appears to be effective in inducing desensitization in most patients, as well as oral tolerance in a subset of patients with food allergy [34]. Oral immunotherapy was officially introduced in 1996 in "Monographs in Allergy" [36, 37]. Noh & Lee reported the first successful use of oral immunotherapy for food allergy [38]. They used IFN- as the adjuvant for oral immunotherapy for food allergy and named this therapy "specific oral tolerance induction (SOTI)" in 2003. SOTI was attempted for IgE-mediated food allergy in humans by several investigators [5, 34, 39-43]. The complete SOTI protocol for IgE-mediated

Several terms are used to describe oral immunotherapy for food allergy. These terms are based on an escalating dosage of orally ingested foods or food protein to induce immune tolerance for allergenic food(s). Tolerance induction for food allergy (TIFA) was first coined by Noh & Lee in 2003 [38]. Specific oral tolerance induction (SOTI) is currently the more precise term to describe oral tolerance induction for specific allergens in food allergy, and this term, SOTI, was also used first by Noh in 2003 in a report on milk-specific oral tolerance induction for non-IgE-mediated food allergy in atopic dermatitis. Tolerance induction for food allergy (TIFA) is a similar term that has a broader immunologic meaning: to induce

IFN- was introduced for the correction of Th1/Th2 imbalance, which is the basic immunologic mechanism in allergies, including food allergy [21]. As expected, desensitization for house dust mites was successful when IFN- was used, but was ineffective without IFN- [30]. Moreover, IFN- seemed to show tolerogenic effects in addition to its corrective effects in Th1/Th2 imbalance [7]. Especially, IFN- was absolutely necessary for TIFA for non-IgE-mediated food allergy. Other than SOTI, effective treatment methods for non-IgE-mediated food allergy by using IFN- have not been established.

Tolerance induction for food allergy is indicated when (1) nutritional deficiency is expected, (2) the patient is inevitably unable to avoid the allergen (e.g., wheat allergy in a baker), (3) an infant displays allergy to all available formulae, and (4) the patients or parents want an

Breast milk is the gold standard for protective nutrients fed to newborn infants, and present clinical evidence supports the strong protective effect of breast milk against age-related infectious gastroenteritis [44]. An important function of early breastfeeding is its antiinflammatory effect on the immature, excessive inflammatory response in newborns.

food allergy was accomplished by also using IFN- in 2009 by Noh & Lee [6].

Without IFN-, tolerance is not induced in non-IgE-mediated food allergy.

epitopes of ovalbumin.

**or specific oral tolerance induction (SOTI)** 

immune tolerance for allergenic foods by any method.

**5.3 IFN- in food allergy and AD** 

**5.4 Indication for SOTI** 

improved quality of life [2].

**6. Prevention of food allergy** 

**6.1 Breastfeeding for the prevention of food allergy**

formula feeding during the elimination diet in the infant, as described above. Sequential introduction of solid foods should be performed according to the weaning schedule. Nutritional care for the infant is essential.
