Decreased Basophil Activation against House Dust Mite after Japanese Cedar Pollen Subcutaneous Immunotherapy: A Retrospective Study.

BACKGROUND: Allergen-specific immunotherapy (AIT), an established treatment for allergic diseases, prevents the development of other allergic manifestations. Although the mechanisms remain unclear, AIT has been shown to reduce basophil activation (BA) against nontarget allergens. OBJECTIVES: The aim of this study was to assess immunological changes in Dermatophagoides farinae (Der f) after Japanese cedar pollen (JCP)-based subcutaneous immunotherapy (SCIT) monotherapy. METHOD: The data of 16 patients (age: 6-37 years) with JCP-induced allergic rhinitis who were sensitive to Der f (serum Der f-specific immunoglobulin E [IgE] level >0.34 kUA/L) and received JCP-based SCIT for 5 years were reviewed retrospectively. BA by Der f and JCP extracts and serum-specific IgE and immunoglobulin G4 (IgG4) levels against these allergens were evaluated before and after completing 5 years of JCP-based SCIT monotherapy. RESULTS: The areas under the dose-response curves of BA by Der f and JCP extracts were significantly reduced (p = 0.02 and p = 0.002, respectively). JCP-specific IgE levels decreased and JCP-specific IgG4 levels increased significantly (p < 0.001 for both), whereas Der f-specific IgE and IgG4 levels did not change significantly. CONCLUSIONS: JCP-based SCIT monotherapy reduced Der f-specific BA. These findings suggest that JCP-based SCIT has the potential to modulate immune response toward nontarget allergens.

Tolerability of partially and extensively hydrolysed milk formulas in children with cow's milk allergy.

BACKGROUND AND OBJECTIVES: The safety and tolerability of hydrolysed cow's milk protein-based formulas, particularly partially hydrolysed formulas (pHFs), in children with cow's milk allergy (CMA) remain poorly understood. We evaluated the tolerability of hydrolysed cow's milk-based formulas in children with CMA. METHODS AND STUDY DESIGN: A three-period double-blind crossover evaluation compared the allergic tolerance against three dietary cow's milk-based formulas: extensively hydrolysed cow's milk formula (eHF), pHF, and regular cow's milk formula (rCMF). The primary outcome was the rate of tolerance against a maximum of 20.0 mL of formula. RESULTS: Controlled food challenges were performed in 25 children (18 boys; 7 girls) with a median age of 4.25 years (range: 1-9 years) diagnosed with CMA. The median cow's milk-specific immunoglobulin E level was 31.9 UA/mL (range: 1.16-735 UA/mL). The tolerance rate ratios for rCMF were lower than those for pHF (2 vs 16; p<0.01) and eHF (2 vs 22; p<0.01). The allergic symptom scores induced by intake of pHF and eHF were significantly lower than those of rCMF (p=0.01 and p<0.01, respectively), and the pHF and eHF scores were not significantly different. CONCLUSIONS: Compared to rCMF, the partially and extensively hydrolysed whey and casein formulas evaluated in this study were better tolerated and therefore safer for children with CMA. Although further confirmation from additional centres is needed, our findings suggest the use of pHF in patients with mild CMA. Some children with CMA react to hydrolysed formulas; therefore, food challenge tests in these children should be undertaken with caution.

Oral Immunotherapy Using Partially Hydrolyzed Formula for Cow's Milk Protein Allergy: A Randomized, Controlled Trial.

BACKGROUND: Partially hydrolyzed cow's milk protein-based formula (pHF) possesses low allergenicity. Here, we investigate the safety and efficacy of oral immunotherapy using pHF for children with cow's milk protein allergy (CMPA). OBJECTIVES: A randomized, double-blind, controlled single-center trial was conducted to evaluate the efficacy and safety of pHF oral immunotherapy in children with CMPA. METHODS: Participants were randomized into double-blind pHF-pHF and extensively hydrolyzed cow's milk protein-based formula (eHF)-pHF groups. During this phase, the pHF-pHF group received pHF and the eHF-pHF group received eHF. During the open phase, all participants received pHF. The primary end point was a change in thresholds between baseline and the end of the first phase. Secondary end points were changes in thresholds between baseline and the end of the second phase, and casein-specific immunoglobulin (Ig)E, IgG4, and basophil activation. RESULTS: Twenty-five children, aged 1-9 years, were randomized into pHF-pHF and eHF-pHF groups. The threshold between baseline and the end of the first phase was significantly elevated in the pHF-pHF group (p = 0.048), but not in the eHF-pHF group. The threshold between other phases did not change significantly in either group. There were significant decreases in casein-specific IgE antibody levels between baseline and the second phase in the eHF-pHF group (p = 0.014). No participants suffered systemic allergic reactions requiring adrenaline or systemic corticosteroids after receiving the formulas. CONCLUSIONS: The results of this trial suggest that, in children with CMPA, tolerance to cow's milk might be safely enhanced by intake of pHF, relative to that of eHF.

Long-term safety of subcutaneous immunotherapy with TO-204 in Japanese patients with house dust mite-induced allergic rhinitis and allergic bronchial asthma: Multicenter, open label clinical trial.

BACKGROUND: To evaluate the long-term safety of subcutaneous immunotherapy with TO-204, a standardized house dust mite (HDM) allergen extracts, we conducted a multicenter, open label clinical trial. METHODS: Japanese patients aged 5-65 years were eligible for the study, if they had HDM-induced allergic rhinitis (AR), allergic bronchial asthma (BA), or both. TO-204 was administered in a dose titration scheme, and the maintenance dose was determined according to the predefined criteria. The treatment period was 52 weeks, and patients who were willing to continue the treatment received TO-204 beyond 52 weeks. This clinical trial is registered at the Japan Pharmaceutical Information Center (Japic CTI-121900). RESULTS: Between July 2012 and May 2015, 44 patients (28 with AR and 16 with allergic BA) were enrolled into the study. All patients were included in the analysis. The duration of treatment ranged from 23 to 142 weeks and the median maintenance dose was 200 Japanese allergy units (JAU). Adverse events occurred in 22 patients (50%). The most common adverse event was local reactions related to the injection sites. Four patients experienced anaphylactic reactions when they were treated with the dose of 500 JAU. Two patients experienced anaphylactic shock with the doses of 1000 JAU at onset. These 6 patients could continue the study with dose reduction. CONCLUSIONS: Safety profile of TO-204 was acceptable in Japanese patients with HDM-induced AR or allergic BA. Higher doses should be administered carefully, because the risk of anaphylaxis increased at doses of 500 or 1000 JAU.

Evaluation of allergenic potential for rice seed protein components utilizing a rice proteome database and an allergen database in combination with IgE-binding of recombinant proteins.

Among 131 rice endosperm proteins previously identified by MS-based proteomics, most of the proteins showed low or almost no sequence similarity to known allergens in databases, whereas nine proteins did it significantly. The sequence of two proteins showed high overall identity with Hsp70-like hazel tree pollen allergen (Cor a 10) and barley α-amylase (Hor v 16), respectively, whereas the others showed low identity (28-58%) with lemon germin-like protein (Cit l 1), corn zein (Zea m 50 K), wheat chitinase-like xylanase inhibitor (Tri a XI), and kinase-like pollen allergen of Russian thistle (Sal k 1). Immuno-dot blot analysis showed that recombinant proteins for these rice seed homologs were positive in the IgE-binding, but not necessarily similarity dependent, from some allergic patients. These results suggest that utilization of proteome and sequence databases in combination with IgE-binding analysis was effective to screen and evaluate allergenic potential of rice seed protein components.

[AN EVALUATION OF SPONTANEOUS HISTAMINE RELEASE AND THE LOW RESPONDERS IN A BASOPHIL HISTAMINE RELEASE TEST].

BACKGROUND: We evaluated the clinical significance of the spontaneous histamine release ratio (SHR/T) and low responders in the automated basophil histamine release test (AllerportⓇ HRT). METHODS: This study analyzed the outcomes of 101 oral food challenges (OFC) with egg, milk or wheat (challenge-positive: n=79) in relation to the SHR/T. The traditional HRT low responders (n=27) were separated into two groups:"LOW"responders (n=10), who showed a ≥10% concentration-dependent maximum histamine release in response to the anti-human IgE stimulation, and"NON"responders who did not fulfill the criteria (n=17). RESULTS: Among the 34 patients with ≥20% SHR/T, 32 patients (94%) had a positive OFC with a low threshold dose which provoked severe symptoms. Among the"LOW"responders, four cases showed ≥10% allergen-specific maximum histamine release. On the other hand, concentration-dependent histamine release was not seen in the"NON"responders, suggesting the basophil function was not detected in this subgroup. CONCLUSION: The present study suggested that SHR/T could be an indicator of basophil activation and hypersensitivity in vivo. We also suggested that significant basophil functions might be detected among the "LOW"responders, but not among the"NON"responders.

Japanese cedar pollen-based subcutaneous immunotherapy decreases tomato fruit-specific basophil activation.

BACKGROUND: Some patients with Japanese cedar pollen (JCP)-induced allergic rhinitis develop pollen-food allergy syndrome (PFAS) as a reaction to tomato fruit. Pollen allergen-specific subcutaneous immunotherapy (SCIT) is reportedly beneficial for some associated food allergies; however, the reported changes in food allergen-specific immunoglobulin (Ig)E and IgG4 levels are inconsistent. Here, we investigated immunologic reactivity to tomato fruit after JCP-based SCIT. METHODS: Twenty-three children (aged 6-17 years) with JCP-induced allergic rhinitis and sensitized to tomato (serum tomato fruit-specific IgE level >0.34 UA/ml) received JCP-based SCIT. Basophil activation by tomato and JCP extracts and serum-specific IgE and IgG4 levels against these allergens were determined before and after 4 or 5 months of maintenance SCIT. Basophil activation was assessed by monitoring CD203c upregulation on flow cytometry. RESULTS: JCP-based SCIT significantly reduced the basophil activation caused by tomato fruit (p = 0.03) and JCP (p < 0.001) extracts. JCP-specific IgG4 levels markedly increased after SCIT (p < 0.001), whereas tomato fruit-specific IgG4 levels did not. After SCIT, no significant changes were observed in specific IgE levels for tomato fruit (p = 0.11) or JCP (p = 0.19). CONCLUSIONS: Tomato fruit-specific basophil activation decreases after JCP-based SCIT, suggesting that it is efficacious in relieving and preventing the symptoms of PFAS in patients with JCP-induced allergic rhinitis.

Multicolor flow-cytometric analysis of milk allergen-specific T-helper type 2 cells revealed coexpression of interleukin-4 with Foxp3.

BACKGROUND: Allergen-specific T-helper type 2 (TH2) cells play an important role in the development of allergic inflammation; however, investigations of the properties of allergen-specific T cells have been challenging in humans. Despite clear evidence that forkhead box p3 (Foxp3) is expressed in conventional effector T cells, its function has remained unknown. OBJECTIVE: To characterize allergen-specific TH2 cells in milk allergy, with particular focus on the expression of Foxp3. METHODS: Twenty-one children with milk allergy and 11 children without milk allergy were studied. Peripheral blood mononuclear cells from subjects were stimulated with milk allergen for 6 hours and analyzed using multicolor flow cytometry to identify CD154(+) allergen-specific T-helper cells. Simultaneously, the expression of intracellular cytokines and Foxp3 was analyzed. RESULTS: The milk allergy group had significantly larger numbers of milk allergen-specific interleukin (IL)-4- and IL-5-producing CD4(+) T cells than the control group. Subjects in the milk allergy group had significantly more CD154(+)CD4(+) IL-10-producing cells and CD154(+)Foxp3(+)CD4(+) cells than those in the control group. In addition, the number of milk allergen-specific CD154(+)Foxp3(+)CD4(+) cells strongly correlated with that of CD154(+)IL4(+)CD4(+) cells. Bcl-2 expression in CD154(+)IL-4(+)Foxp3(+) T-helper cells was significantly lower compared with that in total CD4 cells. CONCLUSION: Increased numbers of IL-4-producing allergen-specific T-helper cells were found in patients with milk allergy. In addition, Foxp3 was coexpressed with IL-4 in allergen-specific TH2 cells from patients. This coexpression was associated with lower Bcl-2 levels and could contribute to the phenotype and function of TH2 cells.

[Utility of the allerport® HRT in the diagnosis of hen's egg allergy: a pediatric multicenter challenge study].

Purpose This study aimed to evaluate the utility of the Allerport® HRT in the diagnosis of hen's egg allergy. Method We enrolled 51 subjects who underwent the Allerport® HRT before an oral food challenge (OFC) consisting of heated egg. Blood samples were collected within three months prior to OFC to measure histamine release (HR) and specific IgE antibody titers. We examined whether the Allerport® HRT was useful as a means of diagnosing hen's egg allergy and predicting severity of induced symptoms. Of 51 subjects, three whose OFC results were not valid**1** and 13 who were classified as "low responders" to the Allerport® HRT (%HR due to anti-IgE below 20%) were excluded. Of the remaining 35 subjects (average age: 4 years), 23 showed positive reactions to the OFC. Quantities of histamine released in spontaneous HR and egg white (EW)- and ovomucoid (OVM)-induced HR were significantly higher in patients with positive reactions. In our receiver operating characteristic analysis, the area under the curve for %HR against 6 ng/ml of EW was 0.9601 and that against 3 ng/ml of OVM was 0.9022. The cutoff value was 15.0% for EW and 3.7% for OVM. The sensitivity was 95.7% for EW and 91.3% for OVM, and the specificity was 83.3% for EW and 58.3% for OVM. %HR correlated well with the severity of induced symptoms in the OFC. Conclusion Allerport® HRT is useful for the diagnosis of hen's egg allergy, and may also aid in predicting the severity of induced symptoms.

Allergen analysis of sea urchin roe using sera from five patients.

BACKGROUND: Sea urchin roe can cause anaphylactic reactions the first time they are consumed; therefore, careful clinical attention should be paid to their effects. However, no previous study has examined the allergens in sea urchin roe using sera from more than one patient. We attempted to identify sea urchin allergens using sera from 5 patients with sea urchin allergies. METHODS: We enrolled 5 patients with relevant medical histories, positive results on a skin prick test and/or a food challenge test, and high levels of sea urchin-specific IgE in an enzyme-linked immunosorbent assay. We performed SDS-PAGE, immunoblotting, immunoblot inhibition, and N-terminal amino acid sequence detection. RESULTS: Ten protein bands ranging from 18 to 170 kDa were detected in more than 2 patients' sera. In immunoblotting, the protein band for the 170-kDa major yolk protein was recognized by 4 of the 5 sera. Furthermore, the reaction between IgE and the protein band for egg cortical vesicle protein (18 kDa) was inhibited by the addition of salmon roe extract. CONCLUSION: Major yolk protein was confirmed to be one of the main allergens in sea urchin roe. In addition, egg cortical vesicle protein (18 kDa) was demonstrated to be an important protein for cross-reactivity with salmon roe.

Japanese pediatric guideline for the treatment and management of bronchial asthma 2012.

A new version of the Japanese pediatric guideline for the treatment and management of bronchial asthma was published in Japanese at the end of 2011. The guideline sets the pragmatic goal for clinicians treating childhood asthma as maintaining a "well-controlled level" for an extended period in which the child patient can lead a trouble-free daily life, not forgetting the ultimate goal of obtaining remission and/or cure. Important factors in the attainment of the pragmatic goal are: (i) appropriate use of anti-inflammatory drugs; (ii) elimination of environmental risk factors; and (iii) educational and enlightening activities for the patient and caregivers regarding adequate asthma management in daily life. The well-controlled level refers to a symptom-free state in which no transient coughs, wheezing, dyspnea or other symptoms associated with bronchial asthma are present, even for a short period of time. As was the case in the previous versions of the guideline, asthmatic children younger than 2 years of age are defined as infantile asthma patients. Special attention is paid to these patients in the new guideline: they often have rapid exacerbation and easily present chronic asthmatic conditions after the disease is established.

Japanese Guideline for Food Allergy 2014.

A food allergy is defined as "a phenomenon in which adverse reactions are caused through antigen-specific immunological mechanisms after exposure to given food." Various symptoms of food allergy occur in many organs. Food allergies are classified roughly into 4 clinical types: (1) neonatal and infantile gastrointestinal allergy, (2) infantile atopic dermatitis associated with food allergy, (3) immediate-type food allergy (urticaria, anaphylaxis, etc.), and (4) food dependent exercise-induced anaphylaxis and oral allergy syndrome (i.e., specific forms of immediate food allergy). The therapy for food allergies includes treatment of and prophylactic measures against hypersensitivity such as anaphylaxis. A fundamental prophylactic measure is the elimination diet. However, elimination diets should be used only if necessary because of the patient-related burden. For this purpose, it is very important that causative foods be accurately identified. There are a number of means available to identify causative foods, including the history taking, a skin prick test, detection of antigen-specific IgE antibodies in the blood, the basophil histamine release test, the elimination diet test, and the oral challenge test, etc. Of these, the oral challenge test is the most reliable. However, it should be conducted under the supervision of experienced physicians because it may cause adverse reactions, such as anaphylaxis.

Japanese Guideline for Food Allergy 2014.

A food allergy is defined as "a phenomenon in which adverse reactions are caused through antigen-specific immunological mechanisms after exposure to given food." Various symptoms of food allergy occur in many organs. Food allergies are classified roughly into 4 clinical types: (1) neonatal and infantile gastrointestinal allergy, (2) infantile atopic dermatitis associated with food allergy, (3) immediate-type food allergy (urticaria, anaphylaxis, etc.), and (4) food dependent exercise-induced anaphylaxis and oral allergy syndrome (i.e., specific forms of immediate food allergy). The therapy for food allergies includes treatment of and prophylactic measures against hypersensitivity such as anaphylaxis. A fundamental prophylactic measure is the elimination diet. However, elimination diets should be used only if necessary because of the patient-related burden. For this purpose, it is very important that causative foods be accurately identified. There are a number of means available to identify causative foods, including the history taking, a skin prick test, detection of antigen-specific IgE antibodies in the blood, the basophil histamine release test, the elimination diet test, and the oral challenge test, etc. Of these, the oral challenge test is the most reliable. However, it should be conducted under the supervision of experienced physicians because it may cause adverse reactions, such as anaphylaxis.

Effect of Japanese cedar specific immunotherapy on allergen-specific T(H)2 cells in peripheral blood.

BACKGROUND: The involvement of a shift from TH2 to TH1 responses in peripheral blood in pollen subcutaneous immunotherapy (SCIT) has been contentious, partly because of difficulties analyzing antigen-specific TH cells. OBJECTIVES: To use recent technical advances to establish a more direct and simple method to analyze antigen-specific TH cells and to clarify the involvement of a TH2/TH1 shift in peripheral blood in pollen specific immunotherapy. METHODS: After short-term (6-hour) antigen stimulation, antigen-specific TH cells in peripheral blood of Japanese children and young adults with Japanese cedar pollinosis undergoing SCIT were analyzed by multicolor flow cytometry for the presence of the activation marker CD154 and intracellular cytokines. RESULTS: Twenty-eight patients between 5 and 22 years of age were enrolled in the study; 22 had started SCIT after enrolling in the study (SCIT group), and the remaining 6 were planning to start SCIT in the next off-season (control group). The number of Japanese cedar-specific interleukin (IL) 5-, IL-4-, interferon γ-, IL-17A-, IL-10-, and tumor necrosis factor α-producing TH cells without antigen-driven cell proliferation was determined. The seasonal increase in the number of Japanese cedar-specific IL-5- and IL-4-producing TH cells seen in the control group was suppressed in the SCIT group (P < .005 and <.001, respectively). CONCLUSION: We report a powerful method for the analysis of antigen-specific TH cells in peripheral blood. This method will contribute to our understanding of immune mechanisms of immunotherapy and help us develop more sophisticated allergen specific immunotherapy.

Evaluation of the luciferase assay-based in vitro elicitation test for serum IgE.

BACKGROUND: An in vitro elicitation test employing human high-affinity IgE receptor-expressing rat mast cell lines appears to be a useful method for measuring mast cell activation using a patient's IgE and an allergen; however, such cell lines are sensitive to human complements in the serum. We have recently developed a new luciferase-reporting mast cell line (RS-ATL8) to detect IgE crosslinking-induced luciferase expression (EXiLE) with relatively low quantities of serum IgE. METHODS: A total of 30 patients suspected of having egg white (EW) allergy were subjected to an oral food challenge (OFC) test; then, the performances of EW-specific serum IgE (CAP-FEIA), EW-induced degranulation, and EXiLE responses in RS-ATL8 cells were compared using receiver-operating characteristic (ROC) curve analysis. The patients' sera were diluted to 1 : 100, which causes no cytotoxicity when sensitizing the RS-ATL8 cells for the degranulation and EXiLE tests. RESULTS: The area under the ROC curves was highest in the EXiLE test (0.977), followed by CAP-FEIA (0.926) and degranulation (0.810). At an optimal cutoff range (1.648-1.876) calculated from the ROC curve of the EXiLE test, sensitivity and specificity were 0.944 and 0.917, respectively. A 95% positive predictive value was given at a cutoff level of 2.054 (fold increase in luciferase expression) by logistic regression analysis. CONCLUSIONS: In contrast to in vivo tests, the EXiLE test appears to be a useful tool in diagnosing patients suspected of having IgE-dependent EW allergy without the risk of severe systemic reactions.

Generation of transgenic rice lines with reduced contents of multiple potential allergens using a null mutant in combination with an RNA silencing method.

Rice seed proteins are known to be a causative antigen in some patients with food allergy, especially cereal allergy, with clinical symptoms such as eczema and dermatitis. The α-amylase/trypsin inhibitors (14-16 kDa), α-globulin (26 kDa) and ß-glyoxalase I (33 kDa) are regarded as major potential allergens of rice (Oryza sativa L.) seed based on specific recognition by serum IgE from allergy patients. In order to suppress the production of these major allergens in rice grains, a mutant in the 'Koshihikari' background lacking the 26 kDa allergen (GbN-1) was used as a host for RNA silencing. A binary vector harboring two RNA interference (RNAi) gene cassettes for suppression of 14-16 kDa and 33 kDa allergens driven by the 13 kDa and 10 kDa prolamin endosperm-specific promoters, respectively, was introduced into the GbN-1 genome by Agrobacterium-mediated transformation. In the most promising transgenic line, the content of the three potential allergens was remarkably reduced to a very faint level without a change in seed phenotype. IgE binding of 15 patients' sera to the transgenic rice seed mostly deficient in the three major allergens was on average only about 10% that of the control wild-type rice, suggesting that these three accounted for the great majority of rice seed causative allergens recognized by patients' IgE and that the sequential allergen deletion/reduction strategy works in the development of hypo-allergenic rice lines.

Effects of oral administration of Lactobacillus acidophilus L-92 on the symptoms and serum markers of atopic dermatitis in children.

BACKGROUND: Few studies have investigated the complementary effects of long-term oral administration of Lactobacillus acidophilus on traditional medical therapy in the treatment of patients with atopic dermatitis (AD). METHODS: The Atopic Dermatitis Area and Severity Index was used to evaluate AD severity. Symptom severity was assessed using the symptom score. The effect of medical therapy was evaluated by adding the medication score, calculated as the sum of each product of the amount of steroid ointment used for therapy and its designated strength graded on a 4-point scale, to the symptom score. The complementary effect of long-term oral administration of L. acidophilus strain L-92 (L-92) as a probiotic or biogenic strain in patients with AD was evaluated using the symptom-medication score, which was calculated as the sum of the symptom score and medication score. Both a preliminary casuistic study and a double-blinded, placebo-controlled study were performed to evaluate the effects of L-92 on the symptoms of AD in children. RESULTS: Orally administered L-92 significantly ameliorated the symptoms of AD in Japanese children. L-92 also affected the serum concentrations of thymus and activation-regulated chemokine in a time-dependent manner. CONCLUSIONS: The results of the preliminary trial and the double-blinded, placebo-controlled study revealed a complementary effect of oral L-92 on the standard medical therapy (topical application of a steroid ointment) in patients with AD that was mediated, at least in part, by alterations in the Th1/Th2 balance.

Japanese guideline for food allergy.

Food allergy is defined as "a phenomenon in which adverse reactions (symptoms in skin, mucosal, digestive, respiratory systems, and anaphylactic reactions) are caused in living body through immunological mechanisms after intake of causative food." Various symptoms of food allergy occur in many organs. Food allergy falls into four general clinical types; 1) neonatal and infantile gastrointestinal allergy, 2) infantile atopic dermatitis associated with food allergy, 3) immediate symptoms (urticaria, anaphylaxis, etc.), and 4) food-dependent exercise-induced anaphylaxis and oral allergy syndrome (i.e., specific forms of immediate-type food allergy). Therapy for food allergy includes treatments of and prophylactic measures against hypersensitivity like anaphylaxis. A fundamental prophylactic measure is the elimination diet. However, elimination diets should be conducted only if they are inevitable because they places a burden on patients. For this purpose, it is highly important that causative foods are accurately identified. Many means to determine the causative foods are available, including history taking, skin prick test, antigen specific IgE antibodies in blood, basophil histamine release test, elimination diet test, oral food challenge test, etc. Of these, the oral food challenge test is the most reliable. However, it should be conducted under the supervision of experienced physicians because it may cause adverse reactions such as anaphylaxis.