A 60-minute dosing interval is safer than a 30- or 40-minute interval in oral food challenge.

BACKGROUND: The interval between antigen ingestion may influence the safety of oral food challenge tests (OFCs), especially in patients with severe food allergies. METHODS: This retrospective chart review of OFCs eliciting objective reactions to wheat, egg, and milk that were performed between April 2012 and January 2021 evaluated an equivalent number of low-dose OFCs performed at 30-, 40-, or 60-min intervals. To avoid the influence of the potential allergy severity of the patients, the prediction scores of all intervals were matched. We evaluated the total symptom score (TS), total ingested dose, and the proportions of severe reactions (TS ≥ 30) and adrenaline use. RESULTS: We analyzed 945 OFCs (wheat, n = 186; egg, n = 561; milk, n = 198). The 60-min OFC had significantly lower TS than the 30- and 40-min OFC methods in wheat (p < 0.001 and p = 0.003, respectively), egg (p < 0.001 for both), and milk (p < 0.001 and p = 0.018, respectively). The total dose in the 60-min method was significantly lower than in the 30-min method (p < 0.001 for all). The proportion of severe reaction (TS ≥ 30) in the 60-min method was significantly lower than that in the 30-min method for the egg and milk OFCs (p = 0.001 and p < 0.001, respectively). There was no difference in the rates of adrenaline injection. CONCLUSIONS: The 60-min interval is safer than 30- or 40-min intervals in wheat, egg, and milk OFCs in patients with a low threshold dose for food allergy.

The clinical cross-reactivity and immunological cross-antigenicity of wheat and barley.

BACKGROUND: Some patients with wheat allergy have been reported to show clinical cross-reactivity to barley. However, it is not clear whether the development of barley allergy in patients with wheat allergy is due to cross-antigenicity between wheat and barley. This study aimed to determine the clinical cross-reactivity and immunological cross-antigenicity of wheat and barley. METHODS: The results of barley oral food challenges (OFCs) were compared before and after oral immunotherapy (OIT) for wheat in nine patients with wheat allergy to estimate the clinical cross-reactivity of wheat and barley. Moreover, we performed enzyme-linked immunosorbent assay (ELISA) inhibition and immunoblotting inhibition using serum from seven patients allergic to wheat and barley. RESULTS: Nine patients who had positive barley-OFC results performed before OIT for wheat were all negative on barley-OFC performed after OIT. In ELISA inhibition, preincubation of serum from patients allergic to wheat and barley with a high barley extract concentration inhibited binding of IgE to wheat extract by less than 10%. On the other hand, wheat and barley extracts equally inhibited binding to barley sIgE at high concentrations. In the immunoblotting inhibition test, the spots of wheat were inhibited but weakly by barley extracts, and most of the spots of barley were inhibited even by low concentrations of the wheat and barley extract. CONCLUSIONS: We showed that barley allergy associated with wheat allergy is caused by cross-reactivity from wheat. The OIT for wheat is one of the promising options for barley allergy.

[COMPARISON OF WHEAL SIZE INDUCED BY BIFURCATED NEEDLE® AND SMARTPRACTICE® PRICK LANCET].

BACKGROUND: There is reportedly a difference in the diameter of the skin reaction induced by different types of skin prick test (SPT) devices. We compared the SPT diagnostic accuracy and wheal size between a Bifurcated Needle® (BN) and SmartPractice® Prick Lancet (PL), which are commercially available in Japan. METHODS: An SPT was performed on 15 adults with and 10 without subjective symptoms of cedar pollinosis who wished to be examined for Japanese cedar pollen (JCP) sensitization. The SPT was performed blindly with a BN or PL with 10mg/ml of histamine dihydrochloride, 50% glycerosaline control, and JCP extract solution (TORII PHARMACEUTICAL CO., LTD., Tokyo, Japan). The wheal sizes induced by the BN and PL were then compared. The JCP-specific IgE antibody titer was measured to compare the sensitivity and specificity of the SPT. RESULTS: Histamine wheal diameters were 6.0 (5.5-6.5) mm by BN and 6.0 (5.5-6.5) mm by PL (p=0.67), and none of the negative control solutions induced wheal. The respective sensitivity and specificity for cedar sensitization were 100% and 86% for BN, 100% and 79% for PL, and the areas under the ROC curve were 0.72 and 0.69 (p=0.32). CONCLUSION: The diagnostic accuracy of cedar pollen extract based on specific IgE-JCP sensitization and the diameter of the wheal produced by a BN and PL were considered equivalent.

Purification and molecular characterization of a truncated-type Ara h 1, a major peanut allergen: oligomer structure, antigenicity, and glycoform.

Peanut allergies are among the most severe food allergies, and several allergenic proteins referred to as Ara h 1-Ara h 17 have been identified from peanut seeds. The molecular characterization of Ara h 1 (63 kDa), a glycosylated allergen, has almost been completed, and the occurrence of two homologous genes (clone 41B and clone P17) has been identified. In this study, we found a new variant of Ara h 1 i.e. 54 kDa, in which the N-terminal amino acid sequence was EGREGEQ-, indicating that the N-terminal domain of 63 kDa Ara h 1 had been removed. This new isoform was obtained from the run-through fraction of hydrophobic interaction chromatography while 63 kDa Ara h 1 was tightly bound to the hydrophobic resins, suggesting that the removal of the N-terminal domain resulted in extreme hydrophilic properties. We found that 63 kDa Ara h 1 occurs as higher order homo-oligomeric conformations such as decamer or nonamer, while 54 kDa Ara h 1 occurs exclusively as a homotrimer, indicating that the N-terminal domain of the 63 kDa molecule may be involved in higher order oligomerization. When antisera from peanut-allergic patients were treated with both the Ara h 1 molecules, the immunoglobulin E (IgE) antibodies in these sera reacted with each Ara h 1 molecule, suggesting that the C-terminal as well as the N-terminal domains of Ara h 1 contribute significantly to the epitope formations of this peanut glycoallergen. Furthermore, the glycoform analyses of N-glycans linked to 63 kDa and 54 kDa Ara h 1 subunits revealed that both typical high-mannose type and ß-xylosylated type N-glycans are linked to the molecules. The cross-reactivity of IgE against Ara h 1 in the serum of one peanut allergy patient was completely lost by de-N-glycosylation, indicating the N-glycan of Ara h 1 was the sole epitope for the Ara h 1- specific IgE in the patient.

Exercise-induced allergic reactions after achievement of desensitization to cow's milk and wheat.

BACKGROUND: We have previously reported that more than half of the patients who achieved desensitization after wheat rush oral immunotherapy (OIT) developed exercise-induced allergic reaction on desensitization (EIARD). However, data on EIARDs after slow OIT are lacking. Therefore, this study aimed to investigate the results of exercise provocation tests (EPTs) in patients after slow OIT for cow's milk and wheat allergies. METHODS: This was a retrospective chart review of 87 EPTs in 74 patients. The EPTs were performed in patients who were desensitized to at least 6,600 mg cow's milk protein or 5,200 mg wheat protein with slow OIT and were identified to be at a high risk of EIARDs. EPTs were performed after ingestion of the maximum desensitization dose. The patients' clinical characteristics and symptoms were analyzed. RESULTS: The EPT results were positive for cow's milk in 49% (21/43) of the patients and for wheat in 48% (15/31) of the patients. There was no significant difference in the clinical characteristics between the EIARD-positive and EIARD-negative groups. The specific IgE (sIgE) levels before OIT and the reduction rates of sIgE before and after OIT did not correlate with the outcomes of the EPTs. Among the EIARD-positive patients, 13 patients (cow's milk, n = 7; wheat, n = 6) underwent a second EPT, and the EIARD disappeared in 8 patients (cow's milk, n = 4; wheat, n = 4). CONCLUSION: EIARDs were observed after slow OIT for cow's milk and wheat. Further research into the predictive factors of EIARDs in these patients is needed to understand its clinical manifestations.

Efficacy, safety, and parental anxiety in a randomized trial of two dietary instruction methods for children with suspected hen's egg allergy.

BACKGROUND: Little has been reported on how to introduce hen's egg into the diet of children with suspected egg allergy. We compared the efficacy, safety, and parental anxiety of two different dietary instruction methods to introduce egg. METHODS: Eligible participants were children aged 1-4 years who were positive for egg white IgE, and ovomucoid IgE <3.5 kUA/L. Participants were either naïve in egg consumption or had a history of an immediate, but non-anaphylactic, allergic reaction to egg. After a negative result of baseline 2 g boiled egg white oral food challenge (OFC), participants were randomly assigned to the step-up OFC testing (SOFT) or home incrementing group. The primary outcome was the proportion of participants who were able to ingest 20 g of boiled egg white 6 months after initiation. This study is registered with the University Hospital Medical Information Network clinical trial registry (UMIN000024192). RESULTS: Between September 2016 and August 2018, we randomly allocated 55 participants to the SOFT (n = 33 [60%]) and home incrementing (n = 22 [40%]) groups and analyzed 51 patients. Four patients were excluded because they were lost to follow-up. Thirty-one (96.9%) of 32 participants in the SOFT and 12 (63.2%) of 19 in the home incrementing group achieved the primary outcome (p = 0.003). No serious adverse reactions were observed in either group. Parental anxiety significantly improved during treatment in both groups. CONCLUSIONS: The SOFT method was more effective than home incrementing as dietary instruction to introduce egg in children with suspected egg allergy.

[A CASE OF PANCAKE SYNDROME IN WHICH MITES COULD BE DETECTED FROM COOKED TAKOYAKI].

A 12-year-old girl experienced anaphylactic shock and respiratory failure immediately after eating 4 pieces of takoyaki made at home. We suspected pancake syndrome because of the three reasons: First, the patient had a history of bronchial asthma and allergic rhinitis without any history of food allergies; Second, takoyaki flour that had been stored at room temperature for one month after opening the package had been used; and Third, both the specific IgE (ImmunoCAP® method) of Dermatophagoides farinae and Dermatophagoides pteronyssinus were found to be above the detection limit. Since the suspected flour had been discarded, a specimen of tako yaki was examined microscopically and 430 mites/g were identified. Although only 21.1ng/g of Der f 1 was detected by an ELISA, this amount was less than expected, based on the number of mites that had been observed. The decrease in the antigenicity of mite allergens due to heating and reducing agents, and the insolubilization of mite allergens due to disulfide bonds between the mite allergens and gluten were thought have made it difficult to identify mite antigens by ELISA.When pancake syndrome is suspected, and the flour that is thought to have caused the condition is difficult to obtain, microscopic identification of mites in cooked food should be considered.

Slow low-dose oral immunotherapy: Threshold and immunological change.

BACKGROUND: We examined the feasibility, efficacy and safety of slow low-dose oral immunotherapy (SLOIT) for egg, milk, wheat allergies, with accepted severity-stratified initial and maintenance doses. METHODS: Children with food allergies defined by low-dose oral food challenges (LD-OFCs) to hen's egg (cumulative protein dose up to 983 mg, n = 133), cow's milk (287 mg, n = 50), and wheat (226 mg, n = 45) were recruited. Participants were divided into two groups [SLOIT and control (complete avoidance]) based on their preferences. Participants who selected SLOIT were instructed to take the safe dose daily, with monthly increases, aiming to increase the dose by 10 times in one year. The primary outcome was the proportion of participants who passed the LD-OFCs following 1 year of therapy. RESULTS: The participants in SLOIT group ingested their antigen 92.9% of the therapy's day on average. The proportion of participants who passed LD-OFCs was 35.9% (61/170) in the SLOIT group and 8.7% (4/46) in the control group (P < .001); no large differences were observed among allergens. Among the subjects who failed LD-OFCs, the median change in the total dose in the LD-OFC was 235% (interquartile range: 100%-512%) in the SLOIT group and 100% (42%-235%) in the control group (P < .001). Provoked allergic symptoms were observed in only 0.58% (280/48,486) per programmed intake and approximately 50% of the SLOIT group did not experience any obvious allergic symptoms throughout therapy. CONCLUSIONS: SLOIT showed significant feasibility, efficacy and safety, providing a promising option to manage patients with severe food allergies.

Food allergy is linked to season of birth, sun exposure, and vitamin D deficiency.

The season of birth and ultraviolet B exposure have been related to the occurrence of food allergy. The levels of vitamin D produced from skin by ultraviolet B exposure might reflect this relationship. Vitamin D is known to induce antimicrobial peptides, protect intestinal flora, enhance the gut epithelial barrier, suppress mast cell activation and IgE synthesis from B cells, and increase the number of tolerogenic dendritic cells and IL-10-producing regulatory T cells. Vitamin D deficiency has been shown to exacerbate sensitization and allergic symptoms in a murine model of food allergy. However, in clinical situations, contradictory observations have been reported regarding the relationship between food allergy and vitamin D deficiency/supplementation. In this review, we have explored the links between food allergy and vitamin D levels. One explanation for the discrepant findings is confounding factors such as race, age, residency, skin color, and epigenetic changes that contribute to vitamin D levels. In addition, the season of birth influences the development of atopic dermatitis, which could lead to food sensitization. Finally, ultraviolet radiation could lead to regulatory T cell expansion and immunosuppression, irrespective of vitamin D status. Based on our current understanding, we believe that correction of vitamin D deficiency by supplementation, appropriate skin care, and sufficient ultraviolet radiation exposure could alter the prognosis of food allergy. To identify potential treatment strategies for food allergy, it is essential to gain a better understanding of the appropriate levels of vitamin D and ultraviolet radiation exposure.

[ORAL AND SYSTEMIC SYMPTOMS IN CHILDREN WITH FRUIT ALLERGY].

BACKGROUND AND PURPOSE: The principal aim of this study was to clarify the clinical profile of pediatric patients with fruit allergies. SUBJECTS AND METHODS: We assigned 265 pediatric patients with fruit allergies who were receiving outpatient treatment at Aichi Children's Health and Medical Center and 32 who underwent kiwi or banana oral food chal- lenge (OFC) test to an oral symptom group or a systemic symptom group and retrospectively examined their clinical profiles and prognosis from their medical records. RESULTS: The most common cause of fruit allergy was kiwi (139 patients, 21% of all patients). Watermelon had the highest oral symptom induction rate (97%), whereas banana had the highest systemic reaction induction rate (46%). In the oral symptom group, the prevalence of hay fever was 54% and 66% of patients showed aller- gic reaction to multiple fruits. In contrast, in the systemic symptom group, the prevalence of pollen allergies was 24% and 77% of patients showed allergic reaction to a single fruit only. The results revealed that 65% of patients allergic to bananas had infant-onset allergy and seven among 20 patients were confirmed acquisition of tolerability by the OFC test. CONCLUSION: Our data suggest that there is a difference in the clinical profile and disease type between patients with oral symptoms and those with primarily systemic symptoms. It is important to differentiate between these patients for accurate diet guidance, safety management, and prognosis estimation.

Jug r 1 sensitization in 0- to 35-month-old children with egg, milk, or wheat sensitization.

Background: The incidence of tree nut allergies in children is increasing, with walnut allergy being the most common in the United States and Japan. Allergic reactions, including anaphylaxis, frequently occur at the first intake of tree nuts, suggesting prior sensitization. Objective: Our aim was to identify which children should be considered for workup for preexisting sensitization. Methods: Juglans regia (Jug r) 1-specific IgE screening for 0- to 35-month-old children who had a positive specific IgE result for egg white, milk, or wheat and had never ingested walnuts was conducted at a food allergy referral hospital between November 2018 and December 2022. Clinical data regarding age; sex; allergic disease complications; and egg, milk, or wheat allergy were examined retrospectively. Results: The rate of Jug r 1-specific IgE positivity (level > 0.34 kUA/L) of 205 children (125 of whom were boys) was 9.8%, with a median Jug r 1-specific IgE level of 12.5 kUA/L in patients with a positive test result. Eczema was observed in 119 patients (58%). The rate of Jug r 1-specific IgE positivity was significantly higher in the eczema-positive group (15.1% [18 of 119]) than in the eczema-negative group (2.3% [2 of 86]) (P = .002). In the eczema-positive group, the rates of Jug r 1-specific IgE positivity per sensitized antigen were 13.7% for egg, 17.0% for milk, and 17.1% for wheat. The rate of Jug r 1-specific IgE positivity was significantly higher in the group with severe eczema (26.6% [17 of 64]) than in the group with nonsevere eczema (1.8% [1 of 55]) (P < .001). Conclusion: Even in children younger than 3 years, 15% of children with eczema and egg, milk, or wheat sensitization were sensitized to Jug r 1.

Exercise-Induced Allergic Reactions in Children Desensitized to Hen's Eggs and Cow's Milk by Oral Immunotherapy.

BACKGROUND: Exercise-induced allergic reactions on desensitization (EIARDs) after successful in-hospital rush oral immunotherapy (OIT) for wheat allergy have been reported. However, the incidence rates of EIARDs after rush OIT for egg allergy and milk allergy have not been determined. OBJECTIVE: To determine the frequency of EIARDs and risk factors associated with rush OIT for egg and milk allergy. METHODS: This retrospective chart review, conducted in January 2020, enrolled 64 and 43 patients who underwent rush OIT for egg and milk allergy, respectively (in 2010 to 2014). In particular, 48 and 32 desensitized patients underwent exercise-provocation tests (Ex-P) after allergen administration (4,400 mg boiled egg white and 6,600 mg cow's milk protein, respectively). The EIARDs were determined by Ex-P or a suspicious event even after passing the Ex-P. Specific IgE levels to egg white, cow's milk, ovomucoid, casein, α-lactalbumin, and ß-lactoglobulin were analyzed using ImmunoCAP. RESULTS: At least one episode of EIARD was observed in 10 and 17 patients with egg and milk allergy (21% and 53%), respectively, which persisted for more than 5 years in one patient with egg allergy (2.1%) and 11 patients with milk allergy (34.4%) as of January 2020. We could not find background differences between the EIARD-positive and EIARD-negative groups, except that the egg white-specific IgE/total IgE ratio before rush OIT was significantly higher in patients with egg allergy with EIARD than in those without it. CONCLUSIONS: Exercise-induced allergic reactions on desensitization were more frequent and common in patients with milk allergy. Moreover, EIARDs to milk allergy were more likely to persist than those to egg allergy.

A case of white bean allergy.

White bean allergy is uncommon and rarely reported. Herein, we report a case of white bean allergy in a patient with Down syndrome. A 7-year-old girl with Down syndrome experienced allergic symptoms twice after eating white bean and visited our hospital for a food allergy investigation. An ImmunoCAP assay revealed a white bean-specific IgE (13.4 kUA/L) in the patient's serum. In addition, her skin prick test result was positive. Moreover, ingestion of 2 g of boiled white beans in an oral food challenge test induced intermittent cough, desaturation, generalized urticaria, abnormal sleep, and mild hypotension. Thus, we diagnosed the patient with white bean allergy. We performed western blotting and mass spectrometric analysis and detected the following allergens: Phytohemagglutinin, group 3 late embryogenesis abundant protein, lipoxygenase, and legumin. In addition, we detected several candidate allergenic proteins for the first time. White bean, runner bean, or azuki bean was considered the primary source of sensitization because although immunoblotting inhibition tests revealed that the abovementioned beans inhibited other legumes, soybean, which she tolerates, showed little inhibition of the other legumes. However, we could not confirm whether the patient could ingest legumes other than soybean or white bean because her family did not wish to continue with further testing. This is the first report of a case of systemic allergic reactions to white bean in a child with Down syndrome. Further studies are needed to identify white bean allergens and understand the relationship between Down syndrome and white bean allergy.

Kestose Increases the Relative Abundance of Faecalibacterium spp. and Nominally Increases Cow Milk Tolerant Dose in Children with Cow's Milk Allergy - Preliminary Results.

A single-arm study was conducted with 10 children aged 2-12 years with severe cow's milk allergy (CMA) requiring complete allergen elimination. Subjects were administered kestose, a prebiotic, at 1 or 2 g/day for 12 weeks. Results of a subsequent oral food challenge (OFC) showed a statistically significant increase in the total dose of cow's milk ingestion (1.6 ml vs. 2.7 ml, p = 0.041). However, the overall evaluation of the OFC results, TS/Pro (total score of Anaphylaxis Scoring Aichi (ASCA)/cumulative dose of protein), showed no statistically significant improvement, although the values were nominally improved in seven out of 10 subjects. The 16S rDNA analysis of fecal samples collected from the subjects revealed a statistically significant increase in the proportion of Faecalibacterium spp. (3.8 % vs. 6.8%, p = 0.013), a type of intestinal bacterium that has been reported to be associated with food allergy. However, no statistically significant correlation was found between Faecalibacterium spp. abundance and the results of the OFC.

Evaluation of peripheral basophil activation during exercise provocation test for desensitized patients.

Some food allergic patients who have undergone oral immunotherapy develop exercise-induced allergic reactions on desensitization (EIARDs). This study investigated basophil activation status during the exercise provocation test (EPT) performed to diagnose EIARD. EPT was performed on 20 participants, and in vivo basophil activation status was analyzed using activation markers CD203c and CD63. The results showed that there was no significant difference between EPT-positive and negative subjects for basophil activation status throughout EPT. Consequently, in vivo basophil activation after ingestion of the causative food may not be associated with EIARDs. New tests are desired for predicting EIARDs.

Orally desensitized mast cells form a regulatory network with Treg cells for the control of food allergy.

Oral immunotherapy (OIT) is an effective approach to controlling food allergy. Although the detailed molecular and cellular mechanisms of OIT are unknown currently, they must be understood to advance the treatment of allergic diseases in general. To elucidate the mechanisms of OIT, especially during the immunological transition from desensitization to allergy regulation, we generated a clinical OIT murine model and used it to examine immunological events of OIT. We found that in mice that completed OIT successfully, desensitized mast cells (MCs) showed functionally beneficial alterations, such as increased induction of regulatory cytokines and enhanced expansion of regulatory T cells. Importantly, these regulatory-T-cell-mediated inhibitions of allergic responses were dramatically decreased in mice lacking OIT-induced desensitized MC. Collectively, these findings show that the desensitization process modulates the activation of MCs, leading directly to enhanced induction of regulatory-T-cell expansion and promotion of clinical allergic unresponsiveness. Our results suggest that efficiently inducing regulatory MCs is a novel strategy for the treatment of allergic disease.