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Allergenicity to heated egg yolks is known to be low in hen's egg allergy. However, there are few reports concerning the safety of an oral food challenge (OFC) with boiled egg yolks. This study aimed to determine the safety of a boiled egg yolk OFC and the clinical characteristics of patients who were OFC-positive.We retrospectively examined the data of patients who underwent an OFC with one boiled egg yolk at Miyagi Children's Hospital between January 2013 and December 2020. Patients were included if they had a history of immediate symptoms due to hen's egg or positive specific IgE levels to egg yolk or egg white.Among 600 patients, 15.0% were positive for OFC, only one patient required an intramuscular adrenaline injection, and 70% of OFC-positive patients had gastrointestinal symptoms.Boiled egg yolk OFC had a low symptom induction rate; however, when symptoms were induced, gastrointestinal symptoms were most commonly observed. Given the low risk of developing severe symptoms, we conclude that the likelihood of safely performing an OFC is high.

Hen’s eggs are one of the most common causes of food allergy. Although hen’s eggs are known to cause more gastrointestinal symptoms than other foods, it is not known whether there is a difference in organ-specific symptoms between egg yolk (EY) and egg white (EW). The present study aimed to determine whether there are organ-specific differences in the immediate symptoms of EY and EW in patients with hen’s egg allergies. We retrospectively investigated the immediate symptoms and treatment contents of those who had a positive result in an oral food challenge (OFC) of boiled whole EY or 10 g of boiled EW in our hospital from January 2013 to July 2019. We compared 80 patients in the EY-OFC-positive group with 106 patients in the EW-OFC-positive group. The EY-OFC-positive group had significantly fewer respiratory symptoms and significantly more gastrointestinal symptoms than the EW-OFC-positive group and had significantly more gastrointestinal symptoms only. In terms of treatment, significantly fewer patients in the EY-OFC-positive group required beta 2-agonist inhalation, and a significantly higher proportion of patients did not require treatment. Compared to EW, EY is more likely to cause gastrointestinal symptoms and less likely to cause respiratory symptoms. It may be necessary to discriminate between EY and EW allergy during diagnosis.

Background There are expanding indications for oral food challenges (OFCs). Although several studies have examined the risk of OFCs, little has been reported on allergic reactions during OFCs depending on the indication. This study assessed the prevalence, severity, and treatment of allergic reactions depending on the indication for OFCs. Methods We performed a prospective multicenter study between March 2012 and May 2013. Severity of symptoms elicited by OFCs was classified according to grading of anaphylaxis that ranges from grade 1 (most mild) to grade 5 (most severe). Results A total of 5062 cases (median age, 3.8 years; males, 65.2%) were analyzed. Allergic reactions were elicited in 2258 (44.6%) OFCs, of which 991 (43.9%) were classified as grade 1, 736 (32.6%) were classified as grade 2, 340 (15.1%) were classified as grade 3, and 191 (8.5%) were classified as grade 4-5. Epinephrine was administered in 7.1% (n = 160) of positive OFCs. Among the top three most common food allergens (hen's egg, cow's milk, and wheat), severity differed significantly depending on the indication for OFC, and adjusted standardized residuals indicated that severity of allergic reactions was higher for the indication to assess threshold level for oral immunotherapy. In addition, the prevalence of epinephrine use was highest for the indication to determine safe intake quantity. Conclusions Our study suggested that prevalence, severity, and treatment of allergic reactions differ depending on the indication for OFC. Further studies are needed to determine differences in risks depending on the indication for OFC.

Standard therapy for food allergies involves avoiding causative foods until a patient has outgrown their allergies. Oral immunotherapy (OIT) is an optional treatment for children unlikely to outgrow their food allergy. However, information about OIT in adult patients with food allergies is very limited. We present a case of severe hen's egg allergy (HEA) in an adult who tried home-based, slow up-dosing OIT, reported to have been tolerable and effective in children. A 20-year-old woman with HEA experienced repeated anaphylaxis since childhood when she consumed a small quantity of hen's egg, so she completely avoided hen's eggs. She underwent inpatient oral food challenge (OFC) with 10-g boiled egg yolk and presented lip swelling and abdominal pain. OFC with 1-g boiled egg yolk the following day induced no adverse reaction. OIT was initiated using a home-based, slow up-dosing protocol. She consumed 1 g of boiled egg yolk at home every day, increasing this by 5%-10% every 2 weeks. She started 0.5-g boiled egg white after reaching a whole egg yolk. If adverse reactions occurred, the daily dose was decreased. After 59 months, she was able to eat an entire boiled egg. Anaphylaxis occurred 3 times during OIT due to accidental consumptions of egg products or insufficient heating of egg. Home-based, slow up-dosing OIT might be applicable for adults with severe HEA. It should be performed with appropriate equipment and education for patients, in case of emergency.

Maintenance therapy of atopic dermatitis (AD) with frequent exacerbations needs proactive use of topical corticosteroids or topical calcineurin inhibitors. However, it can be difficult for children in an unfavorable family environment. Home-visit nursing service (HVNS) plays an important role in delivering care to people who need medical help at home. We report a boy in a difficult family situation who received HVNS to successfully manage AD.

Background While Japanese guideline recommends initial control treatment for preschool children with asthma symptoms more than once a month, Western guidelines do not. To determine whether control treatment with montelukast was more effective than as-needed β 2 -agonists in this population, we conducted a randomized controlled trial. Methods Eligible patients were children aged 1–5 years who had asthma symptoms more than once a month but less than once a week. Patients were randomly assigned in a 1:1 ratio to receive montelukast 4 mg daily for 48 weeks or as-needed β 2 -agonists. The primary endpoint was the number of acute asthma exacerbations before starting step-up treatment with inhaled corticosteroids. This study is registered with the University Hospital Medical Information Network clinical trials registry, number UMIN000002219. Results From September 2009 to November 2012, 93 patients (47 in the montelukast group and 46 in the no-controller group) were enrolled into the study. All patients were included in the analysis. During the study, 13 patients (28%) in the montelukast group and 23 patients (50%) in the no-controller group had acute exacerbations with the mean numbers of 0.9 and 1.9/year, respectively ( P = 0.027). In addition, 10 (21%) and 19 (41%) patients received step-up treatment, respectively. Cumulative incidence of step-up treatment was significantly lower in the montelukast group (hazard ratio 0.45, 95% confidence interval 0.21 to 0.92; P = 0.033). Conclusions Montelukast is an effective control treatment for preschool children who had asthma symptoms more than once a month but less than once a week.

We aim to examine the characteristics of the symptoms induced by exercise provocation tests following allergen consumption in patients who have undergone oral immunotherapy (OIT).Patients who were positive for exercise provocation tests in Miyagi Children's Hospital from April 2012 to January 2019 were retrospectively analyzed. Patients were classified into food-dependent exerciseinduced anaphylaxis (FDEIA) group and post-OIT-FDEIA group.Six patients in the FDEIA group and 19 patients in the post-OIT-FDEIA group were analyzed. There were no significant differences in age, sex, and number of complications between the FDEIA and post-OIT-FDEIA groups, except for level of total serum immunoglobulin E. The median time from the start of exercise to onset of symptoms was 20 min in the FDEIA group and 25 min in the post-OIT-FDEIA group. The rate of adrenaline administration in post-OIT-FDEIA group was significantly lower. The median time from exercise to onset of severe symptoms requiring adrenaline was 32.5 min in the FDEIA group and 25 min in the post-OIT-FDEIA group.These data suggest that FDEIA and post-OIT-FDEIA patients can exhibit similar clinical symptoms, and all symptoms occurred in 60 minutes after exercise.

Oral immunotherapy (OIT) for food allergy requires exercise restrictions following the regular consumption of allergens to prevent immediate symptoms. We investigated the efficacy and the safety of exercise provocation tests to assess exercise tolerance after consumption of allergens following OIT.This study was based on data from patients who underwent exercise provocation tests with consumption of their allergen after OIT in Miyagi Children's Hospital between April 2012 and March 2019. The results of exercise provocation tests and patients' characteristics were retrospectively analyzed.Fifteen out of 91 patients were positive for exercise provocation tests. The positive rates were 12% (4/33) with egg, 15% (5/34) with cow's milk, and 25% (6/24) with wheat. Intramuscular adrenaline injections were administered to two patients with allergies to egg, one with cow's milk, and one with wheat.Following OIT, the assessment using exercise provocation tests should be performed prior to termination of exercise restriction because some patients remain intolerant to exercise.

Hen's egg is the most common allergen in IgE-mediated food allergy among children in Japan. Although the majority of patients with egg allergy can eat heated egg yolk safely because of its low allergenicity, severely allergic patients show an immediate-type reaction to heated egg yolk. We hypothesized that patients with hyperresponsiveness to boiled egg yolk may have difficulty in acquiring tolerance to egg. The purpose of this study was to examine the prognosis of patients with hyperresponsiveness to boiled egg yolk. Data from 121 patients with egg allergy who underwent oral food challenge (OFC) with boiled egg yolk between January 2012 and December 2013 were analyzed retrospectively. The proportion of patients who could consume heated whole egg 3 years after OFC was 15.4% in the OFC-positive group and 75.8% in the OFC-negative group. Hyperresponsiveness to boiled egg yolk in early life might lead to prolonged egg allergy in children. This finding might aid in the selection of an appropriate population requiring practical immunotherapy.

Background: In September 2015, Japan experienced an unusual increase in acute asthma hospitalizations of children that coincided with an enterovirus D68 (EV-D68) epidemic. The objective of this study is to investigate whether EV-D68 had a causal relationship with the spike in asthma hospitalizations. Methods: A nation-wide retrospective survey of asthma hospitalizations of children was performed for the period from January 2010 through October 2015. The Japanese Society of Pediatric Allergy and Clinical Immunology asked its affiliated hospitals to report monthly numbers of hospitalizations, ICU admissions and mechanical ventilations due to acute asthma exacerbation. The data were retrieved from medical databases using predefined search criteria: diagnosis of asthma or asthmatic bronchitis, admission, and age

IL-3 is a potent priming cytokine for human basophils, inducing an increase of mediator release after stimulation. The mechanism of IL-3 priming of the basophil response to FcεRI aggregating stimuli remains unknown. We explored the regulation of several elements of IgE-mediated signaling by a short priming with IL-3. Early signaling events such as phosphorylation of Syk, Shc, linker for activation of T cells, and the calcium signal were not statistically affected by acute IL-3 priming. Downstream in the signaling cascade, a point of up-regulation was found at the level of Raf-1-Mek-Erk. Although the phosphorylation of Raf-1 was not changed by IL-3 priming, IL-3-primed anti-IgE-stimulated basophils showed a strong synergism for Mek and Erk phosphorylation when compared with either IL-3 or anti-IgE alone; pre-exposure to IL-3 induced a final 13-fold average increase over anti-IgE-induced Erk phosphorylation (6-fold above the sum of anti-IgE and IL-3 alone). The kinetics, dose response, and pharmacologic characteristics of the IL-3 priming of stimulus-induced Erk phosphorylation support the involvement of a yet unknown mechanism that is independent of IL-3-induced Erk and PI3K activation. This type of preactivation can be mimicked by incubation with the Ser-Thr kinase inhibitors, Ro-81–3220, or bisindoylmaleimide II.

Background Syk kinase is probably an early necessary tyrosine kinase involved in IgE-mediated secretion from human basophils. Causal testing of the role of syk kinase in the secretion requires a selective pharmacological agent. Piceatannol has previously been used to demonstrate the causal role of syk in secretion but its selectively has recently come into question. Objective To determine whether piceatannol inhibits IgE-mediated signalling events in a manner consistent with its putative inhibitory effects on syk kinase and at concentrations relevant to its inhibition of mediator release. Methods Human basophils were examined for the effects of piceatannol on mediator release or various signalling steps. Results We show that while piceatannol has an IC50 for inhibition of IgE-mediated histamine release of 3–5 µm, these same concentrations inhibit secretion of phorbol 12-myristate 13-acetate (PMA)-induced histamine release (as previously shown) and leukotriene C (LTC)4 release induced by fMLP. Concentrations of piceatannol up to 100 µm also did not inhibit IgE-mediated phosphorylation of shc, a immediate downstream target of syk kinase. Similar concentrations also did not inhibit IgE-mediated cytosolic calcium elevations, another downstream signal thought to be dependent on syk kinase. In contrast, piceatannol did modify the cytosolic calcium response that follows stimulation with formyl methionyl-leucyl-phenylalanine (fMLP). Conclusion Taken together with published studies using other cell types, we conclude that piceatannol does not inhibit secretion from human basophils by inhibiting the activity of syk kinase.

Previous studies have indicated a redundancy in the effects of the cytokines, IL-3, IL-5, and nerve growth factor (NGF) on acute priming of human basophils. In the current study, we have examined the effects of these three cytokines on 18-h priming for leukotriene C4 generation, their ability to induce FcεRIβ mRNA expression, or their ability to sustain basophil viability in culture. We also examine a variety of the signaling steps that accompany activation with these cytokines. In contrast with the ability of IL-3 to alter secretagogue-mediated cytosolic calcium responses following 18-h cultures, 18-h treatment with IL-5 or NGF did not affect C5a-induced leukotriene C4 generation or alter C5a-induced intracellular Ca2+ concentration elevations. IL-3 and IL-5, but not NGF, induced FcεRIβ mRNA expression and all three improved basophil viability in culture with a ranking of IL-3 > IL-5 ≥ NGF. All three cytokines acutely activated the extracellular signal-regulated kinase pathway and the signaling elements that preceded extracellular signal-regulated kinase and cytosolic phospholipase A2 phosphorylation, consistent with their redundant ability to acutely prime basophils. However, only IL-3 and IL-5 induced Janus kinase 2 and STAT5 phosphorylation. This pattern of signal element activation among the three cytokines most closely matched their ability to induce expression of FcεRIβ mRNA. Induction of the sustained calcium signaling that follows overnight priming with IL-3 appeared to be related to the strength of the early signals activated by these cytokines but the relevant pathway required was not identified. None of the signaling patterns matched the ability of the cytokines to promote basophil survival.

IgE-mediated down-regulation of secretion from basophils and mast cells is an important component of the overall cellular response that determines the ultimate extent of mediator release. The down-regulatory process that occurs during active secretion has also been associated with the methodological phenomenon called desensitization, but the mechanisms underlying desensitization are not understood. A variety of studies have suggested that activation of protein kinase C (PKC) results in down-regulation of IgE-mediated secretion so we have examined the effect of the PKC inhibitors Ro-31-8220 (3-[1-[3-amidinothio)propyl-1H-indol-3-yl]-3-(1-methyl-1H-indol-3- yl) maleimide) and bis-indolylmaleimide II on desensitization in human basophils. At concentrations that have been shown previously to inhibit PKC-mediated functions in basophils completely, these two drugs had no effect on IgE-mediated desensitization. We did find, however, that the src-family kinase inhibitors PP1 [4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine] and PP2 [4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3, 4-d]pyrimidine] inhibited desensitization as well as secretion. These data suggest that PKC has little role in down-regulating the IgE-mediated basophil response. However, like the activation signaling cascade, the desensitization process is dependent on the activation of src family kinases.