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Background: The association between pet exposure in infancy, early childhood eczema, and FLG mutations remains unclear. Methods: This was a birth cohort study performed in Tokyo, Japan. The primary outcome was current eczema based on questionnaire responses collected repeatedly from birth to 5 years of age. Generalized estimating equations and generalized linear modeling were used to evaluate the association. Results: Data from 1448 participants were used for analyses. Household dog ownership during gestation, early infancy, and 18 months of age significantly reduced the risk of current eczema. Household cat ownership also reduced the risk of current eczema, albeit without statistical significance. The combined evaluation of children from households with pets, be it cats, dogs or both, the risk of current eczema at 1–5 years of age was lower in those with household pet exposure ownership during gestation (RR = 0.59, 95 % CI 0.45–0.77) and at 6 months (RR = 0.49, 95 % CI 0.36–0.68). , Reduced risks of eczema were also observed at 2–5 (RR = 0.52, 95 % CI 0.37–0.73) and 3–5 years of age (RR = 0.50 95 % CI 0.35–0.74) when the respective household pet ownership were evaluated at 18 months and 3 years of age. These protective associations of reduced risk of eczema were only observed in children without FLG mutations. Conclusions: Household dog and pet (dog, cat, or both) ownership was protective against early childhood eczema in a birth cohort dataset. This protective association was observed only in children without FLG mutations, which should be confirmed in studies with larger cohorts.

Background: Non-IgE-mediated gastrointestinal food allergies (non-IgE-GIFAs) seem to be increasing rapidly worldwide. However, nationwide studies have been limited to food-protein-induced enterocolitis (FPIES) and food-protein-induced allergic proctocolitis (FPIAP), with little attention to other non-IgE-GIFA subgroups. The aim of this study was to elucidate the clinical features of all patients with non-IgE-GIFAs, not just certain subgroups. Methods: We conducted a nationwide cross-sectional survey of non-IgE-GIFAs in Japan from April 2015 through March 2016. A questionnaire was sent to hospitals and clinics throughout Japan. The questionnaire asked about the number of physician-diagnosed non-IgE-GIFA patients, the status of fulfillment of the diagnostic criteria, tentative classification into 4 clusters based on the initial symptoms, the day of onset after birth, complications, and the suspected offending food(s). Results: The response rate to that questionnaire was 67.6% from hospitals and 47.4% from clinics. Analyses were conducted about “diagnosis-probable” patient cohort (n = 402) and the “diagnosis-confirmed” patients (n = 80). In half of the reported non-IgE-GIFA patients, onset occurred in the neonatal period. The patients were evenly distributed among 4 non-IgE-GIFA clusters. In Cluster 1, with symptoms of vomiting and bloody stool, the onset showed a median of 7 days after birth, which was the earliest among the clusters. Cow's milk was the most common causative food. Conclusions: In half of the patients, the onset of non-IgE-GIFAs was in the neonatal period. This highlights the importance of studying the pathogenesis in the fetal and neonatal periods.

To assess the risk of food allergies in foods processed under the Japanese food labeling system, estimating exposure to hidden allergens is necessary. We assessed exposure to egg protein in foods processed according to the Japanese food labeling system. First, we estimated the concentration distribution of egg protein by Bayesian methods using data from the literature and the measurement of food products with precautional declarations in the labeling margin. We then estimated the food-intake portion-size distribution under two scenarios: soft drink consumption as an example of single, high-intake consumption, and confections, which are frequently consumed by children, as a realistic example of low-intake consumption. Finally, we estimated the distribution of unexpected intake of egg proteins in the form of single consumption. The mean exposure to egg protein under the high-intake scenario was estimated to be 0.0164 mg for 1–15-year-olds, 0.0171 mg for 4–15-year-olds, 0.0181 mg for 7–15-year-olds, and ≥0.0188 mg for 16-year-olds. The mean exposure to egg protein under the low-intake scenario was estimated to be 0.0018 mg for 1–15-year-olds, 0.0019 mg for 4–15-year-olds, 0.0020 mg for 7–15-year-olds, and ≥0.0022 mg for 16-year-olds. Compared to the reference dose of 2.0 mg proposed by the Joint the Food and Agriculture Organization (FAO)/World Health Organization (WHO) Expert Committee, the risk of onset of food allergies due to egg protein contamination from foods without egg labeling is considered to be extremely low under the current Japanese food labeling system.

Background: The effectiveness of slow low-dose oral immunotherapy (SLOIT) for cow's milk (CM) allergy has been reported. Most OIT studies have discussed the target populations over 4 years old. Furthermore, no predicting modeling is reported for CM allergy remission by CM-SLOIT under 4 years of age. Objective: We sought to develop a predictive model for CM allergy remission by SLOIT after 3 years in young children who started CM-SLOIT under 4 years of age. Methods: We included young children with cow's milk allergy or cow's milk sensitization (development modeling set with 120 children and validation modeling set with 71 children). We did logistic regression analysis to develop the models. We calculated the area under the receiver operating curves (ROC-AUCs) to evaluate the predictive modeling performance. Results: The model (CM-sIgE before SLOIT + age at beginning SLOIT + serum TARC before starting SLOIT + CM-sIgE titer one year after OIT) showed good discrimination with the ROC-AUC of 0.83 (95% CI:0.76–0.91) on internal validation. Applying the model to the validation set gave good discrimination (ROC-AUC = 0.89, 95% CI:0.80–0.97) and a reasonable calibration (intraclass correlation coefficient = 0.88, 95% CI:0.62–0.97). Conclusion: We developed and validated predictive modeling for determining the remission rate of CM allergy at 3 years after SLOIT under 4 years of age in children with CM allergy. This predictive model is highly accurate and can support CM allergy management. (226 words)

Background: Eczema patients are commonly immunoglobulin (Ig)E polysensitized. Although atopic dermatitis (AD) phenotypes have been recognized, IgE sensitization patterns based on AD phenotypes have not been well illustrated. We aimed to investigate how eczema phenotypes impact IgE component sensitization patterns. Methods: This birth cohort study investigated a general population in the Tokyo Children's Health, Illness, and Development Study (T-Child Study) until children reached the age of 13 years. Eczema was assessed using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Allergen component specific IgE antibody titers were measured using a multiplex array ImmunoCAP ISAC. Results: Persistent eczema phenotype until adolescence was strongly associated with allergic march symptoms, such as wheezing and hay fever, and oral allergy symptoms, and IgE component sensitizations of airborne (Japanese cedar, house dust mite, Timothy, cat, and dog) and cross-reactive allergens (Bet v 1 family) compared to early-remission and late-onset eczema. On the other hand, late-onset eczema did not show any strong associations with allergic symptoms and IgE sensitization. Adolescents with persistent eczema have high comorbidity of symptoms of pollen-food allergy syndrome. Conclusions: Early-onset eczema is deeply connected with the later allergic march, and late-onset eczema differs from the phenotype of allergic march. Early-onset eczema characterizing IgE sensitization was likely to be an extrinsic type, and late-onset eczema, which was not related to IgE sensitization, was likely an intrinsic type. Pollen-Food Allergy Syndrome is one of the allergic features in allergic march.

This article covers the salient and updated themes of the Japanese Pediatric Guidelines for the Treatment and Management of Asthma (JPGL) 2020 published by the Japanese Society of Pediatric Allergy and Clinical Immunology. In the 2020 guidelines, five new clinical questions (CQs) have been added to address the 12 CQs regarding the treatment of childhood asthma. “Infant and preschool asthma” is diagnosed when young children (

Reports of food protein–induced enterocolitis syndrome (FPIES) in Japan have been increasing. However, the disease itself and the treatment options are poorly understood by both patients and medical professionals. The objective of this study is to develop an action plan for acute FPIES in Japan. We prepared a single–sheet action plan that describes the management of acute FPIES episodes for caregivers on one side and medical professionals on the reverse side. To evaluate the content of the action plan, we distributed a questionnaire to caregivers of patients with FPIES and to physicians who would encounter patients with FPIES. Changes to the FPIES action plan were made based on the feedback from the participants. The Delphi method was utilized to finalize the action plan. The participants of the initial survey found the action plan to be useful but the process for determining severity to be impractical. After discussion, the authors made appropriate improvements. By the Delphi method, consensus was reached on the revised FPIES action plan. In conclusion, this Japanese FPIES action plan was created by physicians from multiple subspecialties and caregivers of patients with FPIES. The action plan may improve the management of acute FPIES reactions in the Japanese community.

Background: Allergic diseases are some of the most common diseases worldwide. Genome-wide association studies (GWASs) have been conducted to elucidate the genetic factors of allergic diseases. However, no GWASs for allergen component sensitization have been performed. Objective: We sought to detect genetic variants associated with differences in immune responsiveness against allergen components. Methods: The participants of the present study were recruited from the Tokyo Children’s Health, Illness, and Development study, and allergen component–specific IgE level at age 9 years was measured by means of allergen microarray immunoassays. We performed GWASs for allergen component sensitization against each allergen (single allergen component sensitization, number of allergen components analyzed, n = 31), as well as against allergen protein families (allergen protein group sensitization, number of protein groups analyzed, n = 16). Results: We performed GWAS on 564 participants of the Tokyo Children’s Health, Illness, and Development study and found associations between Amb a 1 sensitization and the immunoglobulin heavy-chain variable gene on chromosome 14 and between Phl p 1 sensitization and the HLA class II region on chromosome 6 (P < 5.0 × 10−8). A GWAS-significant association was also observed between the HLA class II region and profilin sensitization (P < 5.0 × 10−8). Conclusions: Our data provide the first demonstration of genetic risk for allergen component sensitization and show that this genetic risk is related to immune response genes including immunoglobulin heavy-chain variable gene and HLA.

The Japanese Guideline for Childhood Asthma (JGCA) 2020 is a translation of the Japanese Pediatric Guideline for the Treatment and Management of Asthma (JPGL) 2017 into English, which was published by the Japanese Society of Pediatric Allergy and Clinical Immunology. It makes recommendations for best practices in the management of childhood asthma, including management of acute exacerbations and non-pharmacological and pharmacological management. These guidelines will be of interest to non-specialist physicians involved in the care of children with asthma. In JPGL, JPGL2017 is the first evidence-based guidelines updated according to the GRADE system and Minds approach, and it addresses eight clinical questions about the treatment of childhood asthma. In children aged ≤5 years, infant and preschool asthma is diagnosed according to the response to short acting beta2 agonists or the effect of a therapeutic trial during 1 month with controller treatment and worsening after treatment cessation. Long-term management both promotes pharmacological therapy and measures against risk factors that induce exacerbation, better patient education and a partnership with trinity. In addition, long-term management should not be carried out without review but rather be based on a cycle of evaluation, adjustment and treatment. In JPGL2017, the transdermal patch and oral beta2 agonists are positioned as drugs within the concept of “short-term additional treatment” to be used until the symptoms are stabilized when the control state transiently deteriorates.

Five years have passed since the Japanese Pediatric Guideline for Food Allergy (JPGFA) was first revised in 2011 from its original version. As many scientific papers related to food allergy have been published during the last 5 years, the second major revision of the JPGFA was carried out in 2016. In this guideline, food allergies are generally classified into four clinical types: (1) neonatal and infantile gastrointestinal allergy, (2) infantile atopic dermatitis associated with food allergy, (3) immediate-type of food allergy (urticaria, anaphylaxis, etc.), and (4) special forms of immediate-type of food allergy such as food-dependent exercise-induced anaphylaxis and oral allergy syndrome (OAS). Much of this guideline covers the immediate-type of food allergy that is seen during childhood to adolescence. Infantile atopic dermatitis associated with food allergy type is especially important as the onset of most food allergies occurs during infancy. We have discussed the neonatal and infantile gastrointestinal allergy and special forms of immediate type food allergy types separately. Diagnostic procedures are highlighted, such as probability curves and component-resolved diagnosis, including the recent advancement utilizing antigen-specific IgE. The oral food challenge using a stepwise approach is recommended to avoid complete elimination of causative foods. Although oral immunotherapy (OIT) has not been approved as a routine treatment by nationwide insurance, we included a chapter for OIT, focusing on efficacy and problems. Prevention of food allergy is currently the focus of interest, and many changes were made based on recent evidence. Finally, the contraindication between adrenaline and antipsychotic drugs in Japan was discussed among related medical societies, and we reached an agreement that the use of adrenaline can be allowed based on the physician's discretion. In conclusion, this guideline encourages physicians to follow the principle to let patients consume causative foods in any way and as early as possible.

Background: Pediatric atopic dermatitis (PAD) is a pluricausal disease and is frequently seen in dermatological and pediatric practice. Therefore, it is important to find common views in clinical practice and to promote consensus among practitioners. Aiming to obtain common views among dermatologists and pediatricians and to disseminate them widely in clinical practice, we held the PAD Consensus Forums described herein. Methods: Questionnaire surveys of treatment goals and drug therapy were conducted to prepare topics for discussion at the PAD Consensus Forums. Reaching consensus was defined as agreement among at least 70% of the participants. Results: As a result of discussion among 24 dermatologists and 25 pediatricians, consensus was obtained on 7 topics. These topics configure 3 consensus of treatment goals (Attainment targets were divided into the short/medium term and the long term. Attainment targets were associated with the primary evaluation domains of the Harmonising Outcome Measures for Eczema (HOME) roadmap, etc.) and 4 consensus of drug therapy (The number of applications of topical anti-inflammatory drugs in the acute phase and selection and ideal intervals between applications of topical anti-inflammatory drugs in proactive therapy, etc.). Conclusions: The consensus is expected to help practitioners set appropriate treatment goals in clinical practice and facilitate the choice of drugs for treatment. Keywords: Atopic dermatitis, Child, Consensus, Dermatologist, Pediatrician

Background: Although hen's egg (HE) allergy was thought to be usually resolved by late childhood, majority of HE allergy patients with a high level of egg white (HEW)-specific IgE could not acquire tolerance for HE by age 8 years.Objective: The aim is to investigate whether the avoidance of HE until 6 years of age increased the risk of heated HE allergy at age 6 years.Methods: This was a retrospective case-control study. The HE tolerance children (n = 17) and children with low-dose HE reactor [a positive reaction to ≤ 4 g of heated HEW in oral food challenges (OFCs)] children (n = 26) were included based on the results of OFC at 6 years old. Multivariate logistic regression analysis was applied to examine the associations between HE avoidance until age 6 years and HE allergy status confirmed by OFC, adjusting the level of ovomucoid-specific IgE (OM-sIgE) during early infancy.Results: A lower proportion of strict avoidance of HE was observed in the HE tolerance group than in the low-dose HE reactor group (6 vs. 46%, p = 0.006). OM-sIgE levels in children younger than 2 years old were significantly higher in the low-dose HE reactor group than those in the HE tolerance group (median [interquartile], 26.7 UA/mL [11.9–53.4] vs. 7.9 UA/mL [0.35–23.4]; p =0.024). The avoidance of HE until 6 years of age increased the risk of heated HE allergy even after adjusting OM-sIgE levels.Conclusions: The long-term avoidance of HE from infancy increased the risk of heated HE allergy confirmed by OFC at age 6 years.

Allergic rhino-conjunctivitis with pollen allergy has been prevalent worldwide and Pollen-food allergy syndrome (PFAS) refers to individuals with pollen allergy who develop oral allergy syndrome (OAS) on consuming fruits and vegetables. The prevalence of PFAS varies by region and that in Japanese adolescents remains to be elucidated. In this cross-sectional study, we examined the epidemiological characteristics of PFAS in a general population of Japanese adolescents according to pollen allergy, OAS, and IgE component sensitization. Participants comprised adolescents, at age 13 years, from a prospective birth cohort study in Japan. We administered questionnaires to collect information from parents regarding pollen allergy, PFAS and OAS at each child's age 13 years. ImmunoCAP ISAC was used to assess IgE component sensitization. Among 506 participants with a complete questionnaire and ISAC measurement results, 56.5% had a history of hay fever, 16.0% had a history of OAS, 51.0% had pollen allergy, and 11.7% had a history of PFAS; additionally, 72.7% were sensitized to one or more tree, grass, and/or weed allergens. The most common sensitization (95.7%) among adolescents with pollen allergy was to Japanese cedar (Cry j 1). The most common causal foods were kiwi and pineapple (both 39.0%). Knowledge levels about PFAS were poor among affected adolescents. We found a high prevalence of PFAS among adolescents in Japan. Although it affects approximately 1/10 adolescents in the general population, public awareness regarding PFAS is poor. Interventional strategies are needed to increase knowledge and to prevent PFAS in the general population.

Background: Response patterns to allergen components among Japanese children have not been studied extensively. Objective: Our aim was to examine the differences in sensitization patterns at ages 5 years and 9 years to identify longitudinal changes in the degree and patterns of sensitization in a birth cohort of Japanese children. Methods: Our study enrolled 984 children at aged 5 years between 2008 and 2010, and 729 children aged 9 years between 2012 and 2014. Allergic diseases were assessed using the ISAAC and UK Working Party's Diagnostic Criteria. Serum-specific IgE titers to allergen components were measured by multiplex array ImmunoCAP ISAC when the children were aged 5 and 9 years. Principal component analysis (PCA) was performed to characterize IgE sensitization to allergen components. Results: The prevalence of allergic rhinitis increased considerably over time (10.6%–31.2%). Furthermore, the sensitization prevalence to allergen-specific IgE (sIgE) also increased from 57.8% at age 5 years to 74.8% at age 9 years. IgE sensitization prevalence to Der f 1 (mites) was 42.1% at age 5 years and 54.3% at age 9 years. Furthermore, children were highly sensitized to Cry j 1 (Japanese cedar) (32.8% at age 5 years and 57.8% at age 9 years). Principle component analysis showed that sensitization to PR-10 cross-reactive components was independent of sensitization to mite and that no children acquired sensitization to pollen before acquiring sensitization to mite. Conclusions: The prevalence of allergic rhinitis and related allergen components increased from age 5 years to age 9 years in Japanese children. Keywords: Allergy, Asthma, Atopic dermatitis, Child, Cohort, Eczema, IgE, ISAAC, ISAC, Prospective birth cohort, Rhinitis, Sensitization, Wheeze

BackgroundIn Japan, swimming school attendance is promoted as a form of therapy or as a prophylactic measure against asthma in young children. However, the putative beneficial effects have not been sufficiently verified.ObjectiveThe aim of the present study was to clarify whether or not swimming school attendance at age 3 years affects the onset and/or improvement of wheeze and rhinitis at age 5 years.MethodsThis study was a single-center, prospective, general, longitudinal cohort study (T-CHILD Study). Between November 2003 and December 2005, 1776 pregnant women were enrolled, and their offspring were followed up until age 5 years. Swimming school attendance at age 3 years and the presence of wheeze and/or rhinitis in the previous one year were examined using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. The relationship between swimming school attendance and wheeze and/or rhinitis was analyzed using multivariable logistic regression analysis.ResultsData on the 1097 children were analyzed. At age 3 years, 126 (11.5%) children attended a swimming school, and at age 5 years, the prevalence of wheeze was 180 (16.4%) while that of rhinitis was 387 (35.3%). Swimming school attendance at age 3 showed no significant relationship with the development of either wheeze (aOR 0.83, 95% CI (0.43-1.60) or rhinitis (aOR 0.80, 95% CI (0.43-1.60) at age 5.ConclusionsSwimming school attendance at age 3 years showed neither a preventive nor therapeutic effect on wheeze or rhinitis at age 5 years. There is thus no scientific evidence yet that swimming school attendance has a positive impact on the development of childhood wheeze or rhinitis.