大矢 幸弘

BACKGROUND: Allergic rhinitis and pollen sensitization typically increase with age; however, longitudinal data on the prevalence of pollen-food allergy syndrome (PFAS) among Japanese adolescents are limited. OBJECTIVE: We assessed the prevalence, causal foods, and sensitization status of PFAS among 17-year-olds and explored its association with comorbid allergic conditions. METHODS: This study was conducted as part of the Tokyo Child Health, Disease, and Development Research, a prospective birth cohort study involving the general population. Adolescents aged 17 (range, 16-18) years participated in a cross-sectional survey that included a medical history and health questionnaire, alongside serum IgE testing by ImmunoCAP ISAC. Statistical analyses were performed by descriptive statistics. RESULTS: Among 458 participants, 54.4% had current pollen allergy and 11.2% had PFAS. The most common causal foods were apples (45.1%), kiwis (41.2%), and pineapples (39.2%). Sensitization rates were high for Cry j 1 (96.1%), Bet v 1 (70.6%), Mal d 1 (64.7%), and Pru p 1 (62.7%). Additionally, 43.1% of adolescents with PFAS had a history of atopic dermatitis, suggesting a link between PFAS and the concept of the allergic march. Rhinitis symptoms peaked in spring, with 79.8% reporting symptoms, particularly in March and April. CONCLUSION: This study examined the prevalence and sensitization status of PFAS among Japanese adolescents. PFAS was common in those with pollen allergies and was associated with atopic dermatitis, supporting the allergic march hypothesis. Apples, kiwis, and pineapples were the most frequently implicated foods. These findings underscore the importance of recognizing PFAS in managing adolescent allergic conditions.

BACKGROUND: Epidemiological studies of atopic dermatitis lack standardization in key areas, including how the burden is collected and reported, diagnostic criteria, sociodemographic factors and measurement of disease severity. Therefore, direct cross-study comparisons, recognition of population differences and pooled analyses are challenging or not possible. Consequently, the burden of atopic dermatitis remains difficult to assess and address. The Epidemiological Study Designs for Atopic Dermatitis Research (EPISTAR) initiative aims to reach consensus on which domain items should be recommended for future population-based epidemiological studies on atopic dermatitis and how they should be assessed. METHODS: In phase 1, a steering group consisting of experts from dermatology and epidemiology as well as patient representatives will generate an initial list of items constituting key variables to measure. This list will be created by reviewing the existing literature, prioritizing evidence from systematic reviews where available. Phase 2 will include an international consensus exercise, conducted through eDelphi methodology. Phase 3 will involve an online consensus conference. In each Delphi round, international participants from diverse stakeholder groups will be invited to assess each item by rating their level of agreement with the item and methods by which it can be measured. Items that reach consensus will be removed after each round. Data analysis will follow predefined consensus criteria, with raw numbers, means and frequencies reported. DISCUSSION: This harmonized approach has the potential to transform the field of atopic dermatitis epidemiology by addressing gaps in data quality and comparability, facilitating meta-analyses, and ultimately informing evidence-based policy and clinical guidelines.

BACKGROUND: There is a significant lack of longitudinal research on specific immunoglobulin E (IgE), IgA, and IgG sensitisation levels among preschool-aged children, despite their critical role in elucidating the mechanisms underlying allergic disorders. The current study analysed the trajectories of IgE, IgA, IgG1, and IgG4 levels across general populations and their correlation with allergic diseases in children aged 2-4 years. METHODS: This longitudinal study included 4872 children aged 2 years and 4437 children aged 4 years who participated in the Subcohort Study of the Japan Environment and Children's Study. Allergic diseases were evaluated utilising the diagnostic criteria established by the International Study of Asthma and Allergies in Childhood and the UK Working Party. The serum specific IgE (sIgE), IgG1, IgG4, and IgA levels of participants aged 2-4 years were quantified. RESULTS: The prevalence of atopic dermatitis, hen's egg allergy, cow's milk allergy, and current wheezing decreased between ages 2 and 4 years. The prevalence of allergic rhinitis and conjunctivitis exhibited an upward trend. The serum IgE levels to hen's egg and cow's milk antigens in healthy children were similar to those in children with allergic diseases, and it decreased between ages 2 and 4 years. Der p1 sIgE levels decreased in healthy children, whereas they increased in allergic children. The high sIgE/total IgE and sIgE/specific IgG4 levels to Derf1 and Derp1 at age 2 years were associated with current wheezing at age 4 years. CONCLUSIONS: This study provided foundational benchmark values for IgE, IgG1, IgG4, and IgA levels against different allergens in a general population of children aged < 5 years. The levels of each allergen exhibited distinct characteristics in the general population.

Atopic dermatitis (AD) is a prevalent chronic inflammatory disease that significantly burdens individuals and healthcare systems worldwide. The incidence of AD has risen sharply in both developed and emerging economies, necessitating an understanding of its complex etiological factors, including environmental influences and lifestyle changes. Generally, 2 primary preventive strategies for AD have been implemented so far: (1) the "Inside Out" approach that which involves allergen elimination, probiotic supplementation, fish oil supplementation, and vitamin D supplementation aim to regulate the immune system in pregnancy and early childhood and (2) the "Outside In" approach that focuses on improving skin barrier function through emollient use and environmental changes. Although current evidence suggests the potential benefits from these interventions, randomized controlled trials have revealed inconsistencies in their efficacy. It is imperative not only to explore the minute research gaps in existing studies, but also to develop novel interventional studies that consider individual and regional differences based on the epithelial barrier hypothesis, the biodiversity hypothesis, and the 'old friends' hypothesis evolved from the hygiene hypothesis. Ultimately, reversing the rising trend of AD prevalence will most likely require a multifaceted approach that integrates new scientific evidence and promote comprehensive lifestyle changes.

Topical molecular targeted therapies have recently emerged for the treatment of atopic dermatitis (AD), but their efficacy and safety, particularly in children, remain underexplored. This systematic review and meta-analysis aim to evaluate the efficacy and safety of topical targeted therapies in children with AD. We conducted a comprehensive search of the CENTRAL, MEDLINE, Embase, and ICHUSHI databases for articles published up to January 7, 2023, based on a protocol registered in PROSPERO (CRD42022366449). Randomized controlled trials (RCTs) investigating new topical targeted therapies in children (≤18 years) with AD were included. The primary outcomes were the Eczema Area and Severity Index (EASI) scores and treatment-related adverse events. Secondary outcomes included additional efficacy and safety analyses. A meta-analysis was performed using Revman 5.4, with bias risk assessed via the RoB 2 tool. Nine studies (reported in eight articles) involving 2182 patients were included, with 1469 children treated with Janus kinase inhibitors (ruxolitinib and delgocitinib) and phosphodiesterase-4 inhibitors (crisaborole, lotamilast, and difamilast). These interventions significantly improved EASI scores, with the least square mean change (mean difference: -56.67%; 95% confidence interval [-59.16% to -54.18%]). Additionally, topical targeted therapies did not increase the incidence of treatment-emergent adverse events (risk difference: 0.00; 95% confidence interval [-0.02 to 0.02]). The risk of bias was low across all outcomes. New topical targeted therapies administered over 4 weeks are effective and safe for children with atopic dermatitis aged ≤18 years. Further studies are needed to establish their long-term safety and efficacy.

A study demonstrated that drug provocation tests could be conducted in children with underlying diseases, enabling accurate diagnosis of drug allergy. The study investigators hope that their work will allow more children with underlying conditions to undergo drug provocation tests.

This is an abridged edition of English version of the Clinical Practice Guidelines for the Management of Atopic Dermatitis 2024. Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion. A crucial aspect of AD treatment is the prompt induction of remission via the suppression of existing skin inflammation and pruritus. To achieve this, topical anti-inflammatory drugs such as topical corticosteroids, tacrolimus ointment, delgocitinib ointment, and difamilast ointment have been used. However, the following treatments should be considered in addition to topical therapy for patients with refractory moderate-to-severe AD: oral cyclosporine, subcutaneous injections of biologics (dupilumab, nemolizumab, tralokinumab), oral Janus kinase inhibitors (baricitinib, upadacitinib, abrocitinib), and phototherapy. In the revised guidelines, descriptions of five new drugs, namely, difamilast, nemolizumab, tralokinumab, upadacitinib, and abrocitinib, have been added. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice.

BACKGROUND: In recent years, several targeted therapeutic options have become available for the management of atopic dermatitis in children. In this systematic review and meta-analysis, we assessed the efficacy and safety of systemic targeted therapies for atopic dermatitis in children. METHODS: A systematic review of literature available in CENTRAL, MEDLINE, Embase, and ICHUSHI databases until January 7, 2023, was performed. Randomized controlled trials of systemic targeted therapies (biologics and small molecules) on children aged 18 years or younger with atopic dermatitis were included. The primary outcomes were the eczema area and severity index (EASI) and adverse events. Other efficacy and safety outcomes were also used for meta-analysis and risk of bias analysis. RESULTS: We included 10 studies reported in 11 articles involving three agents (dupilumab, abrocitinib, and upadacitinib) and 1760 children. Systemic targeted therapies significantly improved eczema severity with an EASI-75 response (risk ratio, 2.99; 95 % confidence interval [CI], 2.66-3.37). However, systemic targeted therapies were associated with treatment-emergent adverse events (risk difference, 0.05; 95 % CI, 0.01-0.09), particularly among small molecules in subgroup analysis, while no such trend was observed with biologics. Systemic targeted therapy also significantly improved other efficacy outcomes, and no significant association was found in the other safety outcomes. There was no risk of bias in any of the outcomes. CONCLUSIONS: Our findings indicate that systemic targeted therapies are effective and relatively safe for treating atopic dermatitis in children, although small molecules may pose a slightly higher risk of adverse events.

This is the English version of the 2024 clinical practice guidelines for the management of atopic dermatitis (AD). AD is a disease characterized by relapsing eczema with pruritus as a primary lesion. A crucial aspect of AD treatment is the prompt induction of remission via the suppression of existing skin inflammation and pruritus. To achieve this, topical anti-inflammatory drugs, such as topical corticosteroids, tacrolimus ointment, delgocitinib ointment, and difamilast ointment, have been used. However, the following treatments should be considered in addition to topical therapy for patients with refractory moderate-to-severe AD: oral cyclosporine, subcutaneous injections of biologics (dupilumab, nemolizumab, tralokinumab), oral Janus kinase inhibitors (baricitinib, upadacitinib, abrocitinib), and phototherapy. In these revised guidelines, descriptions of five new drugs, namely, difamilast, nemolizumab, tralokinumab, upadacitinib, and abrocitinib, have been added. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice.

OBJECTIVE: To quantify the association between a combination of modifiable prepregnancy lifestyle factors and the risk of adverse pregnancy outcomes (APOs). DESIGN: Prospective cohort study. SETTING: The Japan Environment and Children's Study. POPULATION: A total of 79 703 pregnant Japanese women without chronic disease. METHODS: Maternal lifestyle before pregnancy was assessed using a self-administered questionnaire. A healthy lifestyle score (HLS, 0-5 points) was calculated based on adherence to five prepregnancy healthy lifestyle factors: healthy weight, high-quality diet, regular physical activity, not smoking, and not drinking alcohol. Relative risks (RRs) and 95% credible intervals (CrIs) were estimated using a Bayesian log-binomial regression model. MAIN OUTCOME MEASURES: Composite APOs, defined as the development of any APO, including gestational diabetes, hypertensive disorders of pregnancy, preterm birth, low birth weight, and small-for-gestational-age, transcribed from medical records. RESULTS: A total of 13 894 women (17.4%) experienced one or more APOs. HLS was inversely associated with the risk of APOs in a dose-response manner. Women with an HLS of 5 points had a 33% (RR 0.67; 95% CrI, 0.61-0.74) lower risk of APOs than those with the lowest HLS (0-1 points). The population attributable fraction of five healthy lifestyle factors was 10.3%. A 1-point increase of HLS could have reduced APO cases by 6.6%. CONCLUSIONS: A higher HLS was associated with a lower risk of APOs, suggesting that adopting a healthy lifestyle before pregnancy may reduce the risk of APOs, which can increase the risk of future chronic diseases in both mother and child.

Down syndrome (DS) is a risk factor for severe food protein-induced enterocolitis syndrome (FPIES), with DS patients tending to have multiple-food FPIES. This is the first case where a DS infant with a history of severe chronic FPIES to milk and soy could effectively be introduced with some untested high-risk foods through hospital-based oral food challenges (OFCs). The infant is a 20-month-old girl with DS, who was diagnosed with milk- and soy-induced FPIES. Considering her history of intensive care unit care for severe FPIES reactions, we considered that introducing other high-risk foods, such as wheat and hen's egg (white and yolk), at home was not appropriate for her. We offered hospital-based OFCs effectively and safely by introducing wheat and hen's egg as high-risk foods against FPIES to the 20-month-old infant. As a result, she tolerated soy-based seasoning, wheat, and egg whites without any symptoms, but she developed frequent vomiting after ingesting egg yolk. We did a prompt intervention with intravenous fluid replacement to prevent severe adverse conditions. After discharge, she exhibited an FPIES symptom as a consequence of ingesting green peas and miso; hence, we recommended the elimination of peas, in addition to soy, milk, and egg yolk, from her diet. She remained symptom-free since adhering to this dietary regimen. In severe FPIES children, it is encouraged to introduce unconsumed high-risk foods in the hospital safely to avoid severe reactions at home and prevent unnecessary food eliminations.

INTRODUCTION: Similar to other countries, in Japan, the demand for primary care pediatricians has increased due to the surge in pediatric allergic diseases, and with the change in a paradigm shift regarding the prevention of pediatric allergic disease in the last 20 years, they have had an increased need for retraining. To offer better support to children and their caregivers, educational needs for bridging the gap between knowledge and practice must be met. Therefore, we developed an educational program including practical and interactive approaches for pediatricians in 2012. METHODS: To evaluate the effectiveness of a 2-week program, behavioral changes, knowledge and skill improvements in clinical practice, and the satisfaction level of participants before and after the course were investigated. Kirkpatrick's four levels of training evaluation were employed to assess the educational effect. Seven years (April 2014 to March 2021) worth of results were assessed. RESULTS: A total of 65 pediatricians voluntarily participated in the program. Most of them were <40 years old and came from various regions of Japan. Results of pretraining and posttraining questionnaires in terms of their knowledge and skills on a four-point scale revealed significant improvements. Participants also reported their behavioral changes after 6 months of the course and evaluated the program's practicality. Each participant set new goals to be achieved in 6 months, and 36 (76.6%) of them set objectives for implementing oral food challenge tests. CONCLUSIONS: The results revealed that the program not only enhanced their knowledge and skills for practice but also changed their behaviors toward clinical practice. In pediatric allergy, where community primary pediatricians have important roles to play, such an educational program should be further developed.

BACKGROUND: Adult food protein-induced enterocolitis syndrome (FPIES) has recently been recognized, and there are no international diagnostic criteria for this disease. Differentiating adult FPIES from immediate-type food allergy reactions and providing specific treatment for each in an emergency is important, but methods have not been developed. OBJECTIVE: To develop a diagnostic scoring system for adult FPIES by comparing it with an immediate-type food allergy (IgE-FA). METHODS: This retrospective cohort study of food-avoidant adults based on the diagnostic criteria for adult FPIES reported by Gonzalez et al. was conducted by telephone interviews. We compared the clinical profiles of the patients with FPIES and IgE-FA. Adult FPIES-associated factors were extracted using multivariate analysis, and a diagnostic scoring system was developed based on odds ratios (OR). RESULTS: Forty-eight (16.7%) of 288 adults with food allergies were diagnosed with FPIES; of these, 240 (83.3%) had IgE-FA. Seafood was the most common cause of FPIES in adults (68.8%). Multivariate analysis identified age of onset > 26, >10 episodes, a longer latency period, cold sweat, abdominal distention, and vomiting as adult FPIES-associated factors. An adult FPIES diagnostic scoring system was developed using ORs with a high area under the curve (AUC = .978), 100% sensitivity and 87.0% specificity. CONCLUSION: Clinical profiles and an adult FPIES diagnostic scoring system were developed for the first time. This scoring system can be useful in differentiating adult FPIES and IgE-FA while treating a food-related acute reactions.

INTRODUCTION: Difamilast is the first selective phosphodiesterase 4 inhibitor approved for atopic dermatitis (AD) in Japan. A phase 3, 52-week, open-label study is ongoing to establish efficacy and safety of difamilast ointments in infants with AD aged 3 to < 24 months because a clinical study has not been conducted in this population. METHODS: This study consisted of a 4-week primary evaluation period in which difamilast 0.3% ointment was applied twice daily to Japanese infants aged 3 to < 24 months (n = 41) and an ongoing 48-week long-term extension period in which difamilast 0.3% or 1% ointment was applied based on existing symptoms. The data on efficacy and safety of difamilast were obtained as of an interim report in the study period. RESULTS: The response rate in Investigator's Global Assessment score was 45.0% at week 1, which was maintained at 56.1% at week 4 and 63.4% at the interim report. Infants achieved the response rate in Eczema Area and Severity Index 75 (improvement of ≥ 75%) of 47.5% at week 1, which further improved to 82.9% at week 4 and 78.1% at the interim report. Adverse events (AEs) were reported in 22 (53.7%) infants in the primary evaluation period: of those the most frequent AE was nasopharyngitis (19.5%) followed by dermatitis contact (7.3%). As of the interim report, 36 (87.8%) infants experienced AEs: of those, nasopharyngitis (70.7%) and gastroenteritis (22.0%) were most frequently observed. The total AEs were mostly mild or moderate in severity. No investigational medicinal product-related AEs and no AEs leading to discontinuation were reported. CONCLUSION: Difamilast ointments applied twice daily to Japanese infants with AD aged 3 to < 24 months is effective and well tolerated as of the interim report in the study period. The final results will be reported in the near future. CLINICAL TRIAL REGISTRATION: Clinical Trials. gov identifier: NCT05372653.