大矢 幸弘

BACKGROUND: The Prevention of Allergy via Cutaneous Intervention (PACI) randomized controlled trial (RCT) demonstrated that early enhanced topical corticosteroid (TCS) therapy modestly reduced food allergy (FA) at 28 weeks of age. The present prospective follow-up study (PACI-ON) evaluated whether these effects persisted to age 3 years. METHODS: Participants were randomized in infancy to early enhanced (proactive) or early conventional (reactive) TCS treatment (1:1) for atopic dermatitis (AD) until 28 weeks. A total of 590 (91%) children who completed the PACI RCT were followed to age 3 years. During follow-up, no protocolized interventions were given; all participants received usual care. Main outcomes included physician-diagnosed FA, AD severity (EASI, POEM), sensitization profiles, allergic comorbidities, and growth parameters as safety outcomes. RESULTS: At age 3 years, the prevalence of any FA remained lower in the early enhanced group than in the conventional group (47.4% vs. 58.8%, p = 0.006), mainly driven by a reduced prevalence of raw egg allergy (30.4% vs. 40.5%, p = 0.013). No between-group differences were observed for wheeze, asthma, or rhinitis. Japanese cedar sensitization at age 2 was lower in the enhanced group (6.1% vs. 12.2%, p = 0.02 6) but not at age 3. AD control and quality of life were well maintained and similar across groups, with > 90% achieving mild or less disease. Early growth suppression at 1 year resolved by age 3. CONCLUSION: Early enhanced AD intervention was associated with a sustained modest reduction in its planned primary follow-up outcome of FA and safety (growth) up to age 3. Although most differences were small and may reflect early diagnosis and good overall management in both groups, the findings support early AD treatment as a potential strategy to modify allergic disease trajectories.

INTRODUCTION: The atopic march describes the progression from early eczema to food allergies and asthma. In Japan, early-onset atopic dermatitis (AD) is linked to allergic diseases, but the role of peanut sensitization-a known asthma risk factor in Western populations-remains uncertain because of its lower prevalence. This study aimed to evaluate whether peanut sensitization predicts asthma development in Japanese children with AD and to compare its predictive value with other common allergens. METHODS: We conducted a retrospective cohort study of 203 children under age two with physician-diagnosed AD who underwent simultaneous measurement of specific immunoglobulin E to egg white, peanut, and house dust mite at a tertiary Allergy Center in Tokyo. Participants were followed until age six. Sensitization was categorized as none, mono (one allergen), or oligo (≥2 allergens). Associations with asthma development were evaluated using multivariate logistic regression and decision tree analysis. RESULTS: Asthma developed in 32.0% of participants. Peanut sensitization was significantly more common in the asthma group (53.8% vs. 29.7%, p = 0.001), as were oligo-sensitization and allergic rhinitis. Decision tree analysis identified peanut sensitization as the most influential predictor, with an 83% asthma incidence among children with both peanut sensitization and rhinitis. Logistic regression confirmed peanut sensitization as an independent risk factor (adjusted odds ratio: 2.74, 95% confidence interval: 1.44-5.24). CONCLUSIONS: Peanut sensitization in infancy strongly predicts asthma in Japanese children with AD. Early allergen-specific sensitization profiling may help identify high-risk children and support targeted asthma prevention strategies.

IMPORTANCE: Allergic diseases in children are influenced by gene-environment interactions. Although advanced parental age has been associated with genetic and epigenetic changes, its relationship with childhood allergy risk remains unclear. OBJECTIVE: To examine the association between parental age at childbirth and the risk of allergic diseases in early childhood. DESIGN, SETTING, AND PARTICIPANTS: This nationwide, multicenter, population-based, prospective birth cohort study used data from the Japan Environment and Children's Study (JECS). Participants were enrolled at 15 regional centers in Japan between January 2011 and March 2014, with follow-up data collected at child ages 1, 2, and 4 years. The present analysis was conducted from July 8, 2024, to February 4, 2025. Eligible participants were singleton live births with data on parental age and allergic outcomes. Physician-diagnosed allergy outcomes were collected via parental report. House dust mite (HDM) sensitization was assessed in a subcohort. MAIN OUTCOMES AND MEASURES: The primary outcomes were physician-diagnosed food allergy, wheeze, asthma, and eczema at ages 1, 2, and 4 years. The secondary outcome was HDM sensitization at ages 2 and 4 years. Adjusted odds ratios (ORs) were calculated using multivariable logistic regression after multiple imputation for missing values. RESULTS: A total of 34 942 mother-child pairs were included; the mean (SD) maternal age at entry was 31.0 (4.7) years, and 17 892 mothers (51.2%) had a medical allergy history. The prevalence of food allergy at age 1 year was 6.6% (95% CI, 6.4%-6.9%), decreasing with maternal age. Compared with children of mothers aged 25 to 29 years, those of mothers aged 35 to 39 years (OR, 0.79; 95% CI, 0.70-0.90) and aged 40 years and older (OR, 0.59; 95% CI, 0.44-0.79) had lower odds of food allergy. Children of parents both aged 35 years or older had lower odds of wheezing at age 4 years (OR, 0.89; 95% CI, 0.82-0.95). HDM was assessed in 1991 children at age 2 years and 1840 children at age 4 years, and children of older mothers also had lower odds of HDM sensitization (children of mothers aged 30-34 years, OR, 0.76; 95% CI, 0.59-0.98; children of mothers aged 35-39 years, OR, 0.68; 95% CI, 0.50-0.91). CONCLUSIONS AND RELEVANCE: In this cohort study of 34 942 mother-child pairs, children of older mothers had reduced odds of food allergy, wheezing, and HDM sensitization in early childhood, suggesting that advanced maternal age may be protective against the development of allergic diseases in early childhood.

BACKGROUND: Understanding factors influencing vaccine-induced immunity in adolescents is important for optimizing COVID-19 vaccination strategies. Allergic diseases have been hypothesized to alter immune responses through Th2-dominant inflammation, but data regarding their impact on SARS-CoV-2 mRNA vaccine antibody production remain limited in real-world adolescent populations. The purpose of this study is to identify factors affecting SARS-CoV-2 antibody titers after mRNA vaccination in a general population of 16- to 17-year-olds. METHODS: This study analyzed data from 233 participants in the T-CHILD Study, a Japanese general birth cohort, who received their 17-year medical checkup between July 2021 and October 2023. Individuals with a history of COVID-19 or serological evidence of prior infection (positive for both S- and N-antibodies) were excluded. Associations between SARS-CoV-2 S-antibody titers and vaccination history, allergic diseases, and other variables were examined. RESULTS: Multivariate analysis revealed that only a higher number of vaccine doses was independently associated with higher SARS-CoV-2 antibody titers. No significant associations were found between antibody titers and vaccine type, the interval since the last vaccination, allergic diseases such as asthma, atopic dermatitis (AD), or food allergy, or with total serum IgE levels. CONCLUSIONS: These findings suggest that adolescents with mild allergic diseases can mount sufficient immune responses to SARS-CoV-2 mRNA vaccines, supporting the safety and efficacy of vaccination in this population. (230 words).

BACKGROUND: Data on the long-term efficacy and safety of topical therapy for atopic dermatitis (AD) remain limited. METHODS: This prospective cohort study included all children with AD who had their first visit to the Allergy Center at the National Center for Child Health and Development between December 2020 and September 2022. Participants were evaluated at enrollment, 6, and 12 months, and also monitored via questionnaires. We analyzed those with an Eczema Area and Severity Index (EASI) score ≥7.1 and complete EASI data at both follow-up points. The primary endpoint was the proportion achieving ≥75 % improvement in EASI from baseline (EASI-75) at 12 months. Secondary outcomes included other clinical endpoints, QOL scores, and skin and ocular complications. RESULTS: Of 763 enrolled children, 107 had EASI ≥7.1, and 77 (72.0 %) had complete follow-up data. Median age at enrollment was 57.0 months [quartile: 13.0-141.0], and 58.4 % were male. Fifty-three had moderate (7.1≤EASI≤21.0) AD, and 24 had severe to very severe (21.1≤EASI) AD. Only two children (2.6 %) required systemic therapy during the study period. Median EASI scores significantly improved from 14.8 at baseline to 0.8 at both 6 and 12 months (P < 0.001). EASI-75 was achieved by 80.5 % at 6 months and 85.7 % at 12 months. Other clinical endpoints, including POEM, pruritus and sleep-disturbance NRS, and QOL scores, were improved. New dermatologic complications were rare, and no ophthalmologic complications occurred. CONCLUSIONS: Most pediatric AD cases with moderate or greater severity can be effectively and safely controlled with topical therapy alone.

Cow's milk allergy (CMA) is a common pediatric food allergy that can cause significant nutritional and quality-of-life challenges. Severe cases, characterized by high milk-specific IgE levels and a history of anaphylaxis, rarely develop natural tolerance. Oral immunotherapy (OIT) is generally avoided in such high-risk patients due to the risk of serious allergic reactions, leaving strict avoidance as the standard treatment. However, prolonged avoidance may delay tolerance acquisition and increase psychosocial burden. We report a female patient with severe CMA and multiple food allergies who underwent a carefully tailored, ultra-low-dose OIT over 10 years. At treatment initiation, her milk-specific IgE was >100 kUA/L, and an oral challenge with 1.1 mL of milk induced anaphylaxis. The OIT protocol started with a dose well below her reaction threshold and increased gradually, resulting in no serious adverse events. Over time, she achieved tolerance to 200 mL of pure milk and resumed unrestricted consumption of milk and other previously avoided foods such as egg and wheat. This is the first report of successful long-term ultra-low-dose OIT in a highly sensitized child with severe CMA, showing that slow, cautious escalation can safely induce unrestricted intake even in patients previously deemed unsuitable for OIT. Given the limitations of biologics and emergency care availability worldwide, this low-risk, home-based protocol using locally available foods offers a feasible and affordable approach for managing severe food allergies globally. Such individualized, sustained OIT may improve long-term outcomes and quality of life for children with severe food allergies.

BACKGROUND: Adverse events could be a barrier to implementing oral immunotherapy (OIT) in children with hen's egg (HE) allergy, highlighting the need for safer OIT methods. OBJECTIVE: To determine the safety and efficacy of a new OIT method in a single-center, phase II, double-blind, parallel-group, randomized controlled trial. METHODS: Children aged 1 to 18 years with HE allergy whose cumulative tolerated dose (CTD) range was greater than or equal to 0.1 g to less than 10 g in the oral food challenge test were randomly assigned to the experimental therapy (ET) group with a very low starting dose or to the standard therapy (ST) group with a fixed-quantity maintenance dose for OIT. The primary outcome was safety, measured by days on OIT before the first IgE-mediated immediate-type reaction. The OIT efficacy, the change in CTD, was to be evaluated. RESULTS: Among 20 participants at registration, 12 (60%) and 8 (40%) participants were allocated to the ET and ST groups, respectively. Although the study was prematurely terminated because of difficulty in the safe supply of immunotherapy food, the number of days before the first IgE-mediated immediate-type reaction was more in the ET group than in the ST group (P = .033, log-rank test). The adverse event rate was also lower in the ET group; all of these might improve adherence to the treatment method. The change in CTD could not be compared between the 2 groups. CONCLUSIONS: OIT with a very low starting dose might be a safer approach with a low treatment burden for children with HE allergies.

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.

Acute food protein-induced enterocolitis syndrome (FPIES) is a non-immunoglobulin E-mediated food allergy characterized by delayed-onset vomiting, which can lead to severe dehydration and shock. Ondansetron, a 5-hydroxytryptamine 3 receptor antagonist, is recommended for managing acute episodes, but granisetron, a similar antiemetic, lacks global approval for FPIES. Our case series aimed to evaluate the effectiveness and safety of intravenous granisetron in acute FPIES episodes. We report three cases of infants with acute FPIES triggered by egg yolk during oral food challenges. Each patient received intravenous granisetron after multiple vomiting episodes. Clinical outcomes, including cessation of vomiting and resumption of oral intake, were assessed. Vomiting ceased within an hour after granisetron administration in all cases, allowing successful oral rehydration. No adverse effects or recurrence of symptoms were observed, and all patients were discharged the following day. The clinical outcomes were comparable to those reported for ondansetron. Our findings suggest that intravenous granisetron is a safe and effective secondary therapy for acute FPIES reactions. Given the limited evidence on granisetron for FPIES, accumulating case reports is essential for guiding clinical trials and regulatory approval. Further comparative studies of granisetron and ondansetron are warranted.

[This corrects the article DOI: 10.31662/jmaj.2024-0127.].

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.