BACKGROUND:Although adrenaline auto-injector (AAI) prescribing has increased in Japan following insurance coverage expansion, real-world utilization during pediatric anaphylaxis remains insufficiently characterized. This study aimed to describe current AAI prescription patterns, actual utilization rates, and factors potentially associated with appropriate use. METHODS:This retrospective descriptive study analyzed AAI prescriptions and anaphylaxis hospitalizations at a tertiary care hospital in Shizuoka, Japan (2023-2024). We reviewed 124 AAI-prescribed children and 34 hospitalized anaphylaxis cases. For hospitalized patients possessing AAI (n = 8), we conducted detailed interviews assessing prior education quality, including hands-on training with expired AAI and smartphone application utilization. RESULTS:Among 124 AAI-prescribed patients, only 5 (4.0%) used AAI during follow-up. Among 34 hospitalized anaphylaxis cases, more than half (55.9%) occurred on first known allergen exposure, particularly for seafood (92.9%). Only 8 patients (23.5%) possessed an AAI prior to the event; among them, 4 (50%) used their AAI. Notably, AAI use appeared to differ by concordance between the triggering allergen and the allergen for which AAI was prescribed: 4/5 (80%) used AAI when allergens matched versus 0/3 (0%) when they differed. CONCLUSIONS:This study characterized current AAI prescription patterns and real-world utilization during pediatric anaphylaxis in Japan. Only 23.5% of hospitalized anaphylaxis cases possessed AAI, and utilization among possessors differed markedly depending on whether the triggering allergen matched the prescription indication. These findings suggest that AAI education should emphasize use for any anaphylaxis symptoms regardless of trigger.

Suppurative lymphadenitis in infancy typically responds well to antimicrobial therapy. However, some cases exhibit elevated inflammatory markers relative to clinical severity, raising questions about host inflammatory regulation. We report a one-month-old female infant with suppurative lymphadenitis caused by methicillin-sensitive Staphylococcus aureus (MSSA). Despite an appropriate clinical response to treatment, she demonstrated elevated ferritin (446 ng/mL) and soluble IL-2 receptor (1,734 U/mL). Systematic evaluation excluded hemophagocytic lymphohistiocytosis and primary immunodeficiency. Family history revealed recurrent lymph node swelling in the maternal lineage. Exploratory genetic testing identified a heterozygous LRBA gene variant (c.8417A>T), classified as a variant of uncertain significance. This case illustrates the importance of systematic evaluation when inflammatory markers appear elevated relative to clinical presentation. The identified LRBA variant is of uncertain significance and does not establish causality. Long-term follow-up is warranted to clarify whether this represents a clinically meaningful phenotype.

BACKGROUND:Oral food challenge (OFC) protocols in food protein-induced enterocolitis syndrome (FPIES) often select starting doses with consideration of prior reaction severity, implying that dose may influence reaction intensity; however, patient-level evidence linking antigen dose to reaction profiles remains limited. OBJECTIVE:To characterize threshold heterogeneity and compare clinical reaction profiles between diagnostic and reactive threshold OFCs within individual patients. METHODS:In this prospective study, 54 infants with OFC-confirmed FPIES (egg yolk, 36; cow's milk, 18) underwent threshold characterization at 0.001 g/kg (ultra-low) and 0.01 g/kg (low); all had previously reacted at a diagnostic OFC (median 0.38 g/kg). For the 30 reacting at a threshold challenge, the primary endpoint was objective reaction intensity (vomiting, examination signs); treatment intensity and a composite burden category were supporting measures. RESULTS:Of 54 patients, 12 (22%) reacted at 0.001 g/kg, 18 (33%) at 0.01 g/kg, and 24 (44%) tolerated both. Among the 30 threshold reactors, reactions were objectively milder than at the diagnostic OFC: median vomiting 2 (IQR 2-3) versus 4 (4-6) (p < .001), pallor 27% versus 63% (p = .019), decreased activity 43% versus 80% (p = .007). No ICG-defined severe features (hypotension/shock, severe lethargy) occurred at either OFC. Treatment intensity was also lower (intravenous fluid and prolonged observation each 27% versus 67%; both p < .001). CONCLUSION:Reactions at ultra-low and low threshold doses were objectively milder than at diagnostic doses within patients, while clinically meaningful reactions still occurred. These findings support systematic threshold assessment beginning at 0.001 g/kg, independent of diagnostic OFC clinical burden.

Background: Asthma comorbidity may reflect the heterogeneity of type 2 inflammation in children with severe atopic dermatitis (AD). However, its impact on long-term clinical and biomarker trajectories during dupilumab treatment remains unclear. Objective: To investigate whether asthma comorbidity influences 52-week clinical and biomarker trajectories in children with severe AD treated with dupilumab. Methods: In this 52-week prospective study, 16 children (6–11 years) with severe AD (Eczema Area and Severity Index [EASI] ≥ 21) were stratified by asthma status: AD + asthma (n = 7) and AD-only (n = 9). The primary endpoint was the longitudinal EASI trajectory assessed by linear mixed-effects models. Serum thymus and activation-regulated chemokine (TARC) dynamics were analyzed as a key secondary endpoint. Exploratory analyses evaluated associations between baseline TARC and early treatment response. Results: Both groups demonstrated marked and sustained clinical improvement. While the AD + asthma group showed numerically faster early EASI improvement (week 0–4), trajectories converged by week 8 and remained similar thereafter (group × time interaction P = 0.68). By week 52, median EASI scores were low in both groups (1.9 vs 3.1). In contrast, serum TARC showed differing observed temporal patterns, with lower postbaseline levels in the AD + asthma group (interaction nominal P = 0.041). Exploratory analyses suggested a possible association between higher baseline TARC and early clinical improvement, although estimates were imprecise and require validation in larger cohorts. Conclusion: Dupilumab provided sustained clinical benefit irrespective of asthma comorbidity. Apparent differences in serum TARC dynamics despite comparable clinical outcomes are consistent with potential heterogeneity in biomarker responses. These findings are exploratory and hypothesis-generating, warranting validation in larger, adequately powered studies.

Cimetidine is effective for treating periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, primarily in children, and is covered by public insurance in Japan. However, as demand for gastric ulcer treatment declines, cimetidine production has been restricted, raising concerns about supply for pediatric patients. We analyzed Japanese prescription trends in adults and children using publicly available data. Specifically, national reimbursement data were used to assess annual cimetidine prescription volumes by age group and pediatric share. Chronological changes were examined based on original formulation supply. In the database, 11 and 6 cimetidine products (including discontinued stock) were available for outpatient and in-hospital dispensing, respectively. Annually, 1.01 million and 80,000 cimetidine tablets (200-mg equivalents) were dispensed for patients under 15 years in outpatient and in-hospital settings, respectively. No inpatient prescriptions were recorded. Pediatric prescriptions peaked at ages 5-9 years, differing from adult trends, and accounted for 2.5% of total prescriptions. Although overall dispensing volumes are declining, pediatric prescriptions are increasing. Despite overall demand decreasing, approximately 1 million 200-mg cimetidine tablets are needed annually for use in children, and pediatric demand is increasing. Therefore, securing production of this new indication is essential.

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated gastrointestinal food allergy of infancy, with cow's milk as a classic trigger and egg yolk increasingly recognized in Japan. We report a term female who developed chronic FPIES to cow's milk in early infancy, followed by acute FPIES to heated egg yolk at six months. Perinatal cytomegalovirus (CMV) infection was documented by positive CMV IgM and persistent urine CMV polymerase chain reaction (PCR) positivity. Symptoms improved with an extensively hydrolyzed formula, yet serial hospital-based oral food challenges (OFCs) over five years repeatedly reproduced emesis two to four hours after milk or heated yolk ingestion, while tolerance to whole egg white (40 g) was achieved by 3.5 years. Across multiple OFCs, we observed consistent increases in TNF-α, IL-8, and TARC/CCL17 approximately 24 hours after symptom onset, alongside persistently low serum and salivary TGF-β. These immune patterns suggest a reproducible pro-inflammatory phenotype with deficient regulatory signaling. Given the biological plausibility that early-life CMV may transiently disrupt epithelial integrity and amplify mucosal cytokines, CMV-related mucosal inflammation may have modulated this patient's disease trajectory, although causality cannot be inferred from a single case. This case highlights prolonged multi-food FPIES with yolk specificity, emphasizes TARC as a pragmatic biomarker during symptomatic episodes, and provides a hypothesis linking gut immaturity and early-life viral inflammation to delayed oral tolerance.

Most pediatric intravenous anesthesia in Japan is performed outside the operating theatre by non-anesthetists. The 2020 revision increased reimbursement for long-term intravenous anesthesia (Category 3) by anesthesiologists, but its impact on practice behavior is unknown. We analyzed the annual number of calculations for each category of intravenous anesthesia and their age distribution from the national reimbursement data for the three-year period fiscal years (FY) 2018-20 to elucidate trends in the pediatric age group. Regional disparities of calculation rate of pediatric addition per capita were examined. According to FY 2019 statistics, 5,774 outpatient intravenous anesthesia and 50,686 inpatient intravenous anesthesia procedures were performed annually in patients under 15 years of age. Of these, no case was complex anesthesia (Category 3) performed by a specialist anesthesiologist in outpatient settings and 1,162(3.9%) in inpatient settings. Category 3 occupancy was slightly higher in infants and decreased with age. (P < 0.01) In FY 2020 data, 41(0.7%) new Category 3 procedure were calculated in outpatient cases. The share of Category 3 in inpatient cases decreased to 2.0%. There was no decrease in the number of overall venous anesthesia due to COVID-19 pandemic. Regional disparities in calculations were up to 20 times greater. Long-term total intravenous anesthesia by anesthesiologists is rarely performed in Japan. Improvements in reimbursement are not sufficient to enable total intravenous anesthesia by a specialized anesthesiologist. A system for safe intravenous anesthesia by non-anesthesiologists is needed.

BACKGROUND:The 2018 revision of social insurance in Japan allows additional fees to be calculated for pediatric magnetic resonance imaging (MRI) that must be performed under sedation. The number and trend of actual claims since this revision was established is unknown. The aim of this study to investigate the use of the additional fees and any regional differences in the use.METHODS:To analyze the claims of additional fees for pediatric sedated MRI after the fiscal year (FY) 2018, the actual claims in inpatient and outpatient practice was analyzed using publicly-available data from the Ministry of Health, Labour and Welfare (MHLW). We analyzed the calculation rate for all MRI scans. Annual changes in the actual number and calculation rate were analyzed. The ratio of the number of additional fees to the overall number of pediatric radiological procedures was used to examine the geographic disparity.RESULTS:The number of calculations from FY 2018 to FY 2020 was available. In FY 2020, only 1347 additional fees were calculated, corresponding to 0.35% of the total number of MRI scans. The number of fees showed a decreasing trend. Most cases were in the 0-4 year age group; however, there were a few cases in the 10-14 year age group without such a decrease. The relative number of calculations by prefecture showed an up to 14-fold disparity.CONCLUSIONS:The requirements for sedation for pediatric MRI are strict, but they are not fully utilized. Measures such as relaxing the requirements for the fee are needed to make MRI-related sedation safer.

BACKGROUND:In Japan, many asthma inhalers do not have formal approval for use in the pediatric population because of the lack of domestic data. In real-world settings, however, numerous off-label medications are prescribed. Currently, the nature of off-label prescriptions of asthma inhalers on pediatric patients in Japan remains unclear.METHODS:Using public open-source national medical claims data, we investigated the real-world descriptive epidemiology of off-label prescriptions for asthma inhalers for pediatric patients. We obtained the number of off-label prescriptions of formulations for patients aged 0-14 years from anonymously summarized prescription data for a 7-year period starting from April 2014. The actual prescription numbers and their chronology over time were then analyzed.RESULTS:In 2019, 143,439 asthma inhalers were used off label in children and adolescents. Overall, 96.1% were inhaled corticosteroids (ICSs) or long-acting beta stimulants (LABAs), and 3.9% were high-dose ICS. Of ICSs and LABAs, 18.8% were off-label prescriptions. The total number of off-label ICS/LABA prescriptions and their percentage relative to the overall formulations gradually decreased but a notable disparity was observed among inhaler types.CONCLUSIONS:There was a surprisingly large number of off-label prescriptions of asthma inhalers in the pediatric population in Japan. The proper use of ICSs/LABAs and expansion of insurance coverage should be advocated to reduce off-label use.

Neutropenia, characterized by a decrease in peripheral blood neutrophil count less than 1500/µL, poses significant clinical challenges due to its association with recurrent infections.This paper presents a rare and intriguing case of alloimmune neonatal neutropenia (ANN), an uncommon variant of neutropenia instigated by the transplacental transfer of maternal anti-neutrophil antibodies that consequently induce opsonization and phagocytosis of the neonate's neutrophils within the reticuloendothelial system.The patient, an 18-day-old boy, was born at 36 weeks five days of gestation and weighed 2465 g, an attribute considered appropriate for gestational age (AGA).He experienced multiple episodes of skin and respiratory infections, coupled with delayed umbilical cord separation and demonstrated a significant reduction in neutrophil count.Despite these symptoms, the patient did not develop bacteremia and his condition improved with antibiotic therapy, leading to his discharge from the hospital.Crucially, both the patient and his mother tested positive for anti-HNA (human neutrophil alloantigen)-1a and anti-HNA-1b antibodies, indicative of a diagnosis of ANN.ANN is intriguing in its clinical course, where despite neutropenia, severe infections are relatively uncommon, and the majority of cases resolve spontaneously within several months post-birth as the maternal antibodies diminish.Nevertheless, there have been reports of moderate to severe infections, demanding clinical intervention and close patient monitoring.The patient in our case was treated with prophylactic antibiotics for six weeks, until a rise in neutrophil count was confirmed, stemming from the severity and recurrence of infections.The issue of using antibiotics and granulocyte colony-stimulating factor (G-CSF) agents in the treatment of ANN remains contentious, with contrasting reports regarding their efficacy and safety.The balance between the prospective therapeutic advantages, potential risks such as antibiotic resistance, and the possibility of inducing leukemia with long-term administration of G-CSF agents necessitates meticulous deliberation.This case underscores the crucial role of early recognition of ANN in neonates presenting with neutropenia.Prompt diagnosis enables a more targeted approach to treatment, reduction in unnecessary antibiotic administration, and specific testing, thus impacting the overall patient management and potentially improving outcomes.Furthermore, in the event of delayed umbilical cord separation in neonates, healthcare providers should consider ANN and other immunodeficiencies related to neutrophil functional abnormalities as potential diagnoses.This patient's story accentuates the need for further investigations to elucidate the precise etiology and pathogenesis of ANN, paving the way for improved diagnostic tools and effective therapeutic strategies.

BACKGROUND:The dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children are continually changing. We conducted a survey of pediatric allergy patients attending our department to determine the prevalence of antibodies against SARS-CoV-2 in children.METHODS:A retrospective study was performed among children aged <11 years, referred to a pediatric allergy department between February 2020 and January 2022 with a chief complaint of allergy. The data of children with blood examination findings were retrospectively studied. Qualitative testing for anti-SARS-CoV-2 IgG and IgM antibodies was performed using a SARS-CoV-2 rapid antibody test. Participants were retested 1 year later to evaluate changes in antibody levels.RESULTS:In total, 310 patients with a median age of 26 months (interquartile range: 11.6-58.4 months) and male/female ratio of 1.31 were included. A total of 32 patients tested positive for anti-SARS-CoV-2 IgG or IgM antibodies. No differences were observed in the severity of allergic disease. The prevalence of antibodies was higher among children enrolled in preschool or school (odds ratio: 13.19, 95% confidence interval; 2.30-249.7). A total of 66.7% of patients underwent follow-up testing. The antibody positivity rate increased between the first and second testing, but this was not related to the number of medical visits or the severity of allergic disease.CONCLUSION:Antibody prevalence in children was low but increased during the study period. The majority of children who tested positive for SARS-CoV-2 antibodies did not have a history of coronavirus disease 2019, suggesting that most infections were subclinical.

Background Inclusion of female authors has been noted as potentially beneficial in the development of medical guidelines. Japanese professional committees representing allergic subspecialties develop practical guidelines with recommendations to caregivers, but these committees may be influenced by their gender composition. The objective of our study was to examine the influence of gender in developing pediatric allergic disease guidelines in Japan from 1999 to 2020. Methods We examined the gender parities among the guideline committee members in allergic rhinitis, atopic dermatitis, bronchial asthma, and food allergy guidelines in Japan. We examined the gender composition of the committees, annual trends, and differences in guideline content. Results The median proportion of women members among the 22 guidelines committees was 6.6% (range: 0%-27.3%). The analysis of the quadrant period did not show a significant increase in the proportion of female members. The food allergy group had a significantly higher proportion of female members than other guidelines (P < 0.01), but the proportion decreased from 25% to 14.3% during the observation period. For the pediatric asthma guidelines, the proportion of female committee members decreased from 5.3% in the 2000 version to 0% in the most recent revision in 2017. Conclusions The proportion of women on the committees that develop pediatric guidelines continues to be low and has not improved over the past 20 years.

Purpose Wheezing is the dominant pathological characteristic of asthma. It is estimated that 50% of all children have experienced wheezing at least once in their first six years of life. This study aimed to investigate initial wheezing attacks in pediatric patients and to determine connection between transient wheezing (TW) attacks and persistent wheezing (PW). Methods The immune responses of children who initially presented with wheezing attacks were studied. A total of 231 children with wheezing attacks at the time of admission were enrolled in the study. The study population consisted of 68 children with wheezing episodes. Children with recurrent wheezing who were introduced to inhaled steroids after 12 months were further grouped into either PW or TW groups. Results At the initial onset, cytokine analysis of the children revealed a marked increase in serum soluble and transmembrane forms of interleukin receptor-2 (ST2) in PW. In contrast, there were no changes in serum levels of IL-4, IL-13, and IL-33. The serum ST2 levels of the PW group were higher compared to those of the TW group. Moreover, a significant increase in ST2 expression was observed in PW children with recurrent wheezing attacks. Conclusion The present study demonstrated that ST2 might be a useful index for predicting the prognosis of infantile asthma. Hence, elucidation of the mechanism of ST2 expression in childhood allergic diseases is essential.

To analyze serum ST2 changes in severe atopic asthma in children by administration of omalizumab. And also find a correlation between the serum ST2 concentration and respiratory function measured by forced oscillation technique. We performed a retrospective study of patients with atopic asthma in children over 6 years old. The subjects of the present study are 9 patients who received omalizumab as a treatment for bronchial asthma in our department in 2016-2017. There were aged from 7-13 years (median 9 years 6 months). The patients were administered in doses of omalizumab determined from body weight and serum IgE levels. We investigated blood examinations and respiratory function, compared with before administration. Blood examination also contains of their serum levels of antigen-specific IgE, IL-33, ST2. We confirmed that ST2 levels did not change, but a significantly lower concentration of IL-33 level was detected in after-administration group, suggesting the improvement of allergic reaction in bronchial epithelial cells. We are currently measuring the concentration of soluble ST2 in some samples. It has already reported that IL-33 plays important roles in inflammation in atopic asthma. It can be inferred from previous reports so far that ST2 was an isolated receptor that was considered to the context of inflammatory and allergic disease. On the other hand, it remains possible that soluble ST2 as decoy receptor selectively inhibited the expressions of membrane bound type ST2. The mechanism is still unknown, but we speculate that ST2, especially soluble ST2, is an important factor in atopic asthma in children.

Most of the children with milk allergy tolerate baked milk. Tolerance of baked milk is a marker of transient IgE mediated milk allergy. IL-1 receptor family member ST2 was an isolated receptor, IL-33 was identified as functional ligands for ST2. IL-33 expressed by a variety of cells, and it is likely that ST2 is marker of milk allergy. We performed a retrospective study of patients with low dose milk allergy. The subjects of the present study are 132 patients aged from 11 to 96 months. (average 31.2 months) who performed oral food challenge in our department in 2015-2016. The patients ate low dose baked milk; using muffin contained 3mL of milk (protein 102mg) and it was baked at 180°C for 30 minutes. We classified the groups according to physical examinations with allergic symptoms in 3 hours as positive group and investigated blood examinations compared to negative group. Blood examination contains of their serum levels of total IgE, milk-specific IgE, casein-specific IgE, IL-33, ST2. We confirmed that median milk IgE levels did not change. But a significantly higher concentration of ST2 level was detected in positive group compared with negative group, suggesting the influence of in allergic reaction due to low dose milk. Interestingly, the elevation of IL-33 was not observed in allergic group. We concluded that ST2 is an important factor in milk allergy and speculated that it is because the relationships ST2 and IL-33 played an important role in food allergy due to low dose allergens.