[DEVELOPMENT AND VALIDATION OF QUALITY OF LIFE QUESTIONNAIRE FOR PARENT BURDEN OF CHILDREN WITH FOOD ALLERGY].

OBJECTIVE: Quality of life (QOL) questionnaires for parents of children with food allergies have been developed in the United States and Europe. However, no original Japanese QOL questionnaire has been developed till date. We aimed to develop an original questionnaire to evaluate the QOL in parents of children with food allergies in Japan. METHODS: We collected QOL-related questions from parents of children with food allergies aged 0-15 years, and created a primary questionnaire. Responses to the primary questionnaire were obtained from the parents again, and question items were reduced using factor analysis to create a secondary questionnaire comprising eight items. In addition to the secondary questionnaire, responses to the Food Allergy QOL Questionnaire-Parent Form (FAQLQ-PF) Japanese version, Parent reported Health-Related QOL in children and adolescents (KINDL) and Health-related QOL (SF-8) were obtained from parents to assess the validity of the secondary questionnaire. RESULTS: A total of 407 parents completed all questionnaires. The secondary questionnaire scores were positively correlated with those of FAQLQ-PF and weakly negatively correlated with the KINDL and SF-8 mental component summary scores. Parents of children with food allergies with ≥3 culprit foods or severe reactions to daily foods, a history of anaphylaxis, and those carrying adrenaline autoinjectors scored higher and had lower QOL. CONCLUSION: The developed original questionnaire is a valid QOL questionnaire for Parents of children with food allergies.

CD14 down-modulation as a real-time biomarker in Kawasaki disease.

Objectives: The objectives of this study were to investigate the pathophysiology of Kawasaki disease (KD) from immunological and oxidative stress perspectives, and to identify real-time biomarkers linked to innate immunity and oxidative stress in KD. Methods: We prospectively enrolled 85 patients with KD and 135 patients with diverse conditions including immune, infectious and non-infectious diseases for this investigation. Flow cytometry was used to analyse the surface expression of CD14, CD38 and CD62L on monocytes, along with a quantitative assessment of CD14 down-modulation. Additionally, oxidative stress levels were evaluated using derivatives of reactive oxygen metabolites (d-ROMs) and antioxidant capacity measured by a free radical elective evaluator system. Results: During the acute phase of KD, we observed a prominent CD14 down-modulation on monocytes, reflecting the indirect detection of circulating innate immune molecular patterns. Moreover, patients with KD showed a significantly higher CD14 down-modulation compared with infectious and non-infectious disease controls. Notably, the surface expression of CD14 on monocytes was restored concurrently with responses to intravenous immunoglobulin and infliximab treatment in KD. Furthermore, d-ROM levels in patients with KD were significantly elevated compared with patients with infectious and non-infectious diseases. Following intravenous immunoglobulin treatment, oxidative stress levels decreased in patients with KD. Conclusion: Monitoring CD14 down-modulation on monocytes in real-time is a valuable strategy for assessing treatment response, distinguishing KD relapse from concomitant infections and selecting second-line therapy after IVIG treatment in KD patients. The interplay between inflammation and oxidative stress likely plays a crucial role in the development of KD.

Suppressed pediatric asthma hospitalizations during the COVID-19 pandemic in Japan, from a national survey.

BACKGROUND: Acute asthma exacerbation in children is often caused by respiratory infections. In this study, a coordinated national surveillance system for acute asthma hospitalizations and causative respiratory infections was established. We herein report recent trends in pediatric acute asthma hospitalizations since the COVID-19 pandemic in Japan. METHODS: Thirty-three sentinel hospitals in Japan registered all of their hospitalized pediatric asthma patients and their causal pathogens. The changes in acute asthma hospitalization in children before and after the onset of the COVID-19 pandemic and whether or not COVID-19 caused acute asthma exacerbation were investigated. RESULTS: From fiscal years 2010-2019, the median number of acute asthma hospitalizations per year was 3524 (2462-4570), but in fiscal years 2020, 2021, and 2022, the numbers were 820, 1,001, and 1,026, respectively (the fiscal year in Japan is April to March). This decrease was observed in all age groups with the exception of the 3- to 6-year group. SARS-CoV-2 was evaluated in 2094 patients from fiscal years 2020-2022, but the first positive case was not detected until February 2022. Since then, only 36 of them have been identified with SARS-CoV-2, none of which required mechanical ventilation. Influenza, RS virus, and human metapneumovirus infections also decreased in FY 2020. In contrast, 24% of patients had not been receiving long-term control medications before admission despite the severity of bronchial asthma. CONCLUSION: SARS-CoV-2 was hardly detected in children with acute asthma hospitalization during the COVID-19 pandemic. This result indicated that SARS-CoV-2 did not induce acute asthma exacerbation in children. Rather, infection control measures implemented against the pandemic may have consequently reduced other respiratory virus infections and thus acute asthma hospitalizations during this period. However, the fact that many hospitalized patients have not been receiving appropriate long-term control medications is a major problem that should be addressed.

Patients with polyethylene glycol allergy can experience immediate-type hypersensitivity reactions after exposure to analog substances.

Polyethylene glycol (PEG) allergy has been recently observed after COVID-19 mRNA vaccination. We present a case of a patient with a history of two hospitalisations for unexplained recurrence of immediate-type hypersensitivity reactions and anaphylaxis who was diagnosed with PEG allergy in early childhood. Subsequently, he was instructed to avoid using PEG-containing daily necessities and drugs. However, in middle childhood, he presented with immediate-type hypersensitivity reactions after taking PEG-free antibiotics. The prick test was positive for the whole drug but negative for its active ingredient. PEG can cross-react with compounds with a C-C-O skeleton as analogue substances; accordingly, the presence of a substance with a similar skeleton in the additive may have been the causative factor. Our findings indicate that patients with PEG allergy may experience immediate-type hypersensitivity reactions to analogue substances.

Prevalence of Allergic Diseases across All Ages in Japan: A Nationwide Cross-Sectional Study Employing Designated Allergic Disease Medical Hospital Network.

Introduction: Allergic diseases affect both children and adults, but generation-specific prevalence rates are unclear. Methods: An online questionnaire was used from December 2021 to January 2022 to survey the prevalence of allergic diseases among staff and their families of designated allergic disease medical hospitals in Japan. In this study, bronchial asthma (BA), atopic dermatitis (AD), food allergies (FAs), allergic rhinitis (AR), allergic conjunctivitis (AC), metal allergies (MAs), and drug allergies (DAs) were the allergic diseases surveyed. Results: In total, 18,706 individuals were surveyed (median age, 36 years; quartile range, 18-50). Allergic disease was reported in 62.2% of respondents. Across all ages, prevalence rates were as follows: BA (14.7%), AD (15.6%), FAs (15.2%), AR (47.4%), AC (19.5%), MAs (1.9%), and DAs (4.6%). The prevalence of BA and AR was higher in male children, whereas that of FAs and AC was higher in adult females. The prevalence of MAs and DAs peaked during adulthood and predominated among females. Conclusions: Our results suggest that approximately two-thirds of the Japanese population may have an allergic disease, with AR being the most prevalent.

The association between early formula and reduced risk of cow's milk allergy during the first three year of life: a Japanese cohort study.

BACKGROUND: Our recent observational study showed that regular consumption of cow's milk (CM) formula during early infancy (3-6 months old) was associated with a reduced risk of CM allergy (CMA) at 12 months old. However, the long-term association is unclear. The present study was aimed to examine how long this inverse association persists after 12 months old. METHODS: This study used the dataset of an ongoing nationwide prospective cohort, the Japan Environment and Children's Study, in which participants were registered between January 2011 and March 2014. We analyzed 65,568 children followed-up until 36 months old. The exposure factors were the consumption statuses of formula milk from 0-3, 3-6, and 6-12 months old. The primary outcome was the prevalence of CMA at 6, 12, 18, 24 and 36 months old. CMA was defined as an allergic reaction and sensitization to CM protein in an individual with no or limited intake of this protein at the evaluation time, combined with physician-diagnosed food allergy. Multivariable regression models were used to estimate the association between the periods of formula consumption and the prevalence of CMA. RESULTS: The prevalence of CMA increased with a peak of 1.51% at 18 months old and then declined to 0.79% at 36 months old. Formula milk from 3-6 months old was associated with a reduced risk of CMA throughout the first 3 years of life, although the extent of the reduction was mitigated with age (adjusted relative risk: [95% confidence interval]: 0.19 [0.10-0.34] at 12 months old, 0.23 [0.16-0.33] at 18 months old, 0.41 [0.26-0.64] at 24 months old, and 0.47 [0.26-0.80] at 36 months old). The association between early formula and CMA were observed in both children with and without eczema, but more prominent and long-lasting in the former than the latter. CONCLUSIONS: Regular exposure to CM protein during infancy was associated with a reduced prevalence of CMA during early childhood. At present, however, this observational study does not necessarily encourage formula feeding, and randomized controlled trials are warranted to confirm the findings and their significance.

Enhanced airway hyperresponsiveness in asthmatic children and mice with A(H1N1)pdm09 infection.

BACKGROUND: Severe asthma exacerbation is an important comorbidity of the 2009 HIN1 pandemic (A(H1N1)pdm09) in asthmatic patients. However, the mechanisms underlying severe asthma exacerbation remain unknown. In this study, airway hyperresponsiveness (AHR) was measured in pediatric asthma patients infected with A(H1N1)pdm09. We also evaluated AHR in asthmatic mice with A(H1N1)pdm09 infection and those with seasonal influenza for comparison. METHODS: AHRs in asthmatic children were defined as the provocative acetylcholine concentration causing a 20% reduction in forced expiratory volume in 1 s (PC20 ). To investigate the pathophysiology using animal models, BALB/c mice aged 6-8 weeks were sensitized and challenged with ovalbumin. Either mouse-adapted A(H1N1)pdm09, seasonal H1N1 virus (1 × 105 pfu/20 µl), or mock treatment as a control was administered intranasally. At 3, 7, and 10 days after infection, each group of mice was evaluated for AHR by methacholine challenge using an animal ventilator, flexiVent. Lung samples were resected and observed using light microscopy to assess the degree of airway inflammation. RESULTS: AHRs in the children with bronchial asthma were temporarily increased, and alleviated by 3 months after discharge. AHR was significantly enhanced in A(H1N1)pdm09-infected asthmatic mice compared to that in seasonal H1N1-infected mice (p < .001), peaking at 7 days postinfection and then becoming similar to control levels by 10 days postinfection. Histopathological examination of lung tissues showed more intense infiltration of inflammatory cells and severe tissue destruction in A(H1N1)pdm09-infected mice at 7 days postinfection than at 10 days postinfection. CONCLUSION: Our results suggest that enhanced AHR could contribute to severe exacerbation in human asthmatic patients with A(H1N1)pdm09 infection.

Possible association between early formula and reduced risk of cow's milk allergy: The Japan Environment and Children's Study.

BACKGROUND: Despite evidence for the protective effects of early regular exposure to peanut and egg proteins against allergies, the optimal timing of cow's milk (CM) protein exposure is unknown. OBJECTIVE: We aimed to determine when during the first year of life CM-based formula consumption becomes associated with lower CM allergy (CMA) risk. METHODS: We used the data set of the Japan Environment and Children's Study (JECS), a nationwide birth cohort involving over 100 000 mother-child pairs. CMA was defined as an allergic reaction to a CM product in an individual not consuming CM products at the time of evaluation, combined with physician-diagnosed food allergy. For each exposure, we identified when formula milk was commenced, and its consumption status during 0-3, 3-6 and 6-12 months old. RESULTS: The prevalence of CMA was 0.23% and 1.03% at 6 and 12 months old, respectively. Multivariable regression analyses revealed that introducing regular consumption of formula within the first 3 months of age was associated with lower risk of CMA at 12 months. Regular consumption at 3-6 months was strongly associated with a reduction in 12-month CMA (adjusted relative risks [95% confidence intervals]: 0.22 [0.12-0.35]), whereas no association was observed at 0-3 months (1.07 [0.90-1.27]). CONCLUSION AND CLINICAL RELEVANCE: Regular exposure to formula milk at age 3 months or older is associated with lower CMA at 12 months old, suggesting that the effect of very early CM exposure on CMA may disappear if the exposure is brief. At present, however, the results of this observational study should not be used for formula recommendation and randomized controlled trials are required to confirm this association.

The severity of reaction after food challenges depends on the indication: A prospective multicenter study.

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.

Risk prediction of severe reaction to oral challenge test of cow's milk.

Cow's milk is one of the most common food allergens among children. Oral food challenge tests determine the threshold dose of allergens, but have not been standardized. To reduce the severe reactions, we developed a practical model of the test. We studied 111 high-risk patients who underwent a first milk oral food challenge on the risk-stratified dose between 2011 and 2017 for predicting the severe reaction risk. Severe reactions were defined as showing > 3 of Sampson's classification grade. Twenty-eight patients (25%) showed severe reactions without death. Prior to oral food challenge, severe reaction patients experienced milk avoidance (71% vs. 45%, p = 0.02) or bronchial asthma (61% vs. 28%, p = 0.003) more frequently and showed higher milk-specific IgE levels (median 28.3 vs. 7.7 UA/mL, p < 0.0001) than non-severe reaction patients. Multivariate logistic regression analyses established a formula including severe reaction-associated factors; increased levels of milk-specific IgE (odds ratio 11.61, p = 0.001), milk avoidance (odds ratio 3.88, p = 0.02), and bronchial asthma (odds ratio 3.75, p = 0.02). This model had 86% sensitivity and 56% specificity (cut-off 0.25) for risk. Five patients with < 25% probability developed severe reactions, which started in > 3 grade dyspnea up to 20 mL of challenge.Conclusion: This model could effectively reduce the severe reaction development on the first milk oral food challenge test according to the individual needs. What is Known: •Higher levels of milk-specific IgE values, bronchial asthma, and complete milk avoidance are independent risk factors of severe reactions during the cow's milk oral food challenge. What is New: •Statistical analyses of our milk oral food challenge records for 111 patients helped us develop a model formula predicting severe reactions at the first test with high specificity and sensitivity. •This simple risk-stratified protocol is useful for minimizing the adverse events in the first milk challenge.

[POLLEN FOOD ALLERGY SYNDROME IN A FIVE-YEAR-OLD BOY AFTER MOVING HOUSE AT THE FOOT OF THE MOUNTAIN: A CASE REPORT].

We report the case of a boy with a history of atopic dermatitis starting in infancy. At the age of four, his family moved into a newly built house at the foot of a mountain. One year later, he was diagnosed with Japanese Cedar pollinosis. During the same year, in March, he began to experience oral symptoms, hoarseness, and coughing, after eating multiple types of fruits and vegetables, like soybeans, apples, etc. His tests for Bet v1 and the pathogenesis-related protein-10 (PR-10) of the corresponding foods were positive; accordingly, he was diagnosed with Pollen Food Allergy Syndrome (PFAS). In order to investigate the relationship between pollen and food allergies, we counted the pollen grains dispersed at the patient's house during a period of one year and measured his specific IgE titers for pollen and food allergens every three months. We found a large amount of Japanese cedar, cypress, oak, and various other species of pollen dispersed at the patient's house. All counts were higher than the average pollen counts in the city of Fukuoka. After the seasonal dispersal of oak pollen, the patient's specific IgE antibody titers against Alder, Oak, Bet v1, Gly m4, and PR-10 protein group of fruits increased, although alder pollen was not detected. We thus inferred that the patient had developed PFAS by exposure to a large amount of Fagales species pollen, including oak.

Infantile hypophosphatasia combined with vitamin B6-responsive seizures and reticular formation lesions on magnetic resonance imaging: A case report.

BACKGROUND: Hypophosphatasia (HPP) is a rare genetic disorder characterized by rachitic bone manifestations and a low serum alkaline phosphatase (ALP) level. It is caused by mutations in the tissue non-specific alkaline phosphatase (TNSALP) gene, which encodes the tissue non-specific isozyme of ALP. HPP patients exhibit various presentations depending on their age at onset, such as infantile HPP combined with vitamin B6-responsive seizures. CASE PRESENTATION: A newborn with infantile HPP presented with tonic convulsions from day 5 after birth and received intravenous vitamin B6 (10mg/kg/day pyridoxal phosphate). Eleven days later, frequent apneic episodes occurred, and head magnetic resonance imaging (MRI) showed bilateral reticular formation lesions in the brain stem, including the medulla oblongata. After the pyridoxal phosphate dose was increased (to 40mg/kg/day), the patient's seizures and apnea resolved, and her MRI findings also improved. Genetic testing revealed that she was homozygous for the 1559delT mutation of TNSALP. CONCLUSIONS: High-dose pyridoxal phosphate is a useful treatment for HPP-induced seizures and might improve reticular formation lesions.