Influence of household pet ownership and filaggrin loss-of-function mutations on eczema prevalence in children: A birth cohort study.

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.

Parental stress and food allergy phenotypes in young children: A National Birth Cohort (JECS).

BACKGROUND: Food allergy children and their families tend to have emotional distress and anxiety. There have been few reports of differences in parenting stress and a child's food allergy phenotypes. METHODS: We examined the associations between food allergy phenotypes in children and parenting stress assessed by the Parenting Stress Index-Short Form (PSI-SF) from a national birth cohort (Japan Environment and Children's Study). RESULTS: We included 65,805 children for statistical analysis. Of them, 7.2% of children had a food allergy diagnosis at 2 years old. The means of the total PSI-SF (39.9 ± 10.3, 39.1 ± 9.9), CD-SF (19.5 ± 5.4, 19.1 ± 5.2), and PD-SF (20.5 ± 6.3, 20.0 ± 6.1) scores are similar for caregivers in the with and without food allergy groups. Food allergy diagnosis resulted in significantly higher total PSI scores (coefficient .47, 95% CI 0.19-0.75, p = .001), CD-SF (coefficient .22, 95% CI 0.07-0.38, p = .004), and PD-SF (coefficient .24, 95% CI 0.08-0.41, p = .004). A similar trend was observed for allergy reactions to hen's egg. However, there was no clear relationship between allergic reactions to milk, wheat, nuts, and PSI-SF. CONCLUSIONS: Parental stress was significantly related to a child's food allergy. Furthermore, hen's egg allergy increased parental stress. Multiple food avoidance might also increase parental stress. Healthcare providers need to be aware of parental stress in our daily clinic.

Teenage and young adult pregnancy and depression: findings from the Japan environment and children's study.

Teenage pregnancy increases the threat of depression because of its many factors. Pregnancy during young adulthood may also have several risk factors for depression compared to older pregnancies. However, data on depression in young adult pregnancies are lacking. This study investigated the association between teenage and young adult pregnancy and depression. Data from the Japan Environment and Children's study was used as a nationwide multicenter prospective cohort study. A multivariate logistic regression was performed to investigate the association between age groups (14-19, 20-24, 25-29, 30-34, ≥ 35 years) and depression, adjusted for behavioral and sociodemographic characteristics. Depression was assessed using the Kessler Psychological Distress Scale. In total, 96,808 pregnant women responded to the questionnaire. Teenage (14-19 years) and young adult (20-24 years) pregnancy were associated with an increased risk of depression compared to older pregnancy (≥ 35 years) (teenage: OR 4.28, 95% confidence interval, CI [3.24-5.64]; young adult: OR 3.00, 95% CI [2.64-3.41]). After adjusting for covariates, the magnitude of the risk of depression was attenuated. However, teenage and young adult pregnancy remained at a significantly increased risk of depression compared to older pregnancy (teenage: OR 2.38, 95% CI [1.77-3.21]; young adult: OR 2.14, 95% CI [1.87-2.46]). Our findings indicate that teenage and young adults' pregnancy are at an increased risk of depression compared to older pregnancy. These findings suggest prioritizing teenage and young pregnant women for prevention and interventions related to depression.

Congenital hypothyroidism and thyroid function in a Japanese birth cohort: data from The Japan Environment and Children's Study.

The most common hormonal and metabolic disease in early childhood is congenital hypothyroidism (CH). This study aimed to describe CH in large-scale birth cohort data and summarize the results of serum thyroid-stimulating hormone (TSH) and free thyroxine (fT4) levels in 2-yr-old children. Data were obtained from the Japan Environment and Children's Study (JECS), and we identified 171 children with CH detected in newborn screenings or medical records (170.5 per 100,000 population). Infants with CH are at higher risk of developing congenital diseases than those without CH. Of 171 children with CH, 20 (11.7%) were diagnosed with congenital heart defects, 33 (19.3%) had chromosomal or other congenital abnormalities, and 23 (13.5%) had Down syndrome. At the age of 2 yr old, the median and 95% reference range values for TSH and fT4 were 2.13 (0.78-5.52) µIU/mL and 1.2 (1.0-1.5) ng/dL, respectively. Moreover, boys had slightly higher TSH and fT4 levels than did girls. Data on the distribution of TSH and fT4 in 2-yr-old children should be useful for decreasing the misclassification of thyroid disorders in the pediatric population. Trial-off treatment and re-evaluation of thyroid function are needed to classify permanent congenital hypothyroidism and transient congenital hypothyroidism after 3 yr of age.

Sex steroid hormones and allergic diseases in children: a pilot birth cohort study in the Japan Environment and Children's Study cohort.

BACKGROUND: Numerous studies suggest that sex steroids might play a role in sex disparity observed in allergic diseases in adults. However, whether sex hormones influence allergic diseases in children remains unclear. The aim of the present study was to examine the association of sex steroid hormones with allergic disease in Japanese children. METHODS: The present cross-sectional study included 145 6-year-old children participating in a pilot birth cohort study in the Japan Environment and Children's Study. Data on allergic diseases were obtained from questionnaires, and serum levels of sex steroid hormones and allergen-specific IgE were measured. Logistic regression was performed to evaluate the association of sex hormones with allergic diseases. RESULTS: After adjusted sex, amount of body fat at 6 years, parental history of allergic disease, and exposure to tobacco smoke, serum dehydroepiandrosterone sulfate level was significantly associated with reduced odds of any allergic disease (adjusted odds ratio, 0.58; 95% confidence interval, 0.36-0.93; P = 0.024) and serum follicle-stimulating hormone level was significantly associated with increased odds of any allergic disease (adjusted odds ratio, 2.04; 95% confidence interval, 1.01-4.11, P = 0.046). Dehydroepiandrosterone sulfate level showed a significant association with number of allergic diseases. CONCLUSIONS: The current study findings suggest that sex hormones may play an important role in the development of allergic diseases in prepubertal children.

Reference blood pressure values obtained using the auscultation method for 2-year-old Japanese children: from the Japan Environment and Children's Study.

BACKGROUND: Reference blood pressure (BP) values for Japanese children based on a large number of measurements by auscultation have not yet been established. METHODS: This was a cross-sectional analysis of data from a birth-cohort study. The data from the sub-cohort study conducted for children at the age of 2 years in the Japan Environment and Children's Study from April 2015 to January 2017 were analyzed. BP was measured via auscultation using an aneroid sphygmomanometer. Each participant was measured in triplicate, and the average value of two consecutive measurements with a difference of less than 5 mmHg was recorded. The reference BP values were estimated using the lambda-mu-sigma (LMS) method and compared with those obtained via the polynomial regression model. RESULTS: Data from 3361 participants were analyzed. Although the difference between the estimated BP values by the LMS and the polynomial regression model was small, the LMS model was more valid based on the results of the fit curve of the observed values and regression models for each model. For 2-year-old children with heights in the 50th percentile, the 50th, 90th, 95th, and 99th percentile reference values of systolic BP (mmHg) for boys were 91, 102, 106, and 112, and that for girls were 90, 101, 103, and 109, respectively, and those of diastolic BP for boys were 52, 62, 65, and 71, and that for girls were 52, 62, 65, and 71, respectively. CONCLUSION: The reference BP values for 2-year-old Japanese children were determined based on auscultation and were made available.

Maternal Dietary Zinc Intake during Pregnancy and Childhood Allergic Diseases up to Four Years: The Japan Environment and Children's Study.

Maternal dietary zinc intake and childhood allergy have inconsistent relationships. Thus, this study aimed to evaluate the influence of low maternal dietary zinc intake during pregnancy on developing pediatric allergic diseases. This study was designed using the Japan Environment and Children's Study dataset. The model building used data from 74,948 mother-child pairs. Maternal dietary zinc intake was estimated based on the food frequency questionnaire, collecting the intake information of 171 food and beverage items. Fitted logistic regression models and generalized estimating equation models (GEEs) estimated the association between energy-adjusted zinc intake and childhood allergic conditions. The energy-adjusted zinc intake did not affect the risk of developing allergic disorders (wheeze, asthma, atopic dermatitis, rhinitis, and food allergy) in offspring. The GEE model revealed similar insignificant odds ratios. No significant association was found between zinc intake during pregnancy and allergic diseases in offspring in early childhood. Further study remains necessary to examine the association between zinc and allergy with reliable zinc status biomarkers in the body.

Enhanced early skin treatment for atopic dermatitis in infants reduces food allergy.

BACKGROUND: Early-onset atopic dermatitis is a strong risk factor for food allergy, suggesting that early effective treatment may prevent transcutaneous sensitization. OBJECTIVES: This study tested whether enhanced treatment of atopic dermatitis to clinically affected and unaffected skin is more effective in preventing hen's egg allergy than reactive treatment to clinically affected skin only. METHODS: This was a multicenter, parallel-group, open-label, assessor-blind, randomized controlled trial (PACI [Prevention of Allergy via Cutaneous Intervention] study). This study enrolled infants 7-13 weeks old with atopic dermatitis and randomly assigned infants in a 1:1 ratio to enhanced early skin treatment or conventional reactive treatment using topical corticosteroids (TCSs). The primary outcome was the proportion of immediate hen's egg allergy confirmed by oral food challenge at 28 weeks of age. RESULTS: This study enrolled 650 infants and analyzed 640 infants (enhanced [n = 318] or conventional [n = 322] treatment). Enhanced treatment significantly reduced hen's egg allergy compared with the conventional treatment (31.4% vs 41.9%, P = .0028; risk difference: -10.5%, upper bound of a 1-sided CI: -3.0%), while it lowered body weight (mean difference: -422 g, 95% CI: -553 to -292 g) and height (mean difference: -0.8 cm, 95% CI: -1.22 to -0.33 cm) at 28 weeks of age. CONCLUSIONS: This study highlighted the potential of well-controlled atopic dermatitis management as a component of a hen's egg allergy prevention strategy. The enhanced treatment protocol of this trial should be modified before it can be considered as an approach to prevent hen's egg allergy in daily practice to avoid the adverse effects of TCSs. After remission induction by TCSs, maintenance therapy with lower potency TCSs or other topical therapies might be considered as alternative proactive treatments to overcome the safety concerns of TCSs.

Relationship between Food Allergy and Endotoxin Concentration and the Toleration Status at 2 Years: The Japan Environment and Children's Study.

Changes in household endotoxin concentration may affect the prognosis of food allergy (FA), but data on the association between household endotoxin concentration and an already-developed FA are scarce. Thus, we investigated the association between environmental endotoxin exposure and tolerance to hen's egg (HE) and cow's milk (CM) using data from children participating in the Japan Environment and Children's Study who had HE allergies (n = 204) and CM allergy (n = 72) in their first year of life. We grouped the endotoxin results into quartiles 1-4 (Q1-Q4). In children with HE allergy and with CM allergy, there was no significant difference in the prevalence of tolerance to HE and CM at 2 years old when comparing endotoxin levels of the children in Q1 with those in Q2, Q3, and Q4, respectively. However, subgroup analyses by the presence of eczema and causal foods revealed that children in Q1 had a lower prevalence of tolerance to foods in some subgroup analyses and lower causal allergen-specific immunoglobulin G4 levels. Although an individually based approach against endotoxin according to background characteristics, such as eczema and causal foods, is necessary, preventing excessive endotoxin removal might contribute to FA resolution in some children.

[A CASE OF INDUCIBLE LARYNGEAL OBSTRUCTION UNSUCCESSFULLY TREATED AS SEVERE ASTHMA WAS WELL CONTROLLED AFTER APPROPRIATE DIAGNOSIS AND INSTRUCTION OF THERAPEUTIC BREATHING MANEUVERS].

BACKGROUND: Inducible laryngeal obstruction (ILO) refers to respiratory disorders caused by airflow limitation in the larynx, including vocal cord dysfunction, and may sometimes be misdiagnosed as bronchial asthma (BA). Here, we report the case of an 11-year-old boy diagnosed with BA in infancy. He was referred to our Allergy Center and was taking a high dose of inhaled corticosteroids (ICS) due to frequent coughing from the age of 10 years and persistent coughing following COVID-19 infection at the age of 11. However, the patient continued to experience frequent coughing attacks and repeated visits to the emergency department after inhalation of ß2-stimulants failed to improve his cough. We admitted him to the allergy center for examinations to assess the BA severity. In the airway hypersensitiveness test, saline inhalation performed prior to methacholine inhalation caused expiratory stridor and respiratory distress in the larynx, which worsened with ß2-stimulant inhalation. Based on these results, we ruled out BA and diagnosed ILO. We instructed him on breathing maneuvers, and he was able to respond appropriately when symptoms appeared. We then started reducing his ICS dose.

Risk factors of admission in school children with severe atopic dermatitis.

There are no data about risk factor of admission and long-term (>1 year) prognosis of proactive therapy using topical corticosteroids (TCSs) in school children. This study aims to identify the prognosis of school children over 3 years treated with proactive therapy after hospitalization due to atopic dermatitis (AD). This retrospective cohort study used electronic medical record data of schoolchildren (aged 5-19 years) with a long-term admission program for AD at the National Center for Child Health and Development from January 2008 to December 2013. Long-term prognosis at 1 and 3 years after discharge were retrospectively identified from their medical records. The most common exacerbation factor was poor adherence (51.8%). At 1 and 3 years after hospitalization, 87.3% and 74.3%, respectively, of the children used TCSs on their trunk and limbs less than twice a week. Investigator's Global Assessment of AD scores were ≤1 for 81.0%and 75.7% at 1 and 3 years after discharge, respectively. AD was well-controlled during follow-up. Rehospitalization due to AD was observed in 11.8% children. Poor adherence was biggest risk factor for admission. Children with severe AD could achieve well-controlled AD with a long-term admission AD program and home-based proactive therapy using TCSs for 3 years after discharge. Maintaining good adherence for AD treatment is required to prevent exacerbation and improve future prognosis in school children. However, we need to engage for the children who required rehospitalization.

STAT6 gain-of-function variant exacerbates multiple allergic symptoms.

BACKGROUND: Allergic diseases were long considered to be complex multifactorial disorders. However, recent findings indicate that severe allergic inflammation can be caused by monogenic immune defects. OBJECTIVES: We sought to clarify the molecular pathogenesis of a patient with early-onset multiple allergic diseases, a high serum IgE level, hypereosinophilia, treatment-resistant severe atopic dermatitis with increased dermal collagen fiber deposition, and eosinophilic gastrointestinal disorder with numerous polypoid nodules. METHODS: A missense variant in STAT6 was identified, and its function was examined using peripheral blood, transfected HEK293 cells, lymphoblastoid cell lines, and knock-in mice with the corresponding mutation. RESULTS: Whole-exome sequencing identified a de novo heterozygous missense variant in signal transducer and activator of transcription 6 (STAT6) (p.Asp419Asn). Luciferase reporter assay revealed that the transcriptional activity of this STAT6 mutant was upregulated even without IL-4 stimulation. Phosphorylation of STAT6 was not observed in either the patient's TH2 cells or lymphoblastoid cell lines without stimulation, whereas it was induced more strongly in both by IL-4 stimulation compared with healthy controls. STAT6 protein was present in the nuclear fraction of the lymphoblastoid cell lines of the patient even in the absence of IL-4 stimulation. The patient's gastric mucosa showed upregulation of STAT6-, fibrosis-, and germinal center formation-related molecules. Some of the knock-in mice with the corresponding mutation spontaneously developed dermatitis with skin thickening and eosinophil infiltration. Moreover, serum IgE levels and mRNA expression of type 2 cytokines were increased in the knock-in mice-with or without development of spontaneous dermatitis-compared with the wild-type mice. CONCLUSIONS: A novel STAT6 gain-of-function variant is a potential cause of primary atopic disorders.

Endotoxin concentration and persistent eczema in early childhood.

Although endotoxin concentration in the environment is negatively associated with atopic dermatitis (AD) onset in early childhood, the association between endotoxin concentration in the environment and eczema resolution in children with preexisting eczema is unclear. The aim of this study was to evaluate the association between endotoxin concentration in house dust and eczema persistence in young children. The authors used data from children participating in JECS (Japan Environment and Children's Study). In children who had AD or AD-like lesions at the age of 1 year, the authors investigated the association between the prevalence of eczema at the age of 3 years and endotoxin concentration (categorized by quartiles) in the dust on children's mattresses at the ages of 1.5 and 3 years. This study included 605 children. Eczema was significantly less prevalent among children whose mattresses were in the second and third quartiles of endotoxin concentration when they were 18 months old than among children whose mattresses were in the first quartile (adjusted odds ratio, 0.57 [95% confidence interval, 0.35-0.93] and adjusted odds ratio, 0.49 [95% confidence interval, 0.29-0.83], respectively). Moreover, of the children with eczema at age 3 years, those whose mattresses had endotoxin concentrations in the first quartile had significantly worse sleep disturbance caused by itchy rash (>1 time per week) than did those whose mattresses were in the third and fourth quartiles (20.0% vs 3.3% and 3.7%, both p values < 0.01). The findings indicate that low endotoxin exposure is associated with a higher prevalence of persistent eczema during early childhood.

Tolerability and safety of a new elimination diet for pediatric eosinophilic gastritis and duodenitis.

BACKGROUND: Non-esophageal eosinophilic gastrointestinal disorders (non-EoE EGIDs) are chronic inflammatory disorders with massive infiltration of eosinophils into the gastrointestinal tract. Food elimination diets are potentially effective treatments. But the existing dietary therapies have various weak points. We developed a new regimen to compensate for the shortcomings of the elemental diet and 6-food elimination diet. The new regimen consists of an amino-acid-based formula, potatoes, vegetables, fruits and restricted seasonings. We named it the "Rainbow Elimination Diet (ED)." The aims of this study were to evaluate the tolerability and safety of this diet. METHODS: A retrospective medical record examination was conducted at the National Center for Child Health and Development covering the period from January 2010 through December 2018. The medical records of patients (age 2-17 y) with histologically diagnosed non-EoE EGIDs were reviewed. The tolerability, nutritional intake, symptoms, and blood test findings were evaluated. RESULTS: Nineteen patients were offered several kinds of food-elimination diets. Seven patients (eosinophilic gastritis: 5; gastroenteritis: 1; duodenitis: 1) were treated with Rainbow ED. Six patients were compliant with this diet. The median duration of the diet induction phase was 15 days (range 14-30). All 5 patients who had had symptoms just before the induction phase became symptom-free. The body weight decreased in 5 patients (median -0.6 kg), probably because the serum protein increased, resulting in reduced edema. All 5 patients with hypoproteinemia had elevated serum albumin (median 2.9-3.5 g/dL). The ingested nutritional elements were calculated, and most of them were sufficient, except for fat and selenium. CONCLUSIONS: The Rainbow ED was well-tolerated and safe for pediatric non-EoE EGIDs.

Remission of Acute Food Protein-Induced Enterocolitis Syndrome Confirmed by Oral Food Challenges in Japan.

The oral food challenge test (OFC) is the gold standard for evaluating the remission of food protein-induced enterocolitis syndrome (FPIES). Few acute FPIES remissions confirmed by OFC were reported. This study aimed to examine the OFC for Japanese children with acute FPIES to evaluate its remission. A retrospective cohort study was performed on children with acute FPIES with remission evaluation by OFC based on one food challenge dose (1/50, 1/10, 1/2, and full dose per day). Acute FPIES remission was observed in 65.2% of patients (15/23 patients). Vomiting episodes occurred with 1/50 full doses on the first day among 75% of positive patients. The median duration between the onset and OFC was 14 months (IQR, 8-24 months). Soy was the most common causative food, followed by egg yolk, milk, and wheat. All patients could receive OFC safely without intensive care unit care, based on the FPIES OFC protocol. The remission rate of acute FPIES was high. However, vomiting episodes commonly occurred with 1/50 full doses on the first day. This study suggested that our OFC protocol for acute FPIES was safe and feasible, but it might be safer for some patients to start at a minimal loading dose.

How a Family History of Allergic Diseases Influences Food Allergy in Children: The Japan Environment and Children's Study.

The influence of family allergic history on food allergy in offspring in Japan is unknown. We analyzed data from a nationwide birth cohort study using logistic regression models to examine the associations of maternal, paternal, and both parental histories of allergic diseases (food allergy, atopic dermatitis, asthma, and rhinitis) with their child's food allergy at 1.5 and 3 years of age. This analysis included 69,379 singleton full-term mothers and 37,179 fathers and their children. All parental histories of allergic diseases showed significant positive associations with their child's food allergy. When both parents had a history of allergic diseases, the adjusted odds ratio (aOR) tended to be higher than when either parent had allergic diseases (p for trend < 0.0001). The highest aOR was detected when both parents had food allergy (2.60; 95% confidential interval, 1.58−4.27), and the aOR was 1.71 when either parent had food allergy (95% confidential interval, 1.54−1.91). The aORs were attenuated but still had significant positive associations after adjusting for the child's atopic dermatitis, a risk factor for allergy development. In conclusion, all parental allergic diseases were significantly positively associated with their child's food allergy. The effect of family history showed a stepwise increase in risk from either parent to both parents, and the highest risk of allergic disease was a parental history of food allergy.

Allergic Disorders and Risk of Anemia in Japanese Children: Findings from the Japan Environment and Children's Study.

Previous epidemiological studies have reported an increased risk of anemia in people with allergic disorders. However, previous studies have followed a cross-sectional design. The aim of this study was to investigate the association between the two conditions with a cohort dataset. We used data of 80,943 children in the Japan Environment and Children's Study, the largest birth cohort in Japan. The association between anemia and allergic disorders was evaluated with a logistic regression model and propensity score analysis. After adjusting for potential confounders, children with asthma (odds ratio [OR], 1.85; 95% confidence interval [CI], 1.32-2.60), atopic dermatitis (OR, 2.18; 95% CI, 1.66-2.85), allergic rhinitis (OR, 1.35; 95% CI, 1.05-1.74), allergic rhinoconjunctivitis (OR, 2.95; 95% CI, 1.91-4.54), and food allergies (OR, 1.92; 95% CI, 1.44-2.56) at 2 years of age predicted high odds of developing anemia in the next year. Any allergy at 2 years of age was associated with an increased risk of anemia at the age of 3 years (OR, 1.80; 95% CI, 1.41-2.29). The findings remained stable in the propensity score analysis. Results suggest that allergic diseases were related to caregiver-reported anemia in children.