Wheat Protein-Induced Enterocolitis Syndrome Complicated With Wheezing: An Approach to Diagnosis and Wheat Reintroduction.

An 11-month-old Japanese girl was diagnosed with food protein-induced enterocolitis syndrome (FPIES) after presenting with vomiting approximately two hours after wheat intake. She showed positive results on the first wheat oral food challenge (OFC) at nine months of age, although serum wheat- and ω-5 gliadin-specific immunoglobulin E (IgE) were not detected. The second wheat OFC, performed at age 13 months, induced wheezing (usually an IgE-mediated symptom) 4.5 hours after ingestion, probably owing to gastroesophageal reflux caused by repetitive vomiting. The third wheat OFC, performed at age 25 months, did not trigger reactions. Therefore, gradual low-dose wheat was reintroduced at home. The fourth wheat OFC performed at age 30 months induced no response either; thus, the patient was deemed to have developed tolerance to wheat. This case report, therefore, demonstrates that careful assessment of natural history and physician-supervised OFCs are necessary for adequate diagnosis and the successful management of reintroduction in wheat-induced FPIES.

Sex Differences in the Prevalence and Severity of Exercise-Induced Bronchoconstriction in Kindergarteners in Japan.

BACKGROUND: Exercise-induced bronchoconstriction (EIB), a strong positive predictor of asthma, becomes progressively less frequent with age. Although asthma tends to become less common only in boys during adolescence, sex differences in EIB, especially in preschoolers, remain unclear. To find EIB for early diagnosis and intervention asthma, mass-screening tests considering sex differences in preschoolers are needed. In this study, we investigated whether sex differences influence the prevalence and severity of EIB in prepubertal children aged 5-6 years. METHODS: Fifty-one children aged 5-6 years who were attending a kindergarten in Matsuyama City, Ehime, Japan, were enrolled in this cross-sectional study. The children underwent a 6-minute free-running test in 2015. The peak expiratory flow rate (PEFR) was measured before exercise and 0, 3, 10, and 20 minutes after exercise. The severity of EIB was classified according to the reduction in PEFR, measured as the difference between the postexercise PEFR and the highest pre-exercise PEFR. RESULTS: Of the 51 children (23 boys and 28 girls) enrolled, the prevalence of EIB defined as three criteria: a ≥15%, ≥20%, or ≥25% decrease was 54.9% (28/51), 41.2% (21/51), and 25.5% (13/51), respectively. The prevalence of EIB defined as ≥25% decrease was significantly higher in girls than in boys (39.3% vs 8.7%, P = .013). In girls, the mean percentage change in PEFR was significantly higher 20 minutes than 10 minutes postexercise (P = .043). CONCLUSIONS: Sex difference in the prevalence and severity of EIB should be considered when evaluating EIB, even in young, prepubertal children.

Fetal Tobacco Smoke Exposure in the Third Trimester of Pregnancy Is Associated with Atopic Eczema/Dermatitis Syndrome in Infancy.

The manifestation of atopic dermatitis (AD) is initially nonatopic eczema in early infancy; the manifestations subsequently change in age-specific stages. Since allergen-specific T-helper 2 cells appear in the fetus primarily after the third trimester of pregnancy and rapidly mature during the first 6 months of life, different timings of tobacco smoke exposure may have different effects on AD. In this study, we investigated whether the timing of fetal or/and infantile tobacco smoke exposure affects the cumulative incidence of atopic eczema/dermatitis syndrome (AEDS) in infants in Japan. This cross-sectional study enrolled 1,177 parent-infant pairs, in which the infants were >6 months old. Parental allergic history, number of older siblings, physician-diagnosed AEDS and food allergy (FA), and the perinatal fetal and/or infantile tobacco smoke exposure timing after 28 weeks gestation and during the first 6 months of life were assessed using self-completed questionnaires. Fetal tobacco smoke exposure after 28 weeks gestation was significantly associated with higher cumulative incidence of AEDS in exposed infants than in unexposed infants: AEDS in all infants, 41.4% versus 34.0% (Chi-squared, P = 0.020; adjusted odds ratio, 5.21; 95% confidence interval, 1.08-25.15); AEDS in those without parental allergic history, 38.0% versus 26.6% (Chi-squared, P = 0.024). Postnatal infantile tobacco smoke exposure timing was not significantly associated with cumulative incidence of AEDS. No significant associations were observed between any tobacco smoke exposure timings and the cumulative incidence of FA. Fetal tobacco smoke exposure during the third trimester of pregnancy was positively associated with AEDS in infancy and might induce epigenetic changes in the fetal allergen-specific immune responses.

Lactobacillus rhamnosus GG and Lactobacillus casei suppress Escherichia coli-induced chemokine expression in intestinal epithelial cells.

BACKGROUND: Recently, some strains of lactic acid bacteria (LAB) have been reported to prevent the development of atopic dermatitis and to improve allergic symptoms, especially in young children. However, the mechanisms involved in these effects are not fully understood. Intestinal microbiota play critical roles in the development of host immune development and are recognized and regulated by the host through intestinal epithelial cells (IECs). We thus hypothesized that LAB influence the host immune system through the activation of IECs. To begin testing this hypothesis, chemokine expression in IECs exposed to intestinal bacteria was investigated. METHODS: Caco-2 cell monolayers were stimulated with different concentrations of various live or heat-killed intestinal bacteria or bacterial components for up to 3 h. Changes in the gene expressions of various chemokines were measured using quantitative real-time PCR. RESULTS: The expressions of CCL20, CXCL8, CXCL10 and CX3CL1 were strongly induced by nonpathogenic Escherichia coli in a dose-dependent manner and were partially induced by some commensal LAB. In contrast, Lactobacillus rhamnosus GG (LGG) and Lactobacillus casei did not induce these chemokine expressions. In addition, LGG significantly suppressed the expressions of CCL20 and CXCL10 induced by E. coli, peptidoglycan or flagellin when cultured simultaneously. CONCLUSIONS: LGG and L. casei markedly suppressed E. coli-induced chemokine expression, presumably through the suppression of the Toll-like receptor-mediated signal transduction pathway, at least in part. The clinical importance of this suppressive effect and the mechanisms involved require further investigation; however, such effects can be used as a marker to identify clinically useful LAB.

Presence of eosinophils in nasal secretion during acute respiratory tract infection in young children predicts subsequent wheezing within two months.

BACKGROUND: In young children with wheezing or bronchiolitis, especially with respiratory syncitial virus, blood eosinophilia and a high eosinophil cationic protein level in nasal secretions predicts subsequent wheezing in later childhood. However, whether eosinophil activation results from virus-induced inflammation or local eosinophilia per se precedes the onset of wheezing remains unknown. In the present study, we examined the association between the presence of nasal eosinophils during respiratory tract infection (RTI) and subsequent wheezing in young children. METHODS: A total of 35 young children less than 3 years of age who visited our outpatient clinic with rhinorrhea between April and July 2004 were enrolled in this prospective cohort study. Subjects who were given diagnoses of allergic rhinitis were excluded. In all the subjects, the presence of eosinophils in nasal secretions was determined. The subjects were followed, and the cumulative incidences of wheezing during the subsequent 2- and 12-month periods were examined. RESULTS: According to a logistic regression analysis adjusted for age, sex, family history, allergies, and wheezing at entry, young children with nasal eosinophil infiltration during acute RTI had a significantly higher risk of wheezing during the subsequent 2 months, compared with those without nasal eosinophil infiltration (adjusted odds ratio, 27.618, p = 0.016). CONCLUSIONS: Our findings not only suggest that nasal eosinophil testing may serve as a convenient clinical marker for identifying young children at risk for subsequent wheezing, but also shed new light on the role of eosinophils in the onset of wheezing in young children.

Symptoms of allergic rhinitis in women during early pregnancy are associated with higher prevalence of allergic rhinitis in their offspring.

BACKGROUND: Epigenetic control of gene expression profiles is a ubiquitous mechanism during cell differentiation, organogenesis and chronic inflammatory reactions. Recent studies have shown that allergen exposure during very early pregnancy increases bronchial hypersensitivity in offspring in a murine model of bronchial asthma. However, no such phenomena were reported in humans. In the present study, the role of epigenetic control in the onset of allergic diseases was investigated. METHODS: A total of 400 pairs of mothers with physician-diagnosed allergic rhinitis (AR) and their offspring (age 7-18 months) who participated in a large-scale medical check-up were enrolled in this retrospective cohort study. Family history of allergic diseases and the presence or absence of AR symptoms during pregnancy were inquired about using a self-answered questionnaire. A logistic regression model adjusted for age, gender, birth month and father's history of allergic diseases was statistically analyzed. RESULTS: Offspring whose mothers had any AR symptoms during early pregnancy showed a significantly higher adjusted odds ratio for the onset of AR in offspring than those whose mothers had no symptoms during pregnancy (adjusted Odds Ratio: 6.26, p = 0.036). However, the symptoms of AR during late pregnancy showed no effects on the odds ratio. In contrast, the presence or absence of AR symptoms during early or late pregnancy showed no association with the prevalence of food allergy, atopic dermatitis or asthma in offspring. CONCLUSIONS: Our results suggest the presence of possible epigenetic mechanisms regulating the onset of AR in humans presumably through increased organ-specific hypersensitivity.

Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity.

Tyrosine kinase 2 (Tyk2) is a nonreceptor tyrosine kinase that belongs to the Janus kinase (Jak) family. Here we identified a homozygous Tyk2 mutation in a patient who had been clinically diagnosed with hyper-IgE syndrome. This patient showed unusual susceptibility to various microorganisms including virus, fungi, and mycobacteria and suffered from atopic dermatitis with elevated serum IgE. The patient's cells displayed defects in multiple cytokine signaling pathways including those for type I interferon (IFN), interleukin (IL)-6, IL-10, IL-12, and IL-23. The cytokine signals were successfully restored by transducing the intact Tyk2 gene. Thus, the Tyk2 deficiency is likely to account for the patient's complex clinical manifestations, including the phenotype of impaired T helper 1 (Th1) differentiation and accelerated Th2 differentiation. This study identifies human Tyk2 deficiency and demonstrates that Tyk2 plays obligatory roles in multiple cytokine signals involved in innate and acquired immunity of humans, which differs substantially from Tyk2 function in mice.

CpG oligodeoxynucleotide prolongs eosinophil survival through activation of contaminating B cells and plasmacytoid dendritic cells in vitro.

BACKGROUND: In our previous study, oligodeoxynucleotides containing unmethylated CpG motifs (CpG ODNs) significantly prolonged eosinophil survival without inducing active release of eosinophil-derived neurotoxin or interleukin 8. In addition, this survival-promoting activity was nuclear factor-kappaB dependent. However, some eosinophil preparations from different donors hardly responded to CpG ODNs at all. To clarify why CpG ODN-induced nuclear factor-kB activation in eosinophils does not cause eosinophil-derived neurotoxin or interleukin 8 release and why the survival-promoting activity of CpG ODNs was not found in some eosinophil preparations, we determined the effect of extensive removal of contaminating B cells and plasmacytoid dendritic cells from human eosinophil preparations. METHODS: Eosinophils were purified from the peripheral blood of healthy or slightly allergic donors by gradient sedimentation and negative selection with anti-CD16 alone or a combination of anti-CD16, anti-CD19 and anti-blood dendritic cell antigen 4 (BDCA4) immunomagnetic beads. Eosinophil survival was measured with FITC-conjugated annexin V and propidium iodide by FACS after incubation with synthetic CpG 2006(CpG-B), CpG 2216 (CpG-A) or their GpC control ODNs for 24 h. RESULTS: The addition of anti-CD19 and anti-BDCA4 immunomagnetic beads reduced the number of contaminating CD19+ cells and CD123+ BDCA2+ cells in eosinophil preparations. CpG 2006 and CpG 2216, but not their GpC control ODNs, significantly prolonged survival of eosinophils purified with anti-CD16 immunomagnetic beads alone but not eosinophils purified with a combination of anti-CD16, anti-CD19 and anti-BDCA4 beads. CONCLUSIONS: These results strongly suggest that contaminating B cells or plasmacytoid dendritic cells in eosinophil preparations critically regulate CpG ODN-mediated prolongation of eosinophil survival and that CpG ODNs do not activate eosinophils directly.

Nutrition during pregnancy may be associated with allergic diseases in infants.

The prevalence of allergic diseases is high in Japan, even in infants. Their risk for developing allergies is influenced by the antigens in the mother's diet during pregnancy. We hypothesized that, apart from the antigens, hypersensitivity induced through high energy and nutrient intake by mothers during pregnancy may be a factor for allergic diseases in their babies. In this study, we tried to confirm our hypothesis. Allergy histories of parents and their infants, body characteristics and food and nutrient intake were measured by a questionnaire and a food frequency questionnaire, respectively. A total of 2,642 responses were obtained (return rate, 94.7%). The major allergic diseases in the infants were atopic dermatitis (6.0%), food allergy (3.7%) and bronchial asthma or asthmatic bronchitis (3.2%). About 60% of the infants with allergies had a family history of allergies. Family history of allergy, age of infant, order of birth, head and chest circumferences of infants, BMI of mothers before pregnancy and delivery and intake of lipids (fat and vegetable oil) and vegetables by mothers related positively, and the intake of protein, carbohydrates and milk and its products correlated negatively with allergic diseases in the infants (p < 0.05). The results, together with previous reports, suggest that a high intake of energy and lipids (fat and vegetable oil) during pregnancy may accelerate allergic diseases in infants.