Developmental disorders in school children are related to allergic diseases.

BACKGROUND: In children, relationships between developmental disorders such as attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder and allergic diseases remain controversial, because these diseases show age- and sex-related differences. A proper understanding of the relationships between developmental disorders and allergic diseases should improve medical care for both diseases. We confirmed the prevalence of allergic diseases in elementary school-age children with developmental disorders by grade and sex. METHODS: The subjects were 446 lower grade and 312 upper grade elementary school-age children who had visited our hospital. The prevalence of allergic diseases among subjects with and without developmental disorders by grade and sex was examined using the diagnostic names on medical records. RESULTS: The prevalence of allergic diseases was significantly higher in lower grade boys and girls with developmental disorders than in those without developmental disorders (boys: OR 3.22, 95%; CI 1.49-6.95; girls: OR: 3.87, 95% CI: 1.27-11.82). The prevalence of allergic diseases was significantly higher in higher grade boys with developmental disorders than in those without developmental disorders (OR: 3.46, 95% CI: 1.59-7.53). Multiple logistic regression analysis in lower grades revealed that ADHD correlated with bronchial asthma (adjusted OR: 3.72, 95% CI: 1.42-9.69) and that autism spectrum disorder correlated with atopic dermatitis (adjusted OR: 4.26, 95% CI: 1.36-13.36). Analyses of children in the upper grades showed that ADHD correlated with atopic dermatitis (adjusted OR: 5.06, 95% CI: 1.28-20.05). CONCLUSIONS: Elementary school-age children with developmental disorders were more likely to have allergic diseases. The types of allergic diseases related to developmental disorders differed by grade and sex.

Infants Hospitalized with Lower Respiratory Tract Infections Were More Likely to Develop Asthma.

INTRODUCTION: Lower respiratory tract infections (LRTIs) have been reported to possibly initiate the development of asthma in children. However, the role of LRTIs in infantile asthma remains controversial. The goal of this study is to investigate whether LRTIs in hospitalized infants are involved in the development of asthma. MATERIALS AND METHODS: The subjects were 251 infants under 2 years of age who were admitted to our hospital with an RTI (59 cases of upper RTI (URTIs) with upper respiratory tract inflammation and pharyngeal tonsillitis; 192 cases of LRTIs with bronchitis, pneumonia, and bronchiolitis). Pathogens of viral infections were examined at admission using viral antigen test kits that could be used in ordinary clinical practice in Japan. When the children reached the age of 3 years, a survey was conducted by mailing a questionnaire to determine the symptoms, diagnosis, and treatment of asthma. RESULTS: The mailed questionnaires were returned by 116 of the 251 subjects. On the questionnaire, the diagnosis of asthma and treatment for asthma were significantly higher in hospitalized infants with LRTIs than in those with URTIs. By diagnosis of LRTIs, infants with pneumonia and bronchiolitis were significantly more likely to develop asthma. However, on pathogen-specific examination, there was no difference in the development of asthma among infants with LRTIs. CONCLUSION: LRTI in infancy may be involved in the development of asthma. The severity of LRTI in hospitalized infants, but not the particular viral pathogen causing infection, may be associated with later asthma onset.

Transient low IgG4 levels cause recurrent wheezing requiring multiple hospitalizations in infancy.

OBJECTIVES: To investigate whether the immunoglobulin G (IgG4) subclass is associated with recurrent wheezing and/or asthma in infants. SUBJECTS AND METHODS: From April 2015 to March 2016, 77 infants under 3 years old who attended our hospital were enrolled in four groups (Group 1, controls; Group 2, infants with recurrent wheezing and multiple hospitalizations despite starting inhaled corticosteroids [ICS]; Group 3, infants with recurrent wheezing and without hospitalization after starting ICS; Group 4, allergic infants without wheezing). The relationship between IgG subclasses, especially IgG4, and recurrent wheezing resistant to ICS and requiring multiple hospitalizations in infants was examined. RESULTS: The serum IgG, IgM, IgA, IgG1, IgG2, and IgG3 levels did not differ significantly among the four groups. The IgG4 level in Group 2 infants (3.1 ± 0.2 mg/dl) was significantly lower than in Groups 1, 3, and 4 (9.9 ± 8.0, 8.4 ± 6.1, and 23.4 ± 18.0 mg/dl). Of the 16 infants in Group 2, 10 could be followed to age 6 years. Nine of them had no recurrent wheezing at 6 years without medication. In addition, their IgG4 levels at age 6 years (16.1 ± 7.1 mg/dl) were significantly increased from those in infancy (3.0 ± 0.1 mg/dl). CONCLUSION: A transient low IgG4 level in infancy might cause recurrent wheezing and/or asthmatic symptoms in infants, and it may be one of the types of early transient wheezing.

Prevalence of ß2-agonist inhalation for outpatients in a pediatric emergency center during enterovirus D68 epidemic.

BACKGROUND: Enterovirus D68 (EV-D68) has been reported to have caused severe bronchial asthma attacks and hospitalization epidemics in Japan in September 2015. OBJECTIVE: To investigate the prevalence of ß2-agonist inhalation in a pediatric emergency center during a period of increased hospitalization for bronchial asthma, which was suggested to be associated with EV-D68. METHODS: We investigated the prevalence of ß2-agonist inhalation in a pediatric emergency center in Saga city, Japan, from April 2013 to October 2015, and also clarified the trends in bronchial asthma hospitalization in the same area during that time. RESULTS: The prevalence of ß2-agonist inhalation in the pediatric emergency center, September 2015 was highest when EV-D68 became widespread. The monthly average for ß2-agonist inhalation during the study period was 91 cases, but the count in September 2015 was 255 cases. Hospitalized cases of bronchial asthma in September 2015 were increased for age ≥3 years and not increased for age <3 years, but the prevalence of ß2-agonist inhalation at the pediatric emergency center was increased even under the age of 3 years. CONCLUSION: During the epidemic period for EV-D68, cases requiring ß2-agonist inhalation were increased. The EV-D68 epidemic may be related to not only severe cases requiring hospitalization, but also exacerbation of relatively mild symptoms of bronchial asthma.

Administration of the adrenaline auto-injector at the nursery/kindergarten/school in Western Japan.

BACKGROUND: In view of the increasing prevalence of food allergies, there has been an associated increase in frequency of situations requiring an emergency response for anaphylaxis at the home, childcare facilities and educational institutions. OBJECTIVE: To clarify the situation of adrenaline auto-injector administration in nursery/kindergarten/school, we carried out a questionnaire survey on pediatric physicians in Western Japan. METHODS: In 2015, self-reported questionnaires were mailed to 421 physicians who are members of the West Japan Research Society Pediatric Clinical Allergy and Shikoku Research Society Pediatric Clinical Allergy. RESULTS: The response rate was 44% (185 physicians) where 160 physicians had a prescription registration for the adrenaline auto-injector. In the past year, 1,330 patients were prescribed the adrenaline auto-injector where 83 patients (6% of the prescribed patients) actually administered the adrenaline auto-injector, of which 14 patients (17% of the administered patients) self-administered the adrenaline auto-injector. "Guardians" at the nursery/kindergarten and elementary school were found to have administered the adrenaline auto-injector the most. Among 117 adrenaline auto-injector prescription-registered physicians, 79% had experienced nonadministration of adrenaline auto-injector at nursery/kindergarten/school when anaphylaxis has occurred. The most frequent reason cited for not administering the adrenaline auto-injector was "hesitation about the timing of administration." CONCLUSION: If the adrenaline auto-injector was administered after the guardian arrived at the nursery/kindergarten/school, it may lead to delayed treatment of anaphylaxis in which symptoms develop in minutes. Education and cooperation among physicians and nursery/kindergarten/school staff will reduce the number of children suffering unfortunate outcomes due to anaphylaxis.

Acute alcohol intoxication in a 15-day-old neonate.

We describe a 15-day-old newborn girl who was fed with formula milk that was accidentally diluted with sake (Japanese wine prepared from fermented rice). The clinical features were flushed skin, tachycardia and low blood pressure indicating circulatory failure, somnolence and metabolic acidosis without hypoglycemia. The serum ethanol concentration was 43.0 mg/dL at 3 h after intake. The patient recovered under intravenous fluid replacement without complications. Follow-up examinations at 1, 2, 3, 6 and 12 months confirmed normal psychomotor development.

Lack of an association between E-selectin gene polymorphisms and risk of Kawasaki disease.

BACKGROUND: Coronary artery lesions (CAL) are a serious complication of Kawasaki disease (KD). The increased serum E-selectin level during the acute phase of KD and the association of E-selectin gene (SELE) polymorphisms with the prevalence of coronary artery disease in adults suggest a possible association between SELE polymorphisms and the development of CAL in KD patients. METHODS: The subjects consisted of 177 KD patients, including 59 with and 118 without CAL, and 305 healthy controls. Two single nucleotide polymorphisms (SNP) of SELE, 98G>T (rs1805193) and Ser128Arg (rs5361), were genotyped by direct sequencing and the high-resolution melting curve method, respectively. The allele distributions were assessed using the chi-squared test. RESULTS: There were no significant differences in the T allele frequency at 98G>T between KD patients and controls (1.4% vs 1.0%, P = 0.55) or between KD patients with and without CAL (1.7% vs 1.3%, P = 0.77). Similarly, there were no differences in the distribution of the C allele (128Arg) at Ser128Arg between KD patients and controls (4.5% vs 3.4%, P = 0.40) or between KD patients with and without CAL (4.2% vs 4.7%, P = 0.86). CONCLUSION: Although no association was detected between these SELE polymorphisms and the prevalence of KD or the development of CAL, this may have been due to the study limitations, including a low frequency of the minor alleles and a small sample size. A larger-scale association study is needed in order for a definitive conclusion to be made as to whether these SNP are associated with susceptibility to KD or not.

Does Chlamydia pneumoniae infection trigger to development of asthma in wheezy infants?

The role of Chlamydia pneumonia (CP) infection in infantile asthma remains obscure. CP infection was serologically determined (Immunoglobulin M antibody titer of index (ID) > or = 2.00) in wheezing infants who were then re-examined at 3 years of age to determine whether asthma is associated with CP infection. Wheezing infants with CP infection progressed to asthma more frequently than those who were not infected. These findings may suggest that CP infection triggers the development of asthma in wheezy infants.

Febrile seizures: characterization of double-stranded RNA-induced gene expression.

An association has long been suspected between febrile seizures and interleukin-1beta, the most potent endogenous pyrogen. Interleukin-1beta production increases after double-stranded RNA stimulation in leukocytes of febrile seizure patients. To elucidate the genetics of the immune response, the gene expression pattern after double-stranded RNA stimulation was investigated using DNA microarray. Compared with the control group, expression of the genes ACCN4 (sodium channel), KCNC3 (potassium channel), GABRE (gamma-aminobutyric acid receptor epsilon subunit), RIPK2 (receptor interacting protein kinase-2), TLR4 (toll-like receptor-4), IL26 (interleukin-26), and TNF (tumor necrosis factor), and CASP1 (caspase-1) was increased in the febrile seizure group (P < 0.01). Because RIPK2 and CASP1 are associated with interleukin-1beta production, increased expression might cause increased interleukin-1beta production in the febrile seizure patients. The induced expression of several ion channel genes by double-stranded RNA may affect neuronal excitability which leads to seizure susceptibility during infection.

The development of asthma in wheezing infants with Chlamydia pneumoniae infection.

Chlamydia pneumoniae infection might play a role in the pathology of asthma, but its role in infantile asthma remains obscure. The presence of Chlamydia pneumoniae was serologically determined in wheezing infants who were then re-examined 1-year later to determine whether or not asthma is associated with this type of infection. Wheezing infants progressed to asthma more frequently after infection with Chlamydia pneumoniae than those who were not infected. These findings suggested that Chlamydia pneumoniae infection triggers asthma in wheezy infants.

Imbalance between leukotriene synthesis and catabolism contributes to the pathogenesis of allergic diseases.

Recently, there has been great progress in elucidating the biochemistry of the arachidonic acid (AA) metabolism. The abnormal production of leukotrienes (LTs), due to the unbalanced-regulation of synthesizing and catabolizing enzymes, is probably induced by many bioactive substances, including Th2 cell-derived cytokines. Imbalances in these processes may play an important role in allergic reactions and other inflammatory diseases, thus making them potentially prime therapeutic targets for these diseases. Further studies on the regulation of LT-synthesis and catabolism are therefore required to clarify the importance of these imbalances on the initiation and progression of allergic and inflammatory diseases.

Estradiol activates mast cells via a non-genomic estrogen receptor-alpha and calcium influx.

BACKGROUND: Allergic airway diseases are more common in females than in males during early adulthood. A relationship between female hormones and asthma prevalence and severity has been suggested, but the cellular and molecular mechanisms are not understood. OBJECTIVE: To elucidate the mechanism(s) by which estrogens enhance the synthesis and release of mediators of acute hypersensitivity. METHODS: Two mast cell/basophil cell lines (RBL-2H3 and HMC-1) and primary cultures of bone marrow derived mast cells, all of which naturally express estrogen receptor-alpha, were examined. Cells were incubated with physiological concentrations of 17-beta-estradiol with and without IgE and allergens. Intracellular Ca(2+) concentrations and the release of beta-hexosaminidase and leukotriene C(4) were quantified. RESULTS: Estradiol alone induced partial release of the preformed, granular protein beta-hexosaminidase from RBL-2H3, BMMC and HMC-1, but not from BMMC derived from estrogen receptor-alpha knock-out mice. The newly synthesized LTC(4) was also released from RBL-2H3. Estradiol also enhanced IgE-induced degranulation and potentiated LTC(4) production. Intracellular Ca(2+) concentration increased prior to and in parallel with mediator release. Estrogen receptor antagonists or Ca(2+) chelation inhibited these estrogenic effects. CONCLUSION: Binding of physiological concentrations of estradiol to a membrane estrogen receptor-alpha initiates a rapid onset and progressive influx of extracellular Ca(2+), which supports the synthesis and release of allergic mediators. Estradiol also enhances IgE-dependent mast cell activation, resulting in a shift of the allergen dose response.

Expression of CD180, a toll-like receptor homologue, is up-regulated in children with Kawasaki disease.

Kawasaki disease (KD) is an acute febrile illness in childhood characterized by the formation of aneurysms in coronary arteries. It is believed that KD is caused by infectious agents because of its epidemic waves and high incidence of familial occurrence. Because an increase in the levels and dysfunction of B cells in peripheral blood was reported in KD, we investigated the expression of cluster of differentiation 180 (CD180), a toll-like receptor homologue, in the B cells of children with KD, and in those with bacterial or viral infections. The percentages of CD180 positive B cells were significantly higher in children with KD or viral infections than in those with bacterial infections or in healthy controls. When the expression levels of CD180 were compared by using the mean fluorescent intensity ratio of patients to healthy controls, the level of CD180 expression was also significantly up-regulated in children with KD or viral infections. To clarify the effect of viral infection on the expression of CD180, B cells were stimulated with poly inosinic-cytidyric acid [poly(IC)], a synthetic double-stranded RNA. Poly(IC) clearly enhanced CD180 expression in B cells in vitro, both at the protein and messenger RNA levels. These results suggest that similar mechanisms may be involved in the up-regulation of B cell CD180 expression in patients with either KD or viral infections.

Interleukin-18 primes human basophilic KU812 cells for higher leukotriene synthesis.

The human basophilic cell line KU812 that is an established tool for studying the function of human basophils, is differentiated into mature basophils by interleukin (IL-3) or other agents. However, whether leukotrienes (LTs)-synthesis is affected by cytokines in KU812 cells remains unknown. KU812 cells were incubated with IL-3, IL-4, IL-6, IL-13 or IL-18 for up to 14 days. The A23187 stimulated- and IgE cross-linked-synthesis of LTC(4) and LTB(4) were measured using an enzyme immunoassay (EIA). The expression of messenger RNA (mRNA) for LT-synthesizing enzymes was examined by reverse transcriptase polymerase chain reaction (RT-PCR), and the expression of 5-lipoxygenase (5-LO) was examined by immunostaining. Incubation with IL-3 (10 ng/ml) and IL-18 (10 ng/ml) induced the expression of 5-LO. A23187stimulated LT-synthesis and IgE cross-linked LT-synthesis were enhanced after incubation with IL-3 or IL-18. These results indicated that IL-3 and IL-18 primed human basophils for higher LT-synthesis. Thus, both IL-3 and IL-18 might be important factors for regulating LT-synthesis during the differentiation of human basophils.

Mutations of syntaxin 11 and SNAP23 genes as causes of familial hemophagocytic lymphohistiocytosis were not found in Japanese people.

Although mutations of perforin, MUNC13-4 and syntaxin 11 genes have been found in children with familial hemophagocytic lymphohistiocytosis (FHL), the incidence of each genetic subtype varies in different ethnic groups. We evaluated mutations of syntaxin 11 and SNAP23 genes in 30 Japanese FHL patients. The patients had no mutations and 10% had one polymorphism (146G>A) of syntaxin 11, while no mutation of SNAP23 was observed. Our results indicate that aberrations in the SNARE system may not cause FHL in Japanese families.

Squamous cell carcinoma-related antigen in children with acute asthma.

BACKGROUND: Increased serum levels of squamous cell carcinoma-related antigen (SCCA) have been observed in patients with allergic disorders, such as atopic dermatitis and bronchial asthma. T(H)2 cytokines, which are known to be involved in the pathogenesis of allergic disorders, stimulate new synthesis of SCCA in cultured human airway epithelial cells. OBJECTIVE: To investigate whether SCCA levels increase during acute exacerbations of asthma in children and whether the T(H)2 cytokines, interleukin 4 (IL-4) and IL-13, are associated with SCCA levels. METHODS: Serum levels of SCCA, IL-4, and IL-13 were measured by enzyme immunoassay during the acute phase of an asthma exacerbation (on hospital admission) and in the recovery phase (after symptoms had subsided). RESULTS: In the 35 children who participated in this study, serum levels of SCCA were significantly elevated in the acute phase (mean +/- SD, 3.09 +/- 2.03 ng/mL) compared with the recovery phase (mean +/- SD, 1.47 +/- 0.64 ng/mL) of an asthma exacerbation (P < .001). In 12 children, the IL-13 levels were observed to correlate with SCCA levels during the recovery phase (r = 0.68, P = .02) but not during the acute phase of an asthma exacerbation. CONCLUSIONS: Serum SCCA levels increase during the acute phase of an asthma exacerbation. During this phase, the increased synthesis of SCCA is not associated with IL-13 but rather mediated by other undefined stimuli. IL-13 may contribute to the basal production of SCCA in asthmatic children.

Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions.

Mutations of the perforin (PRF1) and MUNC13-4 genes distinguish 2 forms of familial hemophagocytic lymphohistiocytosis (FHL2 and FHL3, respectively), but the clinical and biologic correlates of these genotypes remain in question. We studied the presenting features and cytotoxic T lymphocyte/natural killer (CTL/NK) cell functions of 35 patients for their relationship to distinct FHL subtypes. FHL2 (n = 11) had an earlier onset than either FHL3 (n = 8) or the non-FHL2/FHL3 subtype lacking a PRF1 or MUNC13-4 mutation (n = 16). Deficient NK cell activity persisted after chemotherapy in all cases of FHL2, whereas some patients with FHL3 or the non-FHL2/FHL3 subtype showed partial recovery of this activity during remission. Alloantigen-specific CTL-mediated cytotoxicity was deficient in FHL2 patients with PRF1 nonsense mutations, was very low in FHL3 patients, but was only moderately reduced in FHL2 patients with PRF1 missense mutations. These findings correlated well with Western blot analyses showing an absence of perforin in FHL2 cases with PRF1 nonsense mutations and of MUNC13-4 in FHL3 cases, whereas in FHL2 cases with PRF1 missense mutations, mature perforin was present in low amounts. These results suggest an association between the type of genetic mutation in FHL cases and the magnitude of CTL cytolytic activity and age at onset.

Upregulation of interleukin-4 receptor by interferon-gamma: enhanced interleukin-4-induced eotaxin-3 production in airway epithelium.

Airway epithelial cells produce a number of chemokines, including eotaxins. Among the three known eotaxins, T helper (Th) type 2 cytokines have been observed to induce the expression of eotaxin-3 mRNA. This study investigated the effect of interferon (IFN)-gamma, a Th1 cytokine, on Th2 cytokine-induced eotaxin-3 production in a bronchial epithelial cell line, BEAS-2B. BEAS-2B cells produced eotaxin-3 after stimulation with the Th2 cytokines interleukin (IL)-13 and IL-4. When BEAS-2B cells were cultured with varying concentrations of IFN-gamma for 24 h, dose-dependent inhibition of Th2 cytokine-induced eotaxin-3 mRNA expression and protein production was observed. This was associated with downregulation of signal transducer and activator of transcription 6 activation. On the other hand, 2-d pretreatment of BEAS-2B cells with IFN-gamma dose-dependently enhanced Th2 cytokine-induced eotaxin-3 mRNA expression and production. IFN-gamma also increased the mRNA expression and protein production of IL-4 receptor (R) alpha in a time- and dose-dependent manner. In addition, IL-2Rgamma, a component of the type 1 IL-4R, was also upregulated by IFN-gamma. These results indicate that IFN-gamma has opposite effects on Th2 cytokine-induced eotaxin-3 production in BEAS-2B cells, depending on the length of exposure. Because high levels of IFN-gamma are produced during viral infection, airway viral infection may affect allergic airway inflammation in vivo by modulation of eotaxin-3 production.