Effects of the tulobuterol patch on the treatment of acute asthma exacerbations in young children.

The tulobuterol patch (TP) is a beta(2)-adrenergic agonist with a favorable pharmacokinetic profile used for asthma management in Japan. Because it contains tulobuterol in a molecular, crystallized form that is gradually absorbed percutaneously, TP exerts a prolonged bronchodilator effect exceeding 24 hours. Although it is a well-established treatment for asthma and wheezing, few studies have investigated whether it can reduce or prevent the symptoms associated with upper respiratory tract infections (URTIs) in young children. This study evaluated the effect of TP on the long-term management of asthma in young children. In this 1-year, randomized, multicenter, double-blind, placebo-controlled study, children aged 0.5-3 years old with mild-to-moderate persistent asthma were treated with either TP or placebo patch. The parents/guardians applied the TP or placebo patch to their children after URTI symptoms appeared. Respiratory symptoms were recorded daily during the 1-year observation period. Overall, 86 patients were enrolled and 80 were treated and analyzed in this study. All patients had been treated with anti-inflammatory drugs before enrollment. The time to symptom resolution was significantly shorter (p = 0.001) and the total respiratory symptom score (p = 0.0457) was significantly lower in the TP group than in the placebo group. In young children with mild-to-moderate asthma who had been treated with anti-inflammatory drugs, using the TP soon after the appearance of URTI symptoms led to quicker resolution of respiratory symptoms and lower respiratory symptom scores.

Effects of the tulobuterol patch on the treatment of acute asthma exacerbations in young children.

The tulobuterol patch (TP) is a beta2-adrenergic agonist with a favorable pharmacokinetic profile used for asthma management in Japan. Because it contains tulobuterol in a molecular, crystallized form that is gradually absorbed percutaneously, TP exerts a prolonged bronchodilator effect exceeding 24 hours. Although it is a well-established treatment for asthma and wheezing, few studies have investigated whether it can reduce or prevent the symptoms associated with upper respiratory tract infections (URTIs) in young children. This study evaluated the effect of TP on the long-term management of asthma in young children. In this 1-year, randomized, multicenter, double-blind, placebo-controlled study, children aged 0.5-3 years old with mild-to-moderate persistent asthma were treated with either TP or placebo patch. The parents/guardians applied the TP or placebo patch to their children after URTI symptoms appeared. Respiratory symptoms were recorded daily during the 1-year observation period. Overall, 86 patients were enrolled and 80 were treated and analyzed in this study. All patients had been treated with anti-inflammatory drugs before enrollment. The time to symptom resolution was significantly shorter (p = 0.001) and the total respiratory symptom score (p = 0.0457) was significantly lower in the TP group than in the placebo group. In young children with mild-to-moderate asthma who had been treated with anti-inflammatory drugs, using the TP soon after the appearance of URTI symptoms led to quicker resolution of respiratory symptoms and lower respiratory symptom scores.

[A trial of hierarchical cluster analysis of hospitalized wheezy infants and young children based on clinical factors].

BACKGROUND: It has been estimated that there are several phenotypes constituting wheezy infants, in addition to true asthma. OBJECTIVE: The aim of this study is categorized wheezy infants and young children by cluster analysis and to turn out of categorized frequency. SUBJECTS AND METHODS: The study included 53 subjects aged less than 2 years old who were admitted with wheezy exacerbation. Based on clinical factors, we classified these subjects into several clinical phenotypes using cluster analysis. RESULTS: The following four phenotypes were identified; cluster 1: almost all were exacerbated by RSV infection without previous wheezy episodes; cluster 2: almost all were younger, males, without previous wheezy episodes, sensitized to allergens and parental asthma, who tended to be exposed to passive smoke and have no siblings; cluster 3: almost all were slightly older males with recurrent wheezy episodes who tended to be sensitized to various allergens; cluster 4: almost all were younger females with exposure to passive-smoke, whose mother or father has a history of asthma. Cluster 4 patients tended to attend a day-care center and to be exclusively breast-fed. CONCLUSION: Although this study covers only a limited number of subjects, cluster analysis is a new and useful method of categorizing heterogeneous wheezy infants and young children. Further analysis may establish clinical classifications of these patients.

[Helper T cell paradigm: Th17 and regulatory T cells involved in autoimmune inflammatory disorders, pathogen defense and allergic diseases].

The helper T cell paradigm, divided into two distinct subsets, Th1 and Th2 cells, characterized by distinct cytokine and functions, has been expanded to IL-17-producing Th17 cells. Th1 cells producing IFN-γ are involved in delayed-type hypersensitivity, effective in intracellular pathogens defense, while Th2 cells secrete IL-4, IL-5, IL-13 and IL-25 and has a central role in IgE production, eosinophilic inflammation, and the protection for helminthic parasite infection. Th17 cell lineages, expressing IL-17 family of cytokines and IL-23-mediated functions on T cells, plays a role in immune response to fungi and extracellular pathogens and autoimmune inflammatory disorders. Th17 cells are required the combination of IL-6 and TGF-ß and the transcription factors, RORC2/RORgt (mice) and STAT3 for differentiation, and produce IL-17, IL-22, IL-17F, IL-21 and CCL20. FOXP3+ regulatory T (Treg) cells produce TGF-ß and IL-10, which regulate effector T cells, and thus maintain peripheral tolerance. Four functionally unique CD4+ T cells, including the regulatory T (Treg) cells are now involved in the regulation of immune responses to pathogens, self-antigens and allergens. Any defect in the entire CD4+T cell population might results in human diseases. In this review, the biology of Th17 cells and Treg cells and their role in immune diseases are presented.

[Relation of the time course of Japanese Pediatric Asthma Control Test (JPAC) and Childhood Asthma Control Test (C-ACT) score with respiratory function and fractional exhaled nitric oxide (FENO)].

BACKGROUND AND OBJECT: Two major convenient questionnaires of asthma control in childhood, Japanese Pediatric Asthma Control Program (JPAC) and Childhood Asthma Control Test (C-ACT) have been available in Japan. The aim of this study is to evaluate relationship of two questionnaires in terms of the changes of respiratory function and fractional nitric oxide (FENO) in each individual. SUBJECT AND METHODS: The 102 samples from patients with asthma aged 6 to 11 years old and their parents' answers for the two questionnaires at regular visits were collected. At the same time, respiratory functions and FENO were measured. The correlations of each difference of scores (+/-JPAC or +/-C-ACT), correlations of +/-JPAC or +/-C-ACT and increased ratio of respiratory functions and FENO (DeltaFENO%) were examined. We analyzed the factors that influences on respiratory functions and FENO. Moreover, the correlations of increased ratio of respiratory functions and DeltaFENO% were examined. RESULTS: Changes of JPAC and C-ACT correlated with each other. (rho=0.725, p<0.0001) DeltaFENO% was influenced by medications, especially ICS. +/-JPAC weakly correlated with DeltaFEV1% and DeltaFEF25-75% and DeltaPEF%, so did C-ACT. +/-JPAC correlated most strongly with the change of DeltaFEF25-75% among the parameters of respiratory functions. (rho=0.357, p=0.0003)+/-JPAC, but not +/-C-ACT weakly correlated with DeltaFENO%. (rho=-0.2045, p=0.0401) CONCLUSION: JPAC and C-ACT reflect the change of the respiratory function of each patient rather than those at random visit. Furthermore, JPAC may reflect FENO. In conclusion, recognition of the changes of the scores of these questionnaires may increase the utilities of the same scores obtained at a single visit. It is needed further study how to use FENO added on these questionnaires.

[The comparison of Japanese pediatric asthma control test (JPAC) with the childhood asthma control test (C-ACT) based on respiratory function and fractional exhaled nitric oxide (FEno)].

BACKGROUND AND OBJECT: Two major convenient questionnaires of asthma control in childhood, Japanese Pediatric Asthma Control Program (JPAC) and Childhood Asthma Control Test (C-ACT) have been available in Japan. The aim of this study is comparison of utilities of these questionnaires by means of respiratory function and fractional nitric oxide (FENO). SUBJECT AND METHODS: The 154 samples from patients with asthma and their parents answered to two questionnaires at regular visits. At the same time, respiratory function and FENO were measured. The patients were divided into two groups according to the control levels defined by JPAC and C-ACT. The correlation of each total scores and respiratory function and FENO were examined. RESULTS: The total scores of JPAC and C-ACT strongly correlated each other. Among 3 groups in JPAC the score of JPAC weakly correlated with %FEV1, FEV1/FVC and %MMF. In contrast there was no correlation between 2 groups C-ACT. FEV1/FVC and %MMF were significantly different among the groups identified by the JPAC, but not among those by the C-ACT. Neither of the total scores of JPAC nor C-ACT correlated with FENO. CONCLUSION: JPAC and C-ACT may partially reflect the respiratory function, with preference to JPAC. In contrast, these questionnaires did not reflect FENO. Thus, physician should use these questionnaires with consideration of these points.

A study of the factors responsible for the development of allergic diseases in early life.

In order to analyze the determinants involved in the development of allergic diseases early in infancy, we examined the environmental and genetic factors that might affect the induction of such diseases during infancy, using a questionnaire. Maternal pharyngitis during pregnancy was significantly related to the development of atopic dermatitis in their progeny. Moreover, the frequency of the maternal infection was associated with a significantly increased risk of allergy in their infants. The prevalence of post-delivery maternal allergy was positively linked to the allergic symptoms in their children while the likelihood of bearing allergic children was related to the numbers of allergic individuals within their family. These results suggested that pre- and post-natal maternal factors and any genetic predisposition might modify the development of allergy in infancy.

Fetal growth promotion in allergic children.

Several in vitro studies have suggested the presence of Th2-skewed immunity during pregnancy in infants with atopic diseases. Our study indicated that allergic infants showed a higher birth weight and shorter gestational period at birth than those of non-allergic peers. Moreover, allergic mothers gave birth to neonates whose birth weights and gestational ages were higher and shorter than those of the non-allergic mothers, respectively. Thus, our data clearly demonstrated the promotion of intrauterine growth, either in the allergic children, or allergic mothers. Such an intrauterine environment favorable for the fetal growth may also accelerate the development of allergic diseases in their offspring that are most probably caused by the Th2-oriented immunity.

Effect of lecithin-bound iodine on the patients with bronchial asthma.

Lecithin-bound iodine (LBI), which has been reported to be a potential candidate for one of the therapeutic modalities for children with bronchial asthma based on the in-vitro study, was also found to be effective in relieving the symptoms of patients with childhood asthma. In addition to the in-vitro effect of downregulation and upregulation of interleukin-4 (IL-4) and interferon-gamma (IFN-gamma), respectively, the clinical effect of LBI was highlighted through the concomitant upregulation of IFN-gamma production by the patients' lymphocytes, which were treated with LBI for 8 weeks. Therefore, LBI may reduce the signs of bronchial asthma by upregulating the synthesis of IFN-gamma that is a representative Th1 cytokine.

Somatropin promotes dermatophagoides farinae-specific IgE generation independently of IL-4 and IL-10.

Interleukin (IL)-10 accelerates the IgE production of anti-CD40- and IL-4-stimulated PBMC by enhancing the IL-6 production of T lymphocytes or antigen-primed spleen cells, in addition to its role as a regulator of the inflammatory responses. To further investigate the mechanisms enhancing IgE synthesis, we determined the effect of somatropin as well as IL-10 on the secretion of Dermatophagoides farinae (Df)-specific IgE by K7 cells, which originate from an EBV-immortalized cell line. Df-pulsed autologous T cells, as well as the supernatants of these cultures, increased the synthesis of Df-specific IgE. Antigen-specific IgE was also enhanced when K7 cells were treated with anti-CD40 antibody and with both IL-4 and IL-10, or with IL-4 and IL-10 without anti-CD40 antibody. The treatment of K7 cells with anti-CD40 antibody and IL-4, or anti-CD40 antibody and IL-10 did not increase IgE production. The Df-specific IgE activity of the supernatants of K7 cells treated with somatropin alone was increased significantly although somatropin did not show any additive effect on the IgE production of anti-CD40 antibody-treated cells. The results indicate that IL-10, a Th2-type cytokine, directly affects the mature B cells that produce IgE, and that the secretion of IgE is increased by treatment with IL-10 in cells that are stimulated with anti-CD40 and IL-4 at the level of the EBV-immortalized cell line, which has already switched to IgE production. Somatropin similarly stimulates activated mature B cells to enhance their production of antigen-specific IgE without class switching, independently of IL-4 and IL-10.

Dermatophagoides-induced interleukin-10 production by peripheral blood lymphocytes from patients with asthma in remission.

Interleukin (IL)-10 is a cytokine that regulates inflammatory responses. We studied the role of IL-10 in the development of tolerance to Dermatophagoides farinae in asthma patients in remission, since asthma improves in most children during adolescence. The spontaneous production of IL-10 by cultured peripheral blood mononuclear cells (PBMC) was higher in patients with active asthma than in normal subjects. IL-10 production decreased when 1 microg/ml D. farinae was added to cultures, but increased again in a dose-dependent manner when higher concentrations of D. farinae were added. In patients with remission of asthma, IL-10 production was lower than in patients with active asthma. However, production of IL-10 showed a reciprocal increase in the presence of 1 microg/ml D. farinae, and decreased again at 10 and 50 microg/ml D. farinae. Such alterations were not observed in normal subjects. Cell lines established from patients asthma in remission showed higher IL-10 production when compared with that by cell lines from normal subjects or patients with active asthma when the cells were stimulated by D. farinae at 1 or 10 microg/ml. Neutralization of IL-10 led to revival of the D. farinae-specific proliferative response of PBMC from patients in remission, which was otherwise decreased. The increase of IL-10 production stimulated by D. farinae was inhibited by addition of an anti-IL-10 antibody. In contrast, antigen-induced interferon (IFN)-gamma production, which was increased by D. farinae stimulation when patients were in remission, did not increase after treatment with anti-IL-10, although spontaneous IFN-gamma production increased to the level seen after D. farinae stimulation. The reduced IL-4 production by cells from patients in remission after stimulation with D. farinae antigen, which was significantly higher in active patients, was not reversed by neutralization of IL-10. The D. farinae-induced IL-10/IL-4 production ratio, but not the IL-10/IL-5 production ratio, may be a significant indicator for evaluation of whether a patient has been in remission. In conclusion, D. farinae-specific anergy of T cells is likely to be induced by increased levels of IL-10 and IFN-gamma that are initially produced by specific T cells after exposure to relevant mite allergen in patients in remission.

Roxithromycin promotes lymphocyte apoptosis in Dermatophagoides-sensitive asthma patients.

A new macrolide, roxithromycin, may be an effective treatment for asthma. Lymphocyte apoptosis is impaired in patients with asthma, while spontaneous apoptosis increases during remission, and such changes may be involved in the onset and remission of mite-sensitive asthma. Lymphocyte apoptosis was evaluated by incubating cells from patients with asthma in the presence of roxithromycin. Low concentrations of roxithromycin (1-500 ng/ml) augmented the early, but not late, phase of apoptosis in Dermatophagoides farinae-stimulated peripheral blood mononuclear (PBM) cells, while high concentrations of roxithromycin (1 microg/ml; 6 microg/ml is the maximum serum level) augmented both the early and late phases of apoptosis. In both unstimulated and phytohemagglutinin-stimulated cells, roxithromycin did not significantly affect the induction of apoptosis. In cells from normal subjects, roxithromycin did not affect the induction of apoptosis. Other antibiotics, including cefazolin and ampicillin, did not cause significant induction of apoptosis. Fas ligand, but not Fas receptor, expression on D. farinae-stimulated cells was up-regulated after stimulation with 1 microg/ml roxithromycin, while Bcl-2 expression on both unstimulated and D. farinae-stimulated cells showed a decrease after the same treatment. Roxithromycin can induce apoptosis of D. farinae-activated lymphocytes in patients with D. farinae-sensitive asthma. Induction of the Fas/Fas ligand system and reduced Bcl-2 expression were involved in the promotion of apoptosis by roxithromycin treatment.