[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.

[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.

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.