[Coagulation activity in the airways of asthmatic patients]

[Article in Japanese]

Kudo K.

Department of Respiratory Disease, International Medical Center of Japan, Tokyo, Japan.

Fibrin deposition in the mucus plugs of asthmatic patients has long been known, and asthmatic sputum has been held to be important in the pathogenesis of bronchial obstruction. We examined the coagulation activity in the airways of asthmatic patients. Albumin as an index of plasma leakage into the bronchial lumen, thrombin antithrombin III complex (TAT), tissue factor, FDP, D-dimer and the TAT/D-dimer ratio as indices of coagulation and fibrinolytic markers were determined in expectorated or hypertonic saline-induced sputum from patients with acute and stable asthma, and with chronic bronchitis, and from normal control subjects. Patients with acute asthma, in comparison with patients with stable asthma or chronic bronchitis and normal control subjects, had significantly higher levels of albumin, TAT and TAT/D-dimer. The fibrin antigen was more positively stained immunohistochemically in sputum from acute asthmatics than in other sputa. In both patients with acute asthma and those with stable asthma, there was a significant positive correlation between albumin and TAT or albumin and TAT/D-dimer in the sputum. However, in normal control subjects, there was no correlation between these markers. These results suggest that the coagulation system in the airways of acute asthmatic patients is activated, that this favors fibrin deposition in the bronchial lumen and that coagulation pathways in the bronchial compartment and the degree of plasma exudation into the airways are dependently regulated in patients with asthma but not in normal control subjects.

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Resource costs for asthma-related care among pediatric patients in managed care.

Weiss KB.

School of Pharmacy, University of Washington, Seattle, Washington, USA. kbgendo mac.com

BACKGROUND: In 1998, the economic burden of asthma in the United States was estimated to be 12.7 billion dollars. Yet few studies have examined the relationship between the total costs of asthma-related care and measures of asthma morbidity. Understanding the relationship between total costs of asthma-related care and morbidity can assist in designing the most cost-effective asthma care strategies to improve patient outcomes and minimize total costs. OBJECTIVE: To investigate correlates of asthma costs for children with mild-to-moderate persistent asthma and, specifically, to characterize how closely the percentage of predicted forced expiratory volume in 1 second (FEV1) and symptom days were correlated with costs of illness. METHODS: A total of 638 parents and children with mild-to-moderate persistent asthma in 4 managed care delivery systems in 3 different US geographic regions were enrolled. Symptom burden and annual resource utilization were determined from reports of physician visits, hospitalizations, emergency department visits, medication use, and parental missed workdays. Spirometry was conducted on children who were 5 years and older. To characterize the relationship between symptom days and the percentage of predicted FEV1 with costs, we specified a multivariate regression model. RESULTS: The median total annual asthma-related cost for the group was 564 dollars (interquartile range [IQR], 131 dollars-1602 dollars). Indirect costs represented 54.6% of total costs. Medicines accounted for 52.6% of direct costs. The mean percentage of predicted FEV1 was 101.6% (range, 39.3%-183.5%; IQR, 91.6%-111.3%), with 91.4% of patients with a percentage of predicted FEV1 of more than 80%. Based on multivariate modeling, increasing asthma severity, use of peak expiratory flow rate meters, younger age, low-income status and nonwhite race, and longer duration of asthma were significantly associated with increasing cost. Symptom days (P < 0.001) predicted annual costs better than percentage of predicted FEV1 (P < 0.16) in this group of children. CONCLUSIONS: For the large number of children with mild-to-moderate persistent asthma and normal or near-normal lung function, symptom days are predictive of health care costs. For these insured children receiving care from 3 large managed care providers, low-income status and nonwhite race were the strongest correlates for increased asthma-related costs.

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A comparison of the clinical characteristics of children and adults with severe asthma.

Spahn JD.

Division of Clinical Pharmacology, the Ira J. and Jacqueline Neimark Laboratory of Clinical Pharmacology in Pediatrics, National Jewish Medical and Research Center and, University of Colorado Health Sciences Center, Denver, CO 80206, USA.

OBJECTIVES: This study sought to better define the clinical characteristics of severe asthma in both children and adults, and to evaluate the effect of asthma duration on multiple parameters of disease severity. DESIGN: Retrospective analysis of prospectively collected data on 275 patients (125 children) with severe asthma who were admitted to a tertiary asthma referral center. METHODS: Demographics, lung function (ie, spirometry and body box plethysmography), glucocorticoid (GC) pharmacokinetic studies, and lymphocyte stimulation assays were performed on all patients. RESULTS:Children were as likely to require therapy with high-dose inhaled GCs and long-term therapy with oral GCs, and to have had a prior intubation, yet they had significantly less airflow limitation (mean [+/- SEM] FEV(1), 74.0 +/- 2.1% predicted vs 57.1 +/- 1.8% predicted, respectively; p < 0.0001), less resistance to airflow (mean airway resistance, 140.3 +/- 8.5% predicted vs 311 +/- 18% predicted, respectively; p < 0.0001), and larger lung volumes (mean total lung capacity, 116.4 +/- 1.6% predicted vs 105.3 +/- 1.8% predicted, respectively; p < 0.0001) compared to adults. Children were more likely to be male and to display greater responsiveness to GCs in vitro. Lung function impairment was associated with asthma duration in children and in adults with onset of asthma in childhood, while there was no relationship between disease severity and asthma duration among those with adult-onset asthma. Despite significant differences in disease duration, patients with adult-onset asthma had equally compromised lung function compared to adults with long-standing asthma. CONCLUSIONS: Children with severe asthma tended to be male, to have less severe airflow obstruction, and to display greater responsiveness to GCs in vitro compared to adults. Symptoms and episodic acute declines in lung function may precede chronic airflow limitation in this group of children. As such, it may be more relevant to follow the deterioration in lung function over time in children. Finally, disease severity in children and adults whose onset of asthma occurred in childhood was related to disease duration, but not in patients with onset of asthma in adulthood.

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[Effects of Huobahuagen tablet on the expression of interleukin-3 receptor mRNA in asthmatic guinea pig bronchoalveolar lavage fluid and eosinophil infiltration]

[Article in Chinese]

Lai WY.

Department of Respiratory Diseases, Nanfang Hospital, First Military Medical University, Guangzhou 510515, China. liangluo93 hotmail.com

OBJECTIVE: To investigate the effects of Huobahuagen tablet on the expression of interleukin-3 (IL-3) receptor mRNA in bronchoalveolar lavage fluid (BALF) and infiltration of eosinophil (Eos) in the airway of asthmatic guinea pigs. METHODS: Thirty-two healthy guinea pigs were randomized into 4 equal groups, the control group, asthmatic group, dexamethasone therapy group and Huobahuagen tablet therapy group. Asthma was induced in the latter 3 groups which were challenged with the asthma-inducing agents and at the same time received treatments as indicated. BALF were collected subsequently from the guinea pigs for examining the total cell number and cell classification, and histopathologic examination of the lung tissue was performed. Semi-quantitative analysis with reverse transcriptional-polymerase chain reaction (RT-PCR) of IL-3 receptor mRNA in the BALF was performed. RESULTS: Compared with the control and the asthmatic group, the number of Eos in the BALF of Huobahuagen tablet therapy group was significantly lower (P<0.05 and P<0.01, respectively). In spite of the presence of hyperemia and edema in the lung tissues of the Huobahuagen tablet therapy group, Eos infiltration was less severe than that in the asthmatic group. As found by RT-PCR, the quantity of IL-3 receptor mRNA in the BALF of the Huobahuagen tablet therapy group did not significantly differ from that in the dexamethasone therapy group, but was significantly higher than that in both the control and asthmatic group (P<0.01). CONCLUSION: Huobahuagen tablet can significantly lower the number of Eos in the airway of asthmatic guinea pigs, a finding that may potentially serve as the elementary theoretical basis for clinical therapy of asthma.

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Association of a disintegrin and metalloprotease 33 (ADAM33) gene with asthma in ethnically diverse populations.

Meyers DA.

Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.

BACKGROUND: Asthma is a complex genetic disease characterized by reversible intermittent airway obstruction and respiratory symptoms primarily caused by acute and chronic bronchial inflammation. Recently, a gene potentially involved in airway remodeling, a disintegrin and metalloprotease 33 (ADAM33), was implicated in asthma susceptibility. OBJECTIVE: We sought to determine whether polymorphisms in ADAM33 are associated with asthma or closely related phenotypes in 4 different asthma populations. METHODS: Eight single nucleotide polymorphisms (SNPs) were evaluated in the 3' portion of ADAM33 in 4 unique asthma populations (African American, US white, US Hispanic, and Dutch white). These SNPs were previously reported to be associated with asthma in white populations from the United States and United Kingdom. RESULTS: Significant associations were observed with at least one SNP and asthma in each population (P =.0009-.04). Related phenotypes that included total serum IgE levels and skin test responsiveness were also associated (P =.003-.05). However, no single SNP was associated across all populations. Additionally, haplotype analysis revealed that no single haplotype accounted for asthma susceptibility risk, although potential risk haplotypes existed within some of the populations. CONCLUSION: Replication of the original ADAM33 findings in these 4 additional asthma populations suggests that this gene (and perhaps others that interact with it) is important in the development and pathogenesis of asthma.

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The development of asthma in children infected with Chlamydia pneumoniae is dependent on the modifying effect of mannose-binding lectin.

Szalai C.

Budai Children's Hospital, Budapest, Hungary.

BACKGROUND: Although several studies found associations between infection with Chlamydia pneumoniae and asthma, these were mainly restricted to the exacerbation of the symptoms in adults with known asthma. Data about the role of C pneumoniae in the initiation and development of asthma in children are controversial. OBJECTIVE: We investigated the role of C pneumoniae infection in 139 children with asthma, comparing them with 174 healthy control subjects. Furthermore, we studied the modifying effect of mannose-binding lectin (MBL) variant alleles on the susceptibility to asthma in children infected with C pneumoniae. METHODS: C pneumoniae-specific antibodies were measured by means of ELISA, and MBL genotypes were determined by means of PCR-RFLP. RESULTS: There were no significant differences in the percentage of children with positive results for C pneumoniae-specific antibodies between patients and control subjects. Among asthmatic children carrying variant MBL alleles, there were significantly more patients with positive results for C pneumoniae-specific IgG than among control children with variant MBL genotypes (63.7% vs 40.7% of asthmatic vs control children, respectively; odds ratio adjusted for age and sex, 2.21; 95% CI, 1.10-4.41; P =.02). Infected children with variant MBL alleles were found to have a higher risk of asthma development than infected children with normal MBL genotype. This risk was especially high in children with chronic or recurrent infection (positive results for both IgA and IgG; adjusted odds ratio, 5.38; 95% CI, 1.75-14.36; P =.01), but no increased risk was seen in children with current C pneumoniae infection (positive results for IgM). CONCLUSION: This study indicates the important role of variant MBL alleles in the susceptibility to asthma in children infected with C pneumoniae.

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Endogenous nitric oxide downregulates the Bcl-2 expression of eosinophils through mitogen-activated protein kinase in bronchial asthma.

Kuo HP.

School of Nursing, Chang Gung University, Taipei, Taiwan.

BACKGROUND: Eosinophil apoptosis might play a crucial role in the maintenance of persistent airway inflammation in asthma. Nitric oxide (NO) synthase activity is upregulated in eosinophils of asthmatic patients. Mitogen-activated protein kinase (MAPK) is implicated in regulating eosinophil apoptosis by modulating Bcl-2 expression. NO-induced cell apoptosis is associated with an inhibition of Bcl-2 expression. OBJECTIVE: We sought to study whether NO might induce eosinophil apoptosis through extracellular signal-regulated protein kinase (ERK) or p38 MAPK pathways and Bcl-2 expression. METHODS: Eosinophils were freshly isolated from peripheral blood of 16 asthmatic patients and 12 healthy subjects and then cultured with or without the NO synthase inhibitor N-nitro-l-arginine methyl ester (L-NAME) at 1 and 10 mmol/L for 16 hours. The expression of Bcl-2 and induced NO synthase on eosinophils was analyzed by means of flow cytometry. Apoptosis was assessed by means of propidium iodide and DNA ladder. The activity of ERK and p38 MAPK was determined by means of Western blotting. RESULTS: The induced NO synthase immunoreactivities and the spontaneous release of nitrite from the eosinophils of asthmatic patients were higher compared with those of healthy subjects. Eosinophils of asthmatic patients were found to express more highly constitutive Bcl-2 than those of healthy subjects. After incubation for 16 hours, the expression of Bcl-2 on eosinophils from patients with asthma was significantly enhanced by L-NAME. The percentage of apoptosis was decreased by the addition of 1 mmol/L L-NAME in patients with asthma. The activity of p38 MAPK and ERK in eosinophils from patients with asthma was enhanced in the presence of L-NAME. An inhibition of MAPK reduced the Bcl-2 expression and increased eosinophil apoptosis in patients with asthma. CONCLUSION: We concluded that inhibition of endogenous NO might increase the expression of Bcl-2 in eosinophils from patients with asthma through the signaling pathway of ERK or p38 MAPK, which in turn decrease the apoptosis.

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Change in prevalence of asthma in Danish children and adolescents.

Backer V.

Department of Internal Medicine, Bispebjerg Hospital, Copenhagen, Denmark. sft city.dk

BACKGROUND: There is evidence suggesting that the prevalence of asthma has increased, especially in industrialized countries. OBJECTIVE: To investigate whether the prevalence of asthma in Danish children and adolescents has changed during the past 15 years. METHODS: Serial cross-sectional studies of 2 different random population samples of children aged 7 to 17 years, living in urban Copenhagen, Denmark, were performed 15 years apart. The first cohort was investigated in 1986 (n = 527) and the second in 2001 (n = 480). The same methods were applied at both occasions. Skin test reactivity was measured using standard techniques. Asthma was defined on the basis of questionnaire responses and was regarded as nonatopic (intrinsic) if no positive reactions were observed on the skin test and as atopic (extrinsic) if at least 1 positive reaction was noted. Current asthma was defined as symptoms within the preceding 12 months. RESULTS: The prevalence of current asthma increased from 5.3% in 1986 to 11.7% in 2001. This was primarily due to an increase in intrinsic asthma, which was 4.2-fold (1.5% to 6.4%), compared with extrinsic asthma, which increased only 1.4-fold (3.8% to 5.5%). The changes were more pronounced in girls. CONCLUSIONS: The prevalence of asthma has increased substantially during the past 15 years. The observed striking increase in intrinsic asthma suggests the possibility of a more heterogeneous disorder, involving more important factors than atopy. Furthermore, our findings suggest that asthma might be shifting toward female predominance in childhood.

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