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Background The combination of budesonide + formoterol (BFC) offers the advantages of dose adjustment in a single inhaler according to asthma symptoms. We analyzed the relationship between asthma symptoms in terms of peak expiratory flow (PEF) and dose adjustment by the patient. Methods Twenty-eight patients with asthma who used BFC for alleviation of their symptoms (12 men, 16 women; 60 years old) were instructed that the inhaled BFC dose could be increased to a maximum of 8 inhalations per day according to symptom severity. Patients measured and recorded PEF every morning and evening in their asthma diary along with their symptoms and the dose of drugs taken. Results Sixteen of the 28 patients increased their dose for asthma symptoms. The time to recovery from the asthma symptoms was significantly shorter when cough was the only symptom present compared with dyspnea or wheeze (1.4 vs. 5.3 or 6.6 days, p

Background:Inflammatory cytokines and chemokines have been reported to play important roles in thepathogenesis of bronchial asthma. However, no criteria for the classification of `smoker' and `atopic' in bronchialasthma have been defined. In this study, we compared the levels of several cytokines found in thebronchoalveolar lavage( BAL) fluid of patients classified as having bronchial asthma.Methods:Cell subpopulations in BAL fluid were counted. BAL fluid levels of interleukin( IL)-4, -5, -13,-17, and -33 and RANTES (regulated on activation, normal T cell expressed and secreted were measuredusing a bead suspension array in 36 asthma patients (13 males, 23 females;mean age, 39.5±92.8 years)who were non-smokers, 18 asthma patients( 11 males, 7 females;mean age, 30.7±2.7 years) who were exor current smokers( Brinkman index( BI):1−399), and 10 asthma patients( 9 males, 1 female;mean age,50.2±5.5 years) who were current heavy smokers( BI:≥ 400). Relationships were assessed by Spearman'srank correlation analysis.Results:The number of lymphocytes in BAL cell subpopulations of non-smokers( 25±7×103/ml) weresignificantly (p

A 56-year-old woman was referred to our hospital because of dyspnea, wheezing, and a productive cough. Eight years before presentation, bronchial asthma was diagnosed and the patient received inhaled corticosteroids plus antiasthmatic agents (a long-acting inhaled p2-agonist, leukotriene modifiers, and theophylline). Chest radiography showed small diffuse nodular shadows, and a computed tomographic scan showed thickening of the bronchi and bronchioles, with diffuse centrilobular nodules in both lung fields. A blood test and microscopic examination of the bronchoalveolar fluid revealed marked eosinophilia. Transbronchial lung biopsy and transbronchial biopsy showed eosinophilic bronchitis and bronchiolitis. After treatment with oral prednisolone (40 mg daily) and inhaled corticosteroids, the symptoms, blood eosinophilia, and radiographic findings improved. Recently, several similar cases of eosinophilic bronchiolitis have been reported. Studies of further cases and elucidation of the pathophysiology of eosinophilic bronchiolitis are necessary to establish a concept for this disease and to determine whether it should be classified as a subtype of bronchial asthma or as a distinct entity.

PGD2, a lipid mediator released from mast cells, is known to participate in allergic reactions. However, the mechanism by which PGD2 contributes to such reactions remains unclear. We established a novel experimental model of asthma that permitted direct assessment of the role of PGD2 in airway inflammation. Antigen-sensitized mice were exposed to aerosolized prostaglandin D2 (PGD2) 1 d before challenge with low-dose aerosolized antigen. Not only the numbers of eosinophils, lymphocytes, and macrophages but also the levels of IL-4 and IL-5 in bronchoalveolar lavage fluid were higher in PGD2-pretreated mice than in control mice. The expression of macrophage-derived chemokine (MDC), a chemoattractant for Th2 cells, was greater in PGD2-pretreated mice than in control. Injection of anti-MDC antibody into PGD2-pretreated mice markedly inhibited inflammatory cell infiltration as well as Th2 cyto-kine production after antigen challenge. These results indicate that PGD2 accelerates Th2 type inflammation by induction of MDC. Our results suggest that this mechanism may play a key role in the development of human asthma and that MDC might be a target molecule for therapeutic intervention.

Numerous in vitro and in vivo studies in both animals and patients with asthma have shown that interleukin (IL)-9 is an important inflammatory mediator in asthma. To examine the effects of IL-9 antagonism on airway inflammation, ovalbumin-sensitized BALB/c mice were intravenously given anti-IL-9 antibody or an isotype-matched control antibody 30 minutes before challenge with aerosolized ovalbumin. Airway response to methacholine was measured, and samples of bronchoalveolar lavage fluid (BALF) were obtained 24 hours after the last antigen challenge. Lung tissue was harvested and examined histopathologically. After ovalbumin challenge, there were significant increases in airway hyperreactivity, the numbers of inflammatory cells in lung, and IL-4, IL-5, and IL-13 production in BALF. Treatment with anti-IL-9 antibody significantly prevented airway hyperreactivity in response to methacholine inhalation. Blockade of IL-9 reduced the numbers of eosinophils (0.3 +/- 0.1 x 10(5) and 23.6 +/- 0.5 x 10(5)/ml, anti-IL-9 antibody/control immunoglobulin G) and lymphocytes (0.2 +/- 0.2 x 10(5) and 0.8 +/- 0.1 x 10(5)/ml) in BALF. Anti-IL-9 antibody treatment also reduced the concentrations of IL-4 (from 70.6 +/- 4.6 to 30.8 +/- 5.2 pg/ml), IL-5 (from 106.4 +/- 12 to 54.4 +/- 6.6 pg/ml), and IL-13 (from 44.2 +/- 7.6 to 30.1 +/- 5.5 pg/ml) in BALF. Macrophage-derived cytokine expression in the airways was also decreased by IL-9 blockade. Taken together, our findings emphasize the importance of IL-9 in the pathogenesis of asthma and suggest that blockade of IL-9 may be a new therapeutic strategy for bronchial asthma.

Background Exacerbation of asthma has a negative impact on quality of life and increases the risk of fatal asthma. One of the known risk factors for patients with a history of near-fatal asthma is reduced sensitivity to dyspnea. Objective We aimed to identify patients with such risk before they experienced severe exacerbation of asthma. Methods We analyzed asthma symptoms and peak expiratory flow rate (PEFR) values of 53 patients recorded daily in a diary over a mean period of 274 days. Patients matched their symptoms to one of eight categories ranging in severity from 'absent' to 'severe attack'. We then analyzed the relationship between PEFR and asthma symptoms by dividing the PEFR value by the values of clinical parameters, including asthma symptom level. Results Average PEFR was 75.2% (50.5-100%) in the 'absent' symptom category, 64.5% (36.6-92.6%) in 'wheeze', 57.3% (25.0-94.7%) in 'mild attack' and 43.6% (20.4-83.1%) in 'moderate attack', with the personal best reading taken as 100%. Thus, differences in PEFR in patients in the same symptom category varied widely. PEFR in wheeze, mild attack and moderate attack did not correlate significantly with duration of asthma, forced expiratory volume in one second or proportion of personal best to standard predicted PEFR values. These PEFRs showed no significant difference in groups divided by type of regular treatment, but showed a significant negative correlation with the coefficient of variation (CV) of PEFR when asthma symptoms were absent. CV for absent symptoms should be between +4.0 and -4.0% when using regression analysis to measure PEFR if the decreased PEFR is in agreement with guidelines. Conclusion To determine which patients have reduced sensitivity to dyspnea, CV of PEFR should be considered when asthma symptoms are reported as absent. When patients present with more than 8% fluctuation in PEFR, we should intervene in their treatment, even when they claim to be stable.

Considerable progress has been made in the management of asthma with the increasing use of inhaled corticosteroids. However, asthma exacerbation remains a problem. To analyze the characteristics of patients with exacerbation of asthma who visited our hospital in order to better understand the risk factors for fatal asthma.We studied 100 patients who presented at Dokkyo Medical University Hospital (DMUH) with asthma exacerbation.Entry sheets were completed by physicians and questionnaires by patients.Before the exacerbation, the severity was assessed as Step 1 in 46% of patients, Step 2 in 15%, Step 3 in 11%, and Step 4 in 18%. With regard to primary care physicians, 45% were treated at DMUH and 36% had no primary care physicians. Among the DMUH group, the largest proportion was aged 60-69 years and was in Step 4 category. According to asthma control test (ACT) scores, disease was poorly controlled in 83%. Patients with no primary care physician were most often aged 20-39 years (p0.01), and severity was assessed as Step 1 in 86% (p0.01). However, 44% were poorly controlled according to ACT (p0.05).Patients could be classified into two groups: older patients with severe intractable asthma, treated by a specialist and younger patients considered to have mild asthma, half of whom had poorly controlled asthma and no primary care physician. Systems are needed that allow the emergency physicians to evaluate the need for regular treatment in patients with exacerbation because such patients often visit the hospital at night or on a non-working day.

The helper (Th)2 cell-attracting chemokines thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) are ligands for the chemokine receptor CCR4. A number of cellular sources of TARC and MDC have been identified, including not only macrophages, dendritic cells, and natural killer cells, but also bronchial epithelial cells. Recent studies report that TARC and MDC may serve as pivotal chemokines for the development of Th2-dominated experimental allergen-induced asthma. This study was designed to assess TARC and MDC production by CD4+ T cells, including naive T cells and memory/effector T cells, purified from peripheral blood mononuclear cells in patients with asthma. Asthmatic subjects included in this study had mild asthmatic symptoms, positive skin test responses to house dust mite allergen, and elevated level of Dermatophagoides farinae immunoglobulin E in the sera. CD4+ T cells--CD45RA+ CD4+ T cells--as naive T cells and CD45RO+ CD4+ T cells--as memory/effector T cells--were purified by negative selection from peripheral blood mononuclear cells obtained from asthmatic patients (n = 6) and healthy controls (n = 6). These cells and established Th1/Th2 cell lines were then cultured in the presence of both anti-CD3 and -CD28 antibodies. After 48 hr of incubation, concentrations of TARC, MDC, interleukin (IL)-4, IL-5, and interferon-gamma in the supernatants were measured by enzyme-linked immunoadsorbent assay. Reverse transcriptase-polymerase chain reaction was performed to analyze mRNA expression of TARC and MDC. Our results clearly showed that TARC and MDC were produced by activated CD45RA+ CD4+ T cells rather than by activated CD45RO+ CD4+ T cells, and the levels of these chemokines in the asthmatic patients were higher than those in the healthy controls. Furthermore, these chemokines production by Th2 cell lines were greater than those by Th1 cell lines, but the level were smaller than those by naive T cells. Our studies suggest that TARC and MDC are produced by naive T cells rather than by memory/effector T cells, including Th2 cells, in asthmatic patients, and these chemokines were produced at modest levels in any T-cell populations from healthy controls. Taken together, naive T cells in asthma have a peculiar function to produce TRAC and MDC, which contribute to local migration of Th2 cells into lung and lymphoid tissues, along with a function as precursor for memory/effector T cell. This novel function of naive T cells may be implicated in the development of asthma.