Microbial contamination of domiciliary nebulisers and clinical implications in chronic obstructive pulmonary disease.

BACKGROUND AND PURPOSE: Domiciliary nebulisers are widely used in chronic obstructive pulmonary disease (COPD) but nebuliser cleaning practice has not been assessed in patients with COPD who are often elderly and may have severe disease and multiple comorbidities. We aimed to evaluate microbial contamination of home nebulisers used by patients with COPD. METHODS: Random microbiological assessment of domiciliary nebulisers was undertaken together with an enquiry into cleaning practices. We also examined the effectiveness of the trust-wide cleaning instructions in eradicating isolated microorganisms in a laboratory setting. RESULTS: The mean age of patients in this study was 71 (range 40-93) years, and in 68% of patients a large number of significant comorbidities were present. Forty-four nebuliser sets were obtained and 73% were contaminated with microorganisms at >100 colony forming units/plate. Potentially pathogenic bacteria colonised 13 of the 44 nebulisers (30%) and organisms isolated included Pseudomonas aeroginosa, Staphylococcus aureus, multidrug resistant Serratia marcesans, Escherichia coli and multiresistant Klebsiella spp, Enterobacteriaceae and fungus Fusarium oxysporum. Washing of nebuliser masks, chambers and mouthpieces achieved complete eradication of Gram-positive bacterial and fungal flora. Gram-negative organisms were incompletely eradicated, which may be attributed to the presence of biofilms. We also found that in patients with pathogenic organisms cultured on the nebuliser sets, there was a higher probability of occurrence of a COPD exacerbation with a mean number of exacerbations of 3.3 (SD=1) per year in the group in whom pathogens were isolated compared with 1.7 (SD=1.2) exacerbations per year in those whose sets grew non-pathogenic flora (p=0.02). CONCLUSIONS: Nebulisers contaminated with microorganisms are potential reservoirs delivering serious pathogens to the lung. Relationships between nebuliser contamination, clinical infection and exacerbations require further examination, but is a potential concern in elderly patients with COPD with comorbidities who fail to effectively maintain reasonable standards of nebuliser cleanliness.

Relation between trunk fat volume and reduction of total lung capacity in obese men.

Reduction in total lung capacity (TLC) in obese men is associated with restricted expansion of the thoracic cavity at full inflation. We hypothesized that thoracic expansion was reduced by the load imposed by increased total trunk fat volume or its distribution. Using MRI, we measured internal and subcutaneous trunk fat and total abdominal and thoracic volumes at full inflation in 14 obese men [mean age: 52.4 yr, body mass index (BMI): 38.8 (range: 36-44) kg/m(2)] and 7 control men [mean age: 50.1 yr, BMI: 25.0 (range: 22-27.5) kg/m(2)]. TLC was measured by multibreath helium dilution and was restricted (<80% of the predicted value) in six obese men (the OR subgroup). All measurements were made with subjects in the supine position. Mean total trunk fat volume was 16.65 (range: 12.6-21.8) liters in obese men and 6.98 (range: 3.0-10.8) liters in control men. Anthropometry and mean total trunk fat volumes were similar in OR men and obese men without restriction (the ON subgroup). Mean total intraabdominal volume was 9.41 liters in OR men and 11.15 liters in ON men. In obese men, reduced thoracic expansion at full inflation and restriction of TLC were not inversely related to a large volume of 1) intra-abdominal or total abdominal fat, 2) subcutaneous fat volume around the thorax, or 3) total trunk fat volume. In addition, trunk fat volumes in obese men were not inversely related to gas volume or estimated intrathoracic volume at supine functional residual capacity. In conclusion, this study failed to support the hypotheses that restriction of TLC or impaired expansion of the thorax at full inflation in middle-aged obese men was simply a consequence of a large abdominal volume or total trunk fat volume or its distribution.

Reduction of total lung capacity in obese men: comparison of total intrathoracic and gas volumes.

Restriction of total lung capacity (TLC) is found in some obese subjects, but the mechanism is unclear. Two hypotheses are as follows: 1) increased abdominal volume prevents full descent of the diaphragm; and 2) increased intrathoracic fat reduces space for full lung expansion. We have measured total intrathoracic volume at full inflation using magnetic resonance imaging (MRI) in 14 asymptomatic obese men [mean age 52 yr, body mass index (BMI) 35-45 kg/m2] and 7 control men (mean age 50 yr, BMI 22-27 kg/m2). MRI volumes were compared with gas volumes at TLC. All measurements were made with subjects supine. Obese men had smaller functional residual capacity (FRC) and FRC-to-TLC ratio than control men. There was a 12% predicted difference in mean TLC between obese (84% predicted) and control men (96% predicted). In contrast, differences in total intrathoracic volume (MRI) at full inflation were only 4% predicted TLC (obese 116% predicted TLC, control 120% predicted TLC), because mediastinal volume was larger in obese than in control [heart and major vessels (obese 1.10 liter, control 0.87 liter, P=0.016) and intrathoracic fat (obese 0.68 liter, control 0.23 liter, P<0.0001)]. As a consequence of increased mediastinal volume, intrathoracic volume at FRC in obese men was considerably larger than indicated by the gas volume at FRC. The difference in gas volume at TLC between the six obese men with restriction, TLC<80% predicted (OR), and the eight obese men with TLC>80% predicted (ON) was 26% predicted TLC. Mediastinal volume was similar in OR (1.84 liter) and ON (1.73 liter), but total intrathoracic volume was 19% predicted TLC smaller in OR than in ON. We conclude that the major factor restricting TLC in some obese men was reduced thoracic expansion at full inflation.

Similar efficacy of ciclesonide versus prednisolone to treat asthma worsening after steroid tapering.

RATIONALE: Oral corticosteroids effectively treat asthma exacerbations but are associated with well-described side effects. OBJECTIVE: This study compared the efficacy and safety of a high dose of an inhaled corticosteroid with oral prednisolone in patients with worsening of their asthma after medication withdrawal. METHODS: Patients tapered off their inhaled corticosteroids until they reached predefined criteria of "worsening asthma". Randomized patients (n=130) were treated double blind with either ciclesonide 800mug twice daily (starting with 800mug hourly for 3h after randomization) or prednisolone 40mg once daily for 2 weeks. Spirometry, daily asthma symptoms, morning and evening peak expiratory flow and blood parameters were assessed in all, methacholine challenge and inflammatory measures were determined in induced sputum in a subset of patients. RESULTS: Ciclesonide was as effective as prednisolone in improving forced expiratory flow in 1s, morning peak expiratory flow and symptoms, the latter improving more rapidly with ciclesonide. No differences were found in methacholine responsiveness or inflammatory measures in sputum or blood. Ciclesonide caused significantly less reduction in morning plasma cortisol levels (p<0.0001). CONCLUSION: This study shows that inhaled ciclesonide (800mug twice daily) has comparable efficacy to oral prednisolone (40mg once daily) to regain asthma control in patients with asthma worsening. The more rapid onset and smaller effect on cortisol suppression suggest a better safety profile of ciclesonide.

Wegener's granulomatosis presenting as acute systemic vasculitis following 20 years of limited tracheobronchial disease.

OBJECTIVE: We report a patient with a 20-year history of apparently idiopathic airways stenoses, who presented with an antineutrophil cytoplasmic antibody (ANCA) associated, acute, systemic vasculitis with necrotising glomerulonephritis, subsequently diagnosed as Wegener's granulomatosis. METHODS: We present a case report and a review of the world literature on airway stenosis in Wegener's granulomatosis. RESULTS: To our knowledge, this is the first report of Wegener's granulomatosis manifesting as local airway disease for such a prolonged period, before transforming into a systemic vasculitis. CONCLUSIONS: This case highlights the need for physicians to be alert to the possibility of Wegener's granulomatosis as a cause of apparently idiopathic airway stenosis, and to be aware that systemic disease may occur in very long-standing, limited Wegener's granulomatosis.

Dendritic cells from control but not atopic donors respond to contact and respiratory sensitizer treatment in vitro with differential cytokine production and altered stimulatory capacity.

BACKGROUND: Chemical haptens induce both contact and allergic respiratory disease with dendritic cells (DCs) controlling and directing immune responses in vivo. Contact and respiratory haptens may promote differential cytokine production yet distinguishing these effects in vitro remains difficult due to human donor variability. Objective We sought to determine the effect of atopic status on the ability of DC to respond to contact and respiratory sensitizer treatment in vitro as DC from atopic donors are believed to promote Th2-type responses. METHODS: Enriched DC from control or atopic donors were treated for 4 h with levels of the contact sensitizer 2,4-dinitrochlorobenzene (DNCB) or the respiratory sensitizer trimellitic anhydride (TMA) that did not reduce cell viability. A sensitive intracellular detection technique was used to measure cytokine production, while T cell responses were assessed in a mixed leucocyte reaction. RESULTS: DC from control, non-atopic, donors produced cytokines differentially in response to sensitizer treatment; DNCB treatment significantly increased the production of Th1 cytokines IL-12 and IFN-gamma while TMA induced the production of IL-13. Control donor DC treated with TMA stimulated less in a mixed leucocyte reaction than untreated cells with any response reduced further by blocking IL-13 in culture. However, DC from atopic donors showed no significant alteration in either cytokine production or T cell stimulatory capacity after sensitizer treatment. CONCLUSION: Haptens modulate DC by changing the production of cytokines that may play a role in T cell stimulation and subsequent polarization of the immune response. DC from atopic donors were unresponsive to chemical sensitizer treatment, and may be deficient in inducing divergent T cell responses.

Results of endoscopic surgery and intralesional steroid therapy for airway compromise due to tracheobronchial Wegener's granulomatosis.

BACKGROUND: Upper airway compromise due to tracheobronchial stenosis commonly occurs in patients with Wegener's granulomatosis (WG). There is at present no consensus on the optimal management of this life threatening condition. OBJECTIVE: To assess the results of laryngo-tracheo-bronchoscopy, intralesional steroid therapy, laser surgery and dilatation in managing obstructive tracheobronchial WG. METHODS: Records of 18 previously untreated stridulous patients with obstructive tracheobronchial WG, treated between 2004 and 2006, were prospectively recorded on an airway database and retrospectively reviewed. Information about patient and lesion characteristics and treatment details were recorded. Treatment progress was illustrated using a timeline plot, and intervention-free intervals were calculated with actuarial analysis. RESULTS: There were nine males and the average age at presentation was 40 (16) years (range 13-74). There were 13 patients with tracheal and five with tracheal and bronchial lesions. The average tracheal lesion height was 8 (3) mm, located 23 (9) mm below the glottis. There were 1, 10 and 7 Myer-Cotton grade I, II and III lesions, respectively. Mean intervention-free interval following minimally invasive treatment was 26 (2.8) months. Following endobronchial therapy, the median intervention-free interval was 22 months (p>0.8 vs tracheal lesions). No patient required a tracheostomy or endoluminal stenting. CONCLUSIONS: Intralesional steroid therapy and conservative endoluminal surgery is an effective strategy for treating airway compromise due to active tracheal and bronchial WG, obviating the need for airway bypass or stenting. We recommend the combination of endotracheal dilatation, conservative laser surgery and steroid therapy as the standard of care for treating airway compromise due to obstructive tracheobronchial WG.

Inhaled allergen-driven CD1c up-regulation and enhanced antigen uptake by activated human respiratory-tract dendritic cells in atopic asthma.

BACKGROUND: Dendritic cells (DC) mediate inflammation in rodent models of allergic airway disease, but the role played by human respiratory-tract DC (hRTDC) in atopic asthma remains poorly defined. Recent data suggest that CD1 antigen presentation by hRTDC may contribute to asthma pathogenesis. OBJECTIVE: To investigate the influence of hRTDC on the balance between atopy and allergic asthma in human subjects and to determine whether CD1 expression by hRTDC is modulated during asthmatic inflammation. METHODS: Sputum cells were induced from steroid-naïve, allergen-challenged and allergen-naïve subjects (atopic asthmatics, atopic non-asthmatics and non-atopic controls). hRTDC were identified using monoclonal antibody labelling and analysis by flow cytometry. RESULTS: hRTDC stained HLA-DR(+) (negative for markers of other cell lineages) were predominantly myeloid and comprised approximately 0.5% of viable sputum cells. Sputum cells were potent stimulators of allogeneic CD4(+) naïve T cells and enrichment/depletion experiments correlated stimulatory potency with DC numbers. Sputum contained cells that exhibited typical dendritic morphology when analysed by electron microscopy. Myeloid hRTDC were endocytically active, but uptake of FITC-dextran was enhanced in cells from asthmatics (P<0.001). Despite their increased endocytic capacity, asthmatic myeloid hRTDC appeared mature and expressed increased levels of maturation markers (P<0.05-P<0.001), CD1c, CD1d and langerin (P<0.05). CD1c expression by asthmatic myeloid hRTDC was enhanced upon in vivo allergen challenge (three to ninefold within 24 h; P<0.05). CD11c(-)CD123(high) hRTDC were only detected in asthmatic sputum and were increased in number following allergen challenge. CONCLUSION: Despite limited cell numbers, it proved possible to analyse human RTDC in induced sputum, providing evidence that increased antigen uptake and enhanced CD1 presentation by activated hRTDC may contribute to allergic airway disease. CD1 presentation by hRTDC in atopic asthma may therefore constitute a novel target for future intervention strategies.

Concurrent therapy (long acting beta agonists and inhaled corticosteroids) in the management of asthma.

BACKGROUND: Asthma is a clinical syndrome characterised by chronic inflammation of the lower respiratory tract in which many cells and cellular elements play a role, in particular mast cells, eosinophils, T-lymphocytes, macrophages, neutrophils and epithelial cells. Patients often require long-term anti-inflammatory and reliever drugs to achieve a normal life. This review aims to highlight role of concurrent therapy in the optimal management of asthma. METHOD: A review of relevant literature was conducted using available medical journals and Science direct via the Internet. The key words employed were: asthma, concurrent therapy, long acting beta agonists and corticosteroids. British Thoracic Society and The National Heart, Lung and Blood Institute websites were also used in sourcing information for this review. RESULTS: Several studies support adding long acting beta agonists (LABA) to inhaled corticosteroids (ICS) than doubling the dose of ICS. This improves lung function, symptoms control and allows the dose of each drug to be adjusted to the patients'needs. CONCLUSION: This review was able to show that concurrent use LABA and ICS in asthmatics helps in adjusting their treatment within limits hence achieving control of the condition with minimal side effects.

Methotrexate therapy of oral corticosteroid-dependent asthmatics reduces serum immunoglobulins: correlation with clinical response to therapy.

BACKGROUND: Concomitant methotrexate (MTX) therapy of oral corticosteroid (CS)-dependent asthmatics has been shown to spare CS therapy, but the mechanism is unknown. In a previous report, we showed that MTX increases T cell inhibition by CS. In this report we focus on effects of MTX on immunoglobulin concentrations and their possible clinical relevance. OBJECTIVE: To monitor changes in circulating leucocytes and Ig in a group of these patients during MTX therapy, and to relate these changes to clinical 'response' as defined by oral CS reduction. METHODS: Sixteen severe asthmatics dependent on oral prednisolone 15 (7.5-25) mg/day in addition to high dose inhaled CS were treated with MTX 15 mg intramuscularly, weekly for 28 weeks. Prednisolone dosages were maintained constant for 12 weeks then reduced systematically over the next 16 weeks provided that asthma control did not deteriorate. Patients were classified a priori as 'responders' or 'non-responders' to MTX (reduction of initial oral prednisolone requirement by >or=50% or <50%, respectively). Patients were followed-up for a further 12 weeks after MTX withdrawal. Serum Ig and differential blood leucocyte counts were measured at baseline, 12, 28 and 40 weeks. RESULTS: MTX therapy allowed significant, but individually variable, reductions in oral prednisolone dosages (P<0.00001) without alteration of lung function or symptoms. This was associated with significant reductions in mean serum concentrations of Ig of all classes, which reversed following MTX withdrawal. Reductions in IgE and IgG were significantly greater in the MTX 'responders' as compared with 'non-responders', and changes in IgE, IgG and IgM correlated with changes in prednisolone requirements. Differential blood leucocyte counts showed no significant variation. CONCLUSION: MTX therapy reduced oral CS requirements in these severe asthmatics to a degree which correlated with reduced circulating Ig but not lymphopaenia, suggesting a possible cause and effect relationship. These reductions might also contribute to the documented incidence of opportunistic infection in these circumstances.

Adjustable and fixed dosing with budesonide/ formoterol via a single inhaler in asthma patients: the ASSURE study.

Patient-guided management of asthma using adjustable dosing of budesonide/formoterol in a single inhaler (Symbicort) was compared with fixed dosing in an open-label, multicentre, randomised study. Patients, uncontrolled on an inhaled corticosteroid (ICS) or controlled on an ICS and a long-acting beta2-agonist, entered a 4-week run-in period and received budesonide/formoterol (80/4.5 or 160/4.5 microg), 2 inhalations b.i.d. Following randomisation, the fixed-dosing group (n = 764) continued this regimen for a further 12 weeks. The adjustable-dosing group (n = 775) could step down to 1 inhalation b.i.d. if symptoms were controlled, and, at early signs of worsening symptoms, promptly step up to 4 inhalations b.i.d. for < or = 2 weeks. During run-in, National Heart, Lung and Blood Institute symptom-severity grading was maintained in 60% and improved in 31% of patients, clinic peak flow increased from 400 to 4191/min (P<0.001), and health-related quality of life (overall MiniAQLQ) improved from 4.6 to 5.4 (P<0.001). Patients effectively used the adjustable-dosing regimen; 79% reduced budesonide/formoterol dosage and, compared with fixed dosing, the number of inhalations were significantly lowered (3.2 vs. 3.8 inhalations/day, P<0.05). Both regimens were well tolerated. In both groups, symptom control was maintained or improved in 85-86% of patients, and 94% experienced no treatment failures. Consistent with current guidelines, adjustable maintenance dosing with budesonide/formoterol in a single inhaler provides effective asthma control at reduced medication doses.

Methotrexate therapy in asthma increases T cell susceptibility to corticosteroid inhibition.

BACKGROUND: Concomitant methotrexate (MTX) therapy of severe, oral corticosteroid-dependent asthmatics has been shown to be corticosteroid sparing, but the mechanism is unknown. We hypothesized that MTX therapy of these patients increases the susceptibility of their T cells to corticosteroid inhibition. OBJECTIVE: To measure prednisolone inhibition of lectin-induced proliferation of peripheral blood T cells from a group of these patients before, during and following MTX therapy. METHODS: Eighteen severe asthmatics (median (range) age 56 (33-68) years, FEV1 61 (38-69)% predicted, dependent on oral prednisolone 15 (7.5-25) mg/day in addition to high-dose, inhaled corticosteroids) were treated with MTX 15 mg intramuscularly, weekly for 28 weeks. After 12 weeks of MTX, oral prednisolone dosages were reduced systematically over 16 weeks, provided that asthma control did not deteriorate. Patients were followed for a further 12 weeks after MTX withdrawal. Concentration-dependent, prednisolone inhibition of lectin-induced proliferation of peripheral blood T cells was measured just prior to MTX therapy (week 1) and at weeks 12, 28 and 40, and IC50 concentrations were interpolated. RESULTS: By week 28 of MTX therapy, patients were able to reduce oral prednisolone dosages from (median, SIQR) 15 (10-20.5) to 5.9 (1.4-9.4) mg/day (P<0.01) without alteration of lung function and symptoms, while median IC50 values for prednisolone inhibition of peripheral blood T cell proliferation were reduced from 49 (21-144) to 4 (1-9) nm (P<0.0001). These increased again to 15 (9.4-25.7) mg/day and 36 (18-67) nm, respectively, following MTX withdrawal. A correlation (P<0.01) was observed between percentage reductions in prednisolone dosages in vivo and fold changes in prednisolone IC50in vitro between weeks 12 and 28. CONCLUSION: This effect of MTX may at least partly account for its oral corticosteroid-sparing effect in severe asthma.

Addition of salmeterol to fluticasone propionate treatment in moderate-to-severe asthma.

This study was designed to determine whether the benefit of adding salmeterol was superior to doubling the dose of fluticasone propionate (FP) over 6 months, compared to a control group who remained on a lower dose of FP. The multi-centre, double-blind, parallel group study involved 496 symptomatic asthmatic patients with a history of exacerbations on 500-800 micrograms (microg) inhaled corticosteroids (ICS) twice daily (b.d.) in a broadly representative group of 100 hospitals and general practices in six countries. Two doses of FP--250 microg b.d. (FP250) or 500 microg b.d. (FP500)--were compared with the lower dose of FP plus a long-acting beta2-agonist, salmeterol 50 microg b.d. (SM/FP250). Patients symptomatic on the run-in dose of FP250 alone formed the control group in the treatment period. Over 6 months, SM/FP250 significantly improved mean morning peak expiratory flow rates (amPEF) by 42.1 l/min, more than twice the improvement achieved with either dose of FP alone. SM/FP250 also resulted in more symptom-free days and nights (P < 0.002) and days and nights with no relief medication (P < 0.001). The number of severe exacerbations was low: 3, 6 and 8% in the SM/FP250, low- and high-dose FP groups, respectively. This study confirms that adding salmeterol to low-dose inhaled FP offers greater improvements than either maintaining or doubling the dose of FP. Significant benefit was gained from adding salmeterol in a group of patients who appeared to have been at the top of their steroid dose-response curve receiving FP250. There was no evidence of tolerance and a low incidence of exacerbations in all treatment groups.

Early clinical investigation of Viozan (sibenadet HCl), a novel D2 dopamine receptor, beta2-adrenoceptor agonist for the treatment of chronic obstructive pulmonary disease symptoms.

Viozan, (Sibenadet HCl, AR-C68397AA) is a dual D2 dopamine receptor, beta2-adrenoceptor agonist that combines bronchodilator activity with the sensory afferent modulating effects associated with D2-receptor agonism. Investigation in animal models of key chronic obstructive pulmonary disease (COPD) symptoms has demonstrated that sibenadet effectively inhibits sensory nerve activity, thereby reducing reflex cough, mucus production and tachypnoea. The results of the early clinical evaluation of this novel agent are reported. An initial proof of concept study (Study 1) aimed to determine the clinical potential of this novel agent by assessing the effects of three doses of sibenadet therapy relative to placebo, with two commonly used bronchodilators, intended to provide a benchmark against which sibenadet activity could be judged. In all, 701 patients were randomized to one of three sibenadet dose groups (400, 600 or 1000 microg ex valve), salbutamol 200 microg, ipratropium bromide (IB) 40 microg or placebo, all three times daily via pressurized metered dose inhaler (pMDI) for 4 weeks. Once the results of Study 1 had been evaluated, a dose-ranging, study (Study 2) involving 872 patients randomized to receive sibenadet (45, 270, or 495 microg ex actuator), or placebo all three times daily via pMDI, for 6 weeks commenced. Both studies were preceded by a 2-week baseline phase and followed by a 2-week follow up period.The primary efficacy variable identified changes in key COPD symptoms over the treatment period (compared with baseline data) as determined by the novel Breathlessness, Cough and Sputum Scale (BCSS). In addition, data on lung function, health-related quality of life and adverse events were collected. Patients receiving sibenadet therapy three times daily exhibited statistically significantly greater improvements in BCSS total score than those receiving placebo or bronchodilator therapy alone. A clear dose-response was evident in Study 2. Symptom improvement in this study was also accompanied by improved lung function and health-related quality of life. Sibenadet therapy was well tolerated with an adverse events profile comparable to current bronchodilator therapy. These data were viewed as extremely encouraging, warranting further, large-scale clinical investigation.

Safety of formoterol by Turbuhaler as reliever medication compared with terbutaline in moderate asthma.

The present study compared the safety of 4.5 microg formoterol with 0.5 mg terbutaline, both by Turbuhaler and used as needed, in addition to regular formoterol in moderate asthma. In this double-blind parallel-group study, 357 patients taking a moderate-to-high dose of inhaled corticosteroids and additional terbutaline (2-5 inhalations x day(-1) during run-in) were randomised to either formoterol or terbutaline as needed in addition to formoterol 9 microg b.i.d. over 12 weeks. Adverse events, serum potassium levels, electrocardiogram, vital signs and lung function were assessed monthly; peak expiratory flow and severe asthma exacerbations were recorded daily. Patients used 2.16 (range 0.0-6.3) formoterol and 2.34 (range 0.1-7.5) terbutaline relief inhalations x day(-1). No clinically significant differences in safety variables were found between treatments. Statistically greater increases in cardiac frequency (2.6 beats x min(-1), p=0.03) were found on terbutaline. There were 44 and 52 severe asthma exacerbations with formoterol and terbutaline, respectively, with no significant difference in time to first exacerbation. There was also no difference between treatments for other efficacy measures (peak expiratory flow, forced expiratory volume in one second and morning/evening symptom scores). Formoterol 4.5 microg as needed was at least as safe, well tolerated and effective as terbutaline 0.5 mg in stable patients (requiring up to 6 relief inhalations x day(-1)) taking formoterol plus inhaled corticosteroids regularly over 12 weeks.