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Introduction Combining long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs) is beneficial in chronic obstructive pulmonary disease (COPD), as the two classes of bronchodilator have complementary modes of action. The optimal dose for the fixed-dose combination of the LAMA tiotropium and the LABA olodaterol needed to be determined. In this phase II trial, the dose response of tiotropium on top of olodaterol was investigated in a free-dose combination, while other phase II studies have explored different doses of olodaterol on top of tiotropium, with both drugs delivered using the Respimat® inhaler. Methods This was a double-blind incomplete crossover trial in which 233 patients with moderate or severe COPD were randomized to receive four out of eight free-dose combinations of olodaterol (5 or 10 µg) and tiotropium (1.25, 2.5, or 5 µg) or placebo for 4 weeks each. Primary end point was trough forced expiratory volume in 1 s (FEV1) change from baseline (response) after 4 weeks. Results Addition of tiotropium 1.25, 2.5, and 5 µg to olodaterol 5 µg increased mean trough FEV1 response by 0.054, 0.065, and 0.084 L, respectively; addition of tiotropium 1.25, 2.5, and 5 µg to olodaterol 10 µg increased mean trough FEV1 response by 0.051, 0.083, and 0.080 L, respectively. All treatments were well tolerated and incidence of adverse events was similar with all treatments. Conclusions Overall, a dose response for tiotropium on top of both doses of olodaterol was observed, with increasing improvements in trough FEV1 compared to olodaterol alone as the tiotropium dose was increased. Funding Boehringer Ingelheim. Trial registration: ClinicalTrials.gov number, NCT01040403. Electronic supplementary material The online version of this article (doi:10.1007/s12325-015-0239-8) contains supplementary material, which is available to authorized users.

Summary Background This randomised, double-blind, four-way, crossover, Phase II study compared the 24-h forced expiratory volume in 1 s (FEV 1 ) profile of alternative dosing frequencies of two total daily doses of olodaterol (5 and 10 μg) in patients with chronic obstructive pulmonary disease (COPD). Methods Patients received olodaterol 2 μg twice daily (BID), 5 μg BID, 5 μg once daily (QD) and 10 μg QD in a randomised sequence over 3-week treatment periods. Co-primary end points were FEV 1 area under the curve from 0 to 12 h (AUC 0–12 ) and area under the curve from 12 to 24 h (AUC 12–24 ) responses. Additional lung-function responses, pharmacokinetics and safety were assessed. Results 47 patients were treated. All olodaterol doses provided significant increases in FEV 1 versus baseline ( p 1 time profiles were nearly identical for olodaterol 5 and 10 μg QD. Olodaterol 5 μg QD demonstrated improved FEV 1 AUC 0–12 and similar AUC 12–24 versus 2 μg BID. Olodaterol 5 μg QD showed slightly increased FEV 1 AUC 0–12 but lower AUC 12–24 compared to 5 μg BID. Bronchodilation over 24 h was similar for olodaterol 5 μg QD and BID. All doses were well tolerated. Conclusions Olodaterol 5 μg QD is efficacious in COPD, with a superior bronchodilatory profile compared to 2 μg BID, which is close to the same total daily dose, and a similar degree of bronchodilation over 24 h compared with double the daily dose (administered as 10 μg QD or 5 μg BID). Trial registration ClinicalTrials.gov: NCT00846768.

Introduction β-Blockers are known to worsen FEV 1 and airway hyperresponsiveness (AHR) in patients with asthma. Both characteristics determine the outcome of COPD, a disease with frequent cardiac comorbidity requiring β-blocker treatment Objective To determine the effects of β-blockers on AHR (provocative concentration of methacholine causing a 20% fall in FEV 1 [PC 20 ]), FEV 1 , and response to formoterol in patients with COPD Design A double-blind, placebo-controlled, randomized, cross-over study Setting An ambulatory, hospital outpatient clinic of pulmonary diseases Patients Patients with mild-to-moderate irreversible COPD and AHR Intervention Fifteen patients received propranolol (80 mg), metoprolol (100 mg), celiprolol (200 mg), or placebo for 4 days, followed by a washout period ≥ 3 days. On day 4 of treatment, FEV 1 and PC 20 were assessed. Immediately hereafter, formoterol (12 μg) was administered and FEV 1 was measured for up to 30 min Results PC 20 was significantly lower (p 1 deteriorated only after propranolol treatment (2.08 ± 0.31 L) [mean ± SD] compared with placebo (2.24 ± 0.37 L). The fast bronchodilating effect of formoterol was hampered by propranolol (mean increase in FEV 1 at 3 min, 6.7 ± 8.9%) but was unaffected by the other β-blockers (16.9 ± 9.8%, 22 ± 11.6%, and 16.9 ± 9.0% for placebo, metoprolol, and celiprolol, respectively) Conclusions Pulmonary effects did not occur by celiprolol. Only propranolol reduced FEV 1 and the bronchodilating effect of formoterol. Both metoprolol and propranolol increased AHR. Thus, different classes of β-blockers have different pulmonary effects. The anticipated beneficial cardiovascular effects of a β-blocker must be weighted against the putative detrimental pulmonary effects, ie , effect on FEV 1 , AHR, and response to additional β 2 -agonists

Objectives:This study evaluated the efficacy and safety of a novel asthma management strategy - budesonide/formoterol for both maintenance and symptom relief (Symbicort Single Inhaler Therapy*) - compared with a higher maintenance dose of budesonide in patients with moderate to severe asthma.Methods:This was a 12-month, randomised, double-blind, parallel-group study. Symptomatic patients with asthma (n = 1890; mean age 43 years [range 11 years-80 years], mean baseline forced expiratory volume in 1 s [FEV1] 70% of predicted, mean inhaled corticosteroid [ICS] dose 746mug/day) received either budesonide (160mug, 2 inhalations twice daily) plus terbutaline 0.4 mg as needed or a daily maintenance dose of budesonide/formoterol (160/4.5 mug, 2 inhalations once daily) with additional inhalations of budesonide/formoterol 160/4.5 mug as needed. Time to first severe exacerbation (hospitalisation/emergency room [ER] treatment or systemic steroids due to asthma worsening or a fall in morning peak expiratory flow [PEF] to less than or equal to 70% of baseline on 2 consecutive days) was the primary outcome variable.Results: A total of 1890 patients were randomised, of whom 1563 (83%) had severe asthma. The time to first severe exacerbation was prolonged by budesonide/formoterol single inhaler therapy (p Conclusion: Budesonide/formoterol single inhaler therapy has the potential to provide a complete asthma management approach with one inhaler, demonstrating a high level of efficacy in patients with moderate to severe asthma.

Virtually all asthma patients use bronchodilators. Formoterol and salbutamol have a rapid onset of bronchodilating effect, whereas salmeterol acts slower. We studied the onset of improvement of dyspnoea sensation after inhalation with these bronchodilators and placebo to reverse a methacholine-induced bronchoconstriction as a model for an acute asthma attack.Seventeen patients with asthma completed this randomised, double-blind, crossover, double-dummy study. On 4 test days, forced expiratory volume in 1 s (FEV1) and Borg score were recorded and patients were challenged with methacholine until FEV1 fell with greater than or equal to 30% of baseline value. Thereafter, formoterol 12 mug via Turbuhaler(R), salbutamol 50 mug via Turbuhaler(R), salmeterol 50 mug via Diskhaler(TM), or placebo was inhaled. FEV1 and Borg scores were assessed during the following 60 min.The first sensed improvement of Borg score was significantly (P The Borg score returned significantly faster to the baseline value with formoterol, salbutamol, and salmeterol (Gmean time 13.8 (1-75), 13.4 (1-60), and 18.0 (175) min, respectively) than with placebo (33.6 (1-75 min).Formoterol and salbutamol act significantly faster than salmeterol in relieving dyspnoea induced by methacholine-induced bronchoconstriction, in patients with asthma. (C) 2004 Elsevier Ltd. All. rights reserved.

Inhalers containing corticosteroids and long-acting beta2-agonists are becoming increasingly important in asthma management. A rapid effect is important to patients, particularly during exacerbations. We compared the onset of bronchodilation and patient-perceived relief from dyspnoea following single-inhaler budesonide/formoterol or salmeterol/fluticasone in a model of acute bronchoconstriction. A randomised, double-blind, double-dummy, single-dose, crossover study included 27 outpatients with asthma (mean age 35 years; mean FEV1 90% predicted normal). Immediately following methacholine-induced bronchoconstriction (fall in FEV1or = 30%), patients inhaled budesonide/formoterol (160/4.5 microg, 1 or 2 inhalations; Symbicort Turbuhaler), salmeterol/fluticasone (50/250 microg; Seretide Diskus) or placebo on 4 study days. Lung function and Borg score were assessed for 30 min. During methacholine-induced provocation (final mean FEV1 62.5% of baseline), mean Borg score increased 10-fold (from 0.3 to 3.0 units). Hereafter, mean FEV1 at 3 min improved significantly more after budesonide/formoterol 1 and 2 inhalations (37 and 38%, respectively) than after salmeterol/fluticasone (23%; P0.001) or placebo (10%; P0.001). Median recovery times to 85% of baseline FEV1 were shorter for budesonide/formoterol (1 or 2 inhalations: 3.3 and 2.8 min, respectively) than salmeterol/fluticasone (8.9 min; P0.001) and placebo (30 min). One min after budesonide/formoterol, dyspnoea was significantly reduced (Borg score -0.86 units, both doses) compared with salmeterol/fluticasone (-0.55 units; P0.05) and placebo (-0.23 units; P0.001). Budesonide/formoterol provides immediate bronchodilation, faster than salmeterol/fluticasone, which patients can feel during acute methacholine-induced bronchoconstriction.

Current asthma guidelines recommend that patients are educated to adjust their medication according to their asthma severity using physician-guided self-management plans. However, many patients take a fixed dose of their controller medication and adjust their reliever medication according to asthma symptoms.This study examined whether asthma control improved if patients adjusted the maintenance dose of budesonide/formoterol (Symbicort Turbuhaler* 160/4.5 microg) according to asthma severity compared with traditional fixed dosing (FD) regimens.Symptomatic patients with asthma (n = 658, mean symptom score 1.5, mean inhaled corticosteroids 735 microg/day, mean forced expiratory volume in 1 second [FEV(1)] 84% predicted) were randomised after 2 weeks' run-in to either: budesonide/formoterol adjustable maintenance dosing (AMD), budesonide/formoterol FD or salmeterol/fluticasone (Seretide Diskus dagger 50/250 microg) FD. In a 4-week double-blind period, both budesonide/formoterol AMD and FD groups received two inhalations twice daily (bid) and salmeterol/fluticasone FD patients received one inhalation bid. In the following 6-month open extension, both FD groups continued with the same treatment. Patients in the AMD group with well-controlled asthma stepped down to one inhalation bid; others continued with two inhalations bid. All AMD patients could increase to four inhalations bid for 7-14 days if symptoms worsened. All patients used terbutaline or salbutamol for symptom relief throughout. The primary variable was the odds of achieving a well-controlled asthma week (WCAW).The odds ratio for achieving a WCAW did not differ between the FD regimens; however, during the open period, budesonide/formoterol AMD increased the odds of achieving a WCAW vs. budesonide/formoterol FD (odds ratio 1.335; 95% CI: 1.001, 1.783; p = 0.049) despite a 15% reduction in average study drug use. Budesonide/formoterol AMD patients had a lower exacerbation rate over the study: 40% lower vs. salmeterol/fluticasone FD (p = 0.018); 32% lower vs. budesonide/formoterol FD (NS). During the double-blind period, there were no clinically relevant differences between the budesonide/formoterol FD and salmeterol/fluticasone FD groups. Budesonide/formoterol AMD patients used less reliever medication in the open extension: 0.58 vs. 0.92 occasions/day for budesonide/formoterol FD (p = 0.001) and 0.80 occasions/day for salmeterol/fluticasone FD (p = 0.011).Adjustable maintenance dosing with budesonide/formoterol provides more effective asthma control by reducing exacerbations and reliever medication usage compared with fixed-dose salmeterol/fluticasone.

BACKGROUND: The extent of epithelial injury in asthma is reflected by expression of the epidermal growth factor receptor (EGFR), which is increased in proportion to disease severity and is corticosteroid refractory. Although the EGFR is involved in epithelial growth and differentiation, it is unknown whether it also contributes to the inflammatory response in asthma. OBJECTIVES: Because severe asthma is characterized by neutrophilic inflammation, we investigated the relationship between EGFR activation and production of IL-8 and macrophage inhibitory protein-1 alpha (MIP-1alpha) using in vitro culture models and examined the association between epithelial expression of IL-8 and EGFR in bronchial biopsies from asthmatic subjects. METHODS: H292 or primary bronchial epithelial cells were exposed to EGF or H2O2 to achieve ligand-dependent and ligand-independent EGFR activation; IL-8 mRNA was measured by real-time PCR and IL-8 and MIP-1alpha protein measured by enzyme-linked immunosorbent assay (ELISA). Epithelial IL-8 and EGFR expression in bronchial biopsies from asthmatic subjects was examined by immunohistochemistry and quantified by image analysis. RESULTS: Using H292 cells, EGF and H2O2 increased IL-8 gene expression and release and this was completely suppressed by the EGFR-selective tyrosine kinase inhibitor, AG1478, but only partially by dexamethasone. MIP-1alpha release was not stimulated by EGF, whereas H2O2 caused a 1.8-fold increase and this was insensitive to AG1478. EGF also significantly stimulated IL-8 release from asthmatic or normal primary epithelial cell cultures established from bronchial brushings. In bronchial biopsies, epithelial IL-8, MIP-1alpha, EGFR and submucosal neutrophils were all significantly increased in severe compared to mild disease and there was a strong correlation between EGFR and IL-8 expression (r = 0.70, P < 0.001). CONCLUSIONS: These results suggest that in severe asthma, epithelial damage has the potential to contribute to neutrophilic inflammation through enhanced production of IL-8 via EGFR- dependent mechanisms.

Salmeterol and formoterol are both long-acting beta(2)-adrenoceptor agonists (beta(2)-agonists). They both provide excellent bronchodilating and bronchoprotective effects in patients with asthma but their are some differences between these two long-acting beta(2)-agonists in vitro and in vivo. Formoterol has a greater potency and intrinsic activity than salmeterol, which can become especially apparent at higher doses than that clinically recommended, and in contracted bronchi. Long-term use of long-acting beta(2)-agonists can induce tolerance, which can be partially reversed with corticosteroids. Long-acting beta(2)-agonists have some anti-inflammatory effects in vitro, but data in vivo are less convincing. Compared with doubling the dose of inhaled corticosteroids, the addition of inhaled long-acting beta(2)-agonists to inhaled corticosteroids improves symptom control in patients with asthma and reduces both the exacerbation rate of asthma and hospital admission rate. No enhanced airway responsiveness or loss of perception of dyspnea has been observed with the use of inhaled long-acting beta(2)-agonists. Monotherapy with long-acting beta(2)-agonists is not recommended.

BACKGROUNDIn vitro the long acting β2agonist salmeterol can, in contrast to formoterol, behave as a partial agonist and become a partial antagonist to other β2agonists. To study this in vivo, the bronchodilating effect of salbutamol was measured during methacholine induced moderate to severe bronchoconstriction in patients receiving maintenance treatment with high dose long acting β2agonists.METHODSA randomised double blind crossover study was performed in 19 asthmatic patients with mean forced expiratory volume in one second (FEV1) of 88.4% predicted and median concentration of methacholine provoking a fall in FEV1of 20% or more (PC20) of 0.62 mg/ml at entry. One hour after the last dose of 2 weeks of treatment with formoterol (24 μg twice daily by Turbuhaler), salmeterol (100 μg twice daily by Diskhaler), or placebo a methacholine provocation test was performed and continued until there was at least a 30% decrease in FEV1. Salbutamol (50 μg) was administered immediately thereafter, followed by ipratropium bromide (40 μg) after a further 30 minutes. Lung function was monitored for 1 hour after provocation.RESULTSThere was a significant bronchodilating and bronchoprotective effect after 2 weeks of active treatment. The dose of methacholine needed to provoke a fall in FEV1of ⩾30% was higher after pretreatment with formoterol (2.48 mg) than with salmeterol (1.58 mg) or placebo (0.74 mg). The difference between formoterol and salmeterol was statistically significant: 0.7 doubling dose steps (95% CI 0.1 to 1.2, p=0.016). The immediate bronchodilating effect of subsequently administered salbutamol was significantly impaired after pretreatment with both drugs (p1relative to the pre-methacholine baseline was 15.8%, 7.3%, and 5.5% for placebo, formoterol and salmeterol, respectively (equivalent to increases of 26%, 14%, and 12%, respectively, from the lowest FEV1after methacholine). At 30 minutes significant differences remained, but 1 hour after completing the methacholine challenge FEV1had returned to baseline values in all three treatment groups.CONCLUSIONFormoterol has a greater intrinsic activity than salmeterol as a bronchoprotective agent, indicating that salmeterol is a partial agonist compared with formoterol in contracted human airways in vivo. Irrespective of this, prior long term treatment with both long acting β2agonists reduced the bronchodilating effect of an additional single dose of salbutamol equally, indicating that the development of tolerance or high receptor occupancy overshadowed any possible partial antagonistic activity of salmeterol. Patients on regular treatment with long acting β2agonists should be made aware that an additional single dose of a short acting β2agonist may become less effective.

We investigated whether treatment with a long-acting beta2-agonist (LAbeta2) is associated with a decrease in patient compliance with regard to inhalation corticosteroids (ICS). Date on prescriptions collected by 15,760 patients suffering from airways disease were provided by 69 Dutch pharmacies. All prescriptions of ICS and LAbeta2 were analysed and divided in four groups by LAbeta2 use during 1997 and 1998. Date from 15,760 patients were available. In the 10,929 patients not treated with LAbeta2, compliance decreased slightly but not significantly. In 3281 patients receiving LAbeta2 compliance also decreased slightly but not significantly. In 404 patients, who used a LAbeta2 in 1997 and discontinued treatment in 1998, the compliance fell significantly (P0.05). In 1147 patients who started to use a LAbeta2 in 1998, compliance with ICS significantly improved (P0.05). These results suggest that the regular use of LAbeta2 improves compliance with ICS. Therefore, the concern that compliance with inhaled corticosteroid therapy will decrease under concomitant use of LAbeta2 appear to be unfounded.

A 49-year-old woman underwent a pneumonectomy because of a mass in the middle lobe. Histological examination of the tumour showed a well-differentiated fetal adenocarcinoma (WDFA). This rare tumour appears to be associated with an excellent prognosis in the absence of metastases following surgical resection.

To improve our understanding of the inflammatory mechanisms underlying severe disease, a biopsy study was performed comparing 15 clinically unstable glucocorticoid-dependent asthmatics, 10 mild asthmatics, and 10 control subjects. Compared with mild asthma, severe asthma was characterized by reduced mucosal eosinophilia. Whilst no significant differences were found in the numbers of mast cells, neutrophils, CD3+ and CD4+ T-cells between the three groups, up to a 4-fold increase In the numbers of activated T-lymphocytes bearing the interleukin (IL)-2 receptor (IL-2R) was found in the mucosa in severe asthma compared to mild asthma (p = 0.03) and control subjects (p = 0.003). Compared to control subjects, the mucosa of severe asthmatics contained significantly (p = 0.02) higher numbers of IL-5+ cells, with no differences between mild and severe disease. In contrast, staining for the anti-IL-4 monoclonal antibody 3H4 revealed that biopsies from mild asthmatics contained more IL4+ cells than biopsies from severe asthmatics and control subjects (p = 0.0008). In the severe asthmatics, a close correlation (r(s) = 0.76, p = 0.005) was found between the numbers of IL-2R-bearing cells and the variability in peak expiratory flow. In conclusion, persistent T-cell activation is a prominent feature of severe asthma. These results also indicate that interleukin-5, and not interleukin-4, is upregulated in severe disease.

We have tested the hypothesis that the expression of interleukin-8 (IL-8) is increased in bronchial tissue and circulating leukocytes of atopic asthmatics, indicating a role for this chemokine in asthma. The concentration of IL-8 in its free form and complexed with IgG or IgA was measured by ELISA in bronchial tissue, serum, and lysates of freshly isolated peripheral blood mononuclear cells and granulocytes from subjects with mild or severe asthma and nonatopic nonasthmatic subjects. Serum ECP was measured by fluorescent enzyme immunoassay. Free IL-8 was detected in the sera (n = 44) and bronchial tissue (n = 9) of all subjects with severe atopic asthma, but it was undetectable in normal subjects and subjects with mild atopic asthma, suggesting that free IL-8 is a marker of severe asthma. A positive correlation between free IL-8 and serum ECP levels found in severe disease suggests that IL-8 is associated with eosinophil activation. Complexes of IL-8 with IgA and IgG were detected in all serum and tissue samples. However, the levels of the IL-8-IgA complex were increased in the bronchial mucosa in asthma, and in blood were related to disease activity. Together, these results point to upregulation of IL-8 production in asthma and the induction of IL-8 binding immunoglobulins of the IgA class in the inflamed mucosa. We suggest a proinflammatory role for these complexes in lung tissue.

The purpose of this study was to investigate the relationship between bronchoalveolar lavage (BAL)-derived parameters of interstitial lung disease and clinical and lung function parameters in 34 patients with sarcoidosis and 23 patients with idiopathic pulmonary fibrosis (IPF). BAL findings of healthy individuals served as controls. Cell content and differentiation of BAL fluid were determined. Oxygen radical (O2-) production of BAL cells and of blood polymorphonuclear (PMN) cells was measured. Phenotypes of lung and blood lymphocytes were determined by immunoperoxidase staining. In addition, lung function was assessed, chest X-rays were made and serum ACE was measured. Lymphocyte alveolitis in sarcoidosis was associated with increased alveolar macrophage (AM) O2- production (P < 0.025 vs. sarcoidosis with normal lymphocyte counts). Patients with extrapulmonary sarcoidosis had higher CD4/CD8 ratios in BAL (P < 0.025) and shorter disease duration (P < 0.01) than those with strictly pulmonary sarcoidosis. Disease duration in sarcoidosis correlated inversely with the number of BAL cells (r = -0.38, P < 0.05), the relative and absolute number of lymphocytes in BAL fluid (r = -0.34, P < 0.05 and r = -0.44, P < 0.01, respectively) and the percentage of CD4-positive cells and the CD4/CD8 ratio (r = -0.43, P < 0.05 and r = -0.48, P < 0.025, respectively). Although significant increases in O2- production by BAL cells were observed in both IPF and sarcoidosis, only in sarcoidosis was a higher AM O2- production associated with a significantly lower total lung capacity (r = -0.67, P < 0.005) and pulmonary diffusing capacity TLCO (r = -0.50, P < 0.05). In conclusion, our findings show that lung lymphocyte phenotypes differ among patients with pulmonary and extrapulmonary sarcoidosis and that O2- production is upregulated in active sarcoidosis. In addition, our findings suggest that different relationships between BAL data and lung function in patients with sarcoidosis and IPF may be explained by differences in disease duration. In IPF, disease duration is likely to be underestimated because of its insidious onset. In sarcoidosis, the presence of extrapulmonary symptoms, helpful to establish an early diagnosis, is associated with significant BAL lymphocytosis.

Background: Bronchial hyperreactivity is a common characteristic of patients with asthma and is often associated with enhanced activities of peripheral blood cells. Signal transduction systems are important in regulating cellular activities and can be modified by allergen challenge. Methods: Patients with allergic asthma ( n = 15) were challenged with house dust mite allergen, resulting in an asthmatic response. Adenylyl cyclase activity was measured in membranes from peripheral blood mononuclear cells before, 3 hours after, and 24 hours after challenge. Results: Allergen challenge proved to have opposite effects in two distinct subgroups of patients. In 10 patients (group I) a heterologous desensitization of the adenylyl cyclase system was observed after challenge, whereas in five patients (group II) an increase in adenylyl cyclase activity was found. Adenylyl cyclase activity before allergen challenge in group II was significantly lower than in group I and comparable to cyclase activity found in group I after allergen challenge. This suggests that in these five patients the adenylyl cyclase system was already desensitized before the start of the study, possibly as a result of natural allergen exposure. Heterologous desensitization in group I was found within 3 hours after allergen challenge, that is before the onset of the late bronchoconstrictive reaction. Conclusions: Because adenylyl cyclase is important in the regulation of cytokine production by mononuclear cells, alteration of cytokine production induced by desensitization of adenylyl cyclase could therefore play a role in the development of the late bronchoconstrictive reaction.

To determine whether a link exists between the recruitment of inflammatory cells in the airways on a bronchial and bronchoalveolar level and the development of allergen-induced increase in bronchial hyperresponsiveness after allergen challenge, we used bronchial lavage and bronchoalveolar lavage to assess the airway responses to allergen. Twelve symptomatic atopic asthmatics were studied. In all patients bronchial and bronchoalveolar lavage was performed before, 3 h, and 24 h after allergen challenge. Monoclonal antibodies were used directed against T cells (CD3, CD4, CD8) and the eosinophil cationic protein (EG2). Eight patients showed a dual asthmatic response; four patients showed only an early asthmatic reaction after allergen challenge. Clear differences were found between bronchial and bronchoalveolar lavage. Activated eosinophils (EG2) were significantly increased both at 3 h (p = 0.01) and 24 h (p = 0.005). The number of activated eosinophils was significantly higher in the dual responders. A correlation was observed between the severity of the late asthmatic reaction (LAR) and the number of epithelial cells in the bronchial recovery at 3 h, but not at 24 h, in patients who clinically developed a LAR. No significant changes in the number of CD3, CD4, and CD8 cells 3 and 24 h after the challenge both in the bronchial and bronchoalveolar recovery were observed. We conclude that the number of activated eosinophils in bronchial lavage is associated with the development of the LAR and allergen-induced increase in bronchial hyperresponsiveness.

Background The budesonide/formoterol combination is successfully used for fast relief of asthma symptoms in addition to its use as maintenance therapy. The temporarily increased corticosteroid dose during increasing inhaler use for symptom relief is likely to suppress any temporary increase in airway inflammation and may mitigate or prevent asthma exacerbations. The relative contribution of the budesonide and formoterol components to the improved asthma control is unclear. Methods The acute protective effect of inhaled budesonide was tested in a model of temporarily increased airway inflammation with repeated indirect airway challenges, mimicking an acute asthma exacerbation. A randomised, double-blind, cross-over study design was used. Asthmatic patients (n = 17, mean FEV1 95% of predicted) who previously demonstrated a ≥30% fall in forced expiratory volume in 1 second (FEV1) after inhaling adenosine 5'-monophosphate (AMP), were challenged on four consecutive test days, with the same dose of AMP (at 09:00, 12:00 and 16:00 hours). Within 1 minute of the maximal AMP-induced bronchoconstriction at 09:00 hours, the patients inhaled one dose of either budesonide/formoterol (160/4.5 μg), formoterol (4.5 μg), salbutamol (2 × 100 μg) or placebo. The protective effects of the randomised treatments were assessed by serial lung function measurements over the test day. Results In the AMP provocations at 3 and 7 hours after inhalation, the budesonide/formoterol combination provided a greater protective effect against AMP-induced bronchoconstriction compared with formoterol alone, salbutamol and placebo. In addition all three active treatments significantly increased FEV1 within 3 minutes of administration, at a time when inhaled AMP had induced the 30% fall in FEV1. Conclusions A single dose of budesonide/formoterol provided a greater protective effect against inhaled AMP-induced bronchoconstriction than formoterol alone, both at 3 and at 7 hours after inhalation. The acute protection against subsequent bronchoconstrictor stimuli such as inhaled AMP and the rapid reversal of airway obstruction supports the use of budesonide/formoterol for both relief and prevention in the treatment of asthma. Trial Registration ClinicalTrials.gov number NCT00272753

Bronchial hyperresponsiveness (BHR) to methacholine and adenosine 5'-monophosphate (AMP) was studied in 15 allergic asthmatic patients before and 3 and 24 h after allergen challenge with house dust mite (HDM). Subjects attended the clinic on 3 consecutive days. On the first day a control solution was inhaled, and methacholine or AMP challenge was performed 3 h later. The next day HDM was inhaled, and 3 and 24 h later methacholine or AMP challenge was performed again. There were no significant difference in FEV1 baseline value between any of the study days. PD20 HDM, percentage decrease in FEV1, and AUC for both the EAR and LAR were not significantly different in the methacholine and AMP studies. After HDM challenge, PC20 methacholine decreased significantly from a geometric mean (+/- SEM) starting value of 1.39 +/- 0.63 mg/ml to 0.30 +/- 0.78 mg/ml (p less than 0.001) at 3 h and to 0.22 +/- 0.75 mg/ml (p less than 0.001) at 24 h. The magnitude of the decrease in PC20 methacholine at 3 h correlated with the severity of the late asthmatic reaction (LAR) as measured by the percentage fall in FEV1 and area under the curve (AUC) (r = -0.60 and r = 0.55; p less than 0.05). A significant decrease was observed in the PC20 AMP at 3 h, from a geometric mean value of 12.2 +/- 0.96 mg/ml after challenge with the control solution to 4.47 +/- 0.99 mg/ml (p less than 0.05) after HDM challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchial hyperresponsiveness (BHR) to methacholine was studied in 14 patients with asthma and five healthy control subjects, with and without pretreatment with nedocromil sodium, 3 and 24 hours after allergen challenge. Eleven patients demonstrated a dual asthmatic response. A significant decrease in the provocative concentration causing a 20% fall in FEV1 was found from a geometric mean starting value of 1.18 mg/ml on the control day to 0.24 mg/ml (p less than 0.001) and to 0.17 mg/ml (p less than 0.001) 3 and 24 hours after allergen challenge. A significant correlation was observed between the increased BHR at 3 hours and the magnitude of the late response (r = -0.57; p less than 0.05). Nedocromil sodium (6 mg) significantly inhibited the increase in BHR, 1 mg/ml (p less than 0.001) at 3 hours and 0.50 mg/ml (p less than 0.001) at 24 hours. Nedocromil sodium shifted the severity of the early allergic reaction (EAR) from mean -34.8% to -6.9% and inhibited the later allergic reaction (LAR) from -30.5% to +0.4% (p less than 0.005). From the study can be concluded that nedocromil sodium inhibits the EAR and LAR and the allergen-induced increase in BHR. The inhibitory effect of nedocromil sodium on the LAR may be related to its ability to inhibit the increased BHR before the development of the LAR.

INTRODUCTION: Assessment by the general practitioner of the presence, the severity or even the changes in time of BHR by a questionnaire would be an advantage in diagnosing and monitoring patients with asthma. AIMS AND OBJECTIVES: The aim of the study is to select a reliable set of respiratory symptoms and stimuli for the preliminary version of the Bronchial Hyperresponsiveness Questionnaire (BHQ). Subjects and method: A preliminary list of 33 symptoms and 64 stimuli was composed by review of literature, in depth interviews and focus group discussions with asthma patients. After a histamine challenge test patients (n= 302) were asked to score each item on a 7-point Likert scale (0 = no; 6=severe complaints). The questionnaires of patients with a positive challenge test (n = 225) were selected for factor and ROC analysis. A Spearman's rank correlation test was performed to investigate the relation between the PC20-histamine and the scores on the questions in the group of patients with doctors diagnosed asthma (n= 181). An expert panel was asked to define criteria for the selection of suitable questions for the BHQ. Selection criteria were: a significant correlation coefficient of =0.20 and/or a significant positive ROC-analysis. RESULTS: 34 symptoms and stimuli showing a relation with the PC20 were selected for the BHQ. Conclusion/discussion: The symptoms and stimuli correlating best with the PC20 may give an indication of the severity of BHR whereas symptoms and stimuli with significantly ROC-scores are probably sensitive for detecting the presence of BHR. To support this hypothesis further (validation) studies are necessary. Conflict of interest and funding Supported by an unrestricted grant from AstraZeneca BV, The Netherlands.

Many asthma patients remain symptomatic despite maintenance therapy with inhaled corticosteroids (ICS) and salbutamol as rescue medication. In the present study the relative efficacy and preference for as-needed formoterol compared with salbutamol was examined. In total, 211 patients with a mean age of 45 yrs (mean forced expiratory volume in one second (FEV1) 77% predicted normal), using ICS, were randomised to 3 weeks' double-blind treatment with as-needed formoterol 4.5 microg Turbuhaler and with as-needed salbutamol 100 mug Turbuhaler in a cross-over fashion. Overall, lung function and symptom control were better with as-needed formoterol than with as-needed salbutamol. During as-needed formoterol treatment daytime and night-time symptom scores were lower, peak expiratory flow and FEV1 were higher and patients experienced fewer disturbed nights (34%) compared with as-needed salbutamol. Patients preferred the formoterol treatment to salbutamol. Of the 162 patients expressing a preference, formoterol was preferred by 68% (95% confidence interval: 60-75). Subjective assessment of effectiveness also favoured formoterol, which was perceived as slightly faster acting than salbutamol. In conclusion, as-needed formoterol improved symptoms and lung function compared with salbutamol and was perceived as more effective and at least as fast acting for symptom relief.

In Thorax 2001; 56: 325-28 wordt gesteld dat de medicamenteuze behandeling van astma in de zwangerschap gelijk is aan die van niet-zwangeren. Het is moeilijk om aan te geven wat de gangbare opvatting van de Nederlandse Longartsenwereld is met betrekking tot de behandeling van astma bij zwangeren. De NVALT (Nederlandse Vereniging voor Longartsen en Tuberculose) beschikt niet over een overkoepelende standaard met betrekking tot dit onderwerp.

The extent of epithelial injury in asthma is reflected by expression of the epidermal growth factor receptor (EGFR), which is increased in proportion to disease severity and is corticosteroid refractory. Although the EGFR is involved in epithelial growth and differentiation, it is unknown whether it also contributes to the inflammatory response in asthma.Because severe asthma is characterized by neutrophilic inflammation, we investigated the relationship between EGFR activation and production of IL-8 and macrophage inhibitory protein-1 alpha (MIP-1alpha) using in vitro culture models and examined the association between epithelial expression of IL-8 and EGFR in bronchial biopsies from asthmatic subjects.H292 or primary bronchial epithelial cells were exposed to EGF or H2O2 to achieve ligand-dependent and ligand-independent EGFR activation; IL-8 mRNA was measured by real-time PCR and IL-8 and MIP-1alpha protein measured by enzyme-linked immunosorbent assay (ELISA). Epithelial IL-8 and EGFR expression in bronchial biopsies from asthmatic subjects was examined by immunohistochemistry and quantified by image analysis.Using H292 cells, EGF and H2O2 increased IL-8 gene expression and release and this was completely suppressed by the EGFR-selective tyrosine kinase inhibitor, AG1478, but only partially by dexamethasone. MIP-1alpha release was not stimulated by EGF, whereas H2O2 caused a 1.8-fold increase and this was insensitive to AG1478. EGF also significantly stimulated IL-8 release from asthmatic or normal primary epithelial cell cultures established from bronchial brushings. In bronchial biopsies, epithelial IL-8, MIP-1alpha, EGFR and submucosal neutrophils were all significantly increased in severe compared to mild disease and there was a strong correlation between EGFR and IL-8 expression (r = 0.70, P0.001).These results suggest that in severe asthma, epithelial damage has the potential to contribute to neutrophilic inflammation through enhanced production of IL-8 via EGFR- dependent mechanisms.

The aim of this study was to investigate formoterol, an inhaled long-acting beta2-agonist, in patients with chronic obstructive pulmonary disease (COPD). Six-hundred and ninety-two COPD patients, mean baseline forced expiratory volume in one second (FEV1) 54%, FEV1/forced vital capacity 75% of predicted, reversibility 6.4% pred, were treated with formoterol (4.5, 9 or 18 microg b.i.d.) or placebo via Turbuhaler for 12 weeks. Symptoms were recorded daily. Spirometry and the incremental shuttle walking test (SWT) were performed at clinic visits. Compared with placebo, 18 microg b.i.d. formoterol reduced the mean total symptom score by 13% and increased the percentage of nights without awakenings by 15%. Formoterol (9 and 18 microg b.i.d.) significantly reduced symptom scores for breathlessness (-7% and -9%, respectively) and chest tightness (-11% and -8%, respectively), reduced the need for rescue medication (-25% and -18%, respectively), and increased symptom-free days (71% and 86%, respectively). FEV1 improved significantly after all three doses of formoterol (versus placebo). No differences were found between groups in SWT walking distance. No unexpected adverse events were seen. In conclusion, 9 and 18 microg b.i.d. formoterol reduced symptoms and increased the number of symptom-free days in a dose-dependent manner in chronic obstructive pulmonary disease patients. Formoterol improved lung function at a dose of 4.5 microg b.i.d. and higher.

BACKGROUND—In vitro the long acting β2 agonist salmeterol can, in contrast to formoterol, behave as a partial agonist and become a partial antagonist to other β2 agonists. To study this in vivo, the bronchodilating effect of salbutamol was measured during methacholine induced moderate to severe bronchoconstriction in patients receiving maintenance treatment with high dose long acting β2 agonists. METHODS—A randomised double blind crossover study was performed in 19 asthmatic patients with mean forced expiratory volume in one second (FEV1) of 88.4% predicted and median concentration of methacholine provoking a fall in FEV1 of 20% or more (PC20) of 0.62 mg/ml at entry. One hour after the last dose of 2 weeks of treatment with formoterol (24 µg twice daily by Turbuhaler), salmeterol (100 µg twice daily by Diskhaler), or placebo a methacholine provocation test was performed and continued until there was at least a 30% decrease in FEV1. Salbutamol (50 µg) was administered immediately thereafter, followed by ipratropium bromide (40 µg) after a further 30 minutes. Lung function was monitored for 1 hour after provocation. RESULTS—There was a significant bronchodilating and bronchoprotective effect after 2 weeks of active treatment. The dose of methacholine needed to provoke a fall in FEV1 of ⩾30% was higher after pretreatment with formoterol (2.48 mg) than with salmeterol (1.58 mg) or placebo (0.74 mg). The difference between formoterol and salmeterol was statistically significant: 0.7 doubling dose steps (95% CI 0.1to 1.2, p=0.016). The immediate bronchodilating effect of subsequently administered salbutamol was significantly impaired after pretreatment with both drugs (p

The onset of the bronchodilating effect of formoterol (12 microg by Turbuhaler) was compared with that of salbutamol (50 microg by Turbuhaler), salmeterol (50 microg by Diskhaler) and placebo in methacholine-induced severe bronchoconstriction. Seventeen subjects with mild-to-moderate asthma completed this randomized, double blind, cross-over, double-dummy study. On four study days, baseline forced expiratory volume in one second (FEV1) was recorded and the subjects were challenged with methacholine until FEV1 fell by at least 30%. Immediately thereafter, the study drugs were inhaled and lung function was assessed for 60 min. The geometric mean time for FEV1 to return to 85% of baseline was 7.2 min with formoterol, 6.5 min with salbutamol, 14.1 min with salmeterol and 34.7 min with placebo (p=0.0001, overall ANOVA). The difference between formoterol and salmeterol was statistically significant (p=0.01); there was no difference between formoterol and salbutamol (p=0.69). In conclusion, formoterol reversed methacholine-induced severe bronchoconstriction as rapidly as salbutamol and more rapidly than salmeterol. Classifying beta2-agonists as "fast"- and "slow"- acting may be supplemental to "short"- and "long"-acting.

BACKGROUND: Improvement of allergic asthma is seen at high altitude partly because of low concentrations of allergen, especially house dust mite. To investigate the effect of a hypoallergenic environment (Davos, 1560 m) on airways inflammation, the changes in bronchial hyperresponsiveness measured with methacholine and adenosine 5'-monophosphate (AMP), blood eosinophils, eosinophil cationic protein (ECP), and serum IgE were studied. METHODS: In 16 allergic asthmatic children tests were performed on admission and after one month. Medication was kept unchanged during the month of investigation and the patients performed peak expiratory flow (PEF) measurements twice daily. RESULTS: After one month at high altitude a considerable improvement was seen in the provocative concentration of AMP causing a 20% fall in forced expiratory volume in one second (PC20 AMP), but not with methacholine. There was also a reduction in total blood eosinophils and ECP. No change in serum IgE was observed. Peak flow variability decreased. CONCLUSIONS: After one month at high altitude a reduction in airways inflammation occurs. The results indicate that AMP responsiveness is a more accurate marker of disease activity in relation to inflammation in asthma than methacholine. The benefits of allergen avoidance at high altitude have important clinical implications for children with allergic asthma.

Enhanced activities of peripheral blood cells are a common characteristic of patients with asthma.Here we tested whether this could be due to a dysfunction in one or more signal transduction systems.The production of 1,2-diacylglycerol (1,2-DAG) and arachidonic acid was compared in mononuclear blood cells from patients with asthma (n = 10) and healthy controls (n = 12).Using three different stimuli (concanavalin A, aluminium fluoride or the calcium ionophore A23187) no difference in the production of both 1,2-DAG and arachidonic acid could be found between patients and controls before allergen challenge. Concanavalin A-induced 1,2-DAG production could be inhibited completely in the presence of isoprenaline; concanavalin A-induced arachidonic acid production, partially. The inhibitory effect of adenylate cyclase activation on the production of 1,2-DAG and arachidonic acid was identical in patients and controls. Following allergen challenge, there was a tendency to an increased production of 1,2-DAG and arachidonic acid in controls, whereas in patients there was a tendency to a decreased production.Enhanced cellular activities found in patients with asthma are not caused by an intrinsic dysfunction in production of 1,2-DAG and arachidonic acid.

We present the case of a 25 year old woman who, 3 yrs after resection of a vascular ring, had persisting complaints of episodic dyspnoea. This was caused by compression of the distal trachea and ostium of the right main bronchus by the descending part of the remaining right-sided aorta. Probable mechanisms are discussed.

The long-acting beta 2-agonist salmeterol has been suggested to have other pharmacologic activities, that is, antiinflammatory capacities, in addition to its bronchodilator properties. We investigated the protective effect of 50 micrograms salmeterol in a placebo-controlled study on house dust mite-induced early- and late-phase reactions in 19 atopic asthmatic subjects. FEV1 and methacholine airway reactivity (AR) were measured. Eosinophils and their activation markers in peripheral blood were counted as indirect parameters of inflammation. Corrections were made for confounding of bronchodilator effects by salmeterol and the spontaneous diurnal variation, using saline inhalation as a control. Salmeterol completely inhibited the fall in FEV1 up to 10 h after the house dust mite challenge. Nevertheless, after correction, a biphasic response was present in the salmeterol group. Salmeterol protected against the allergen-associated increase in AR 3 h after the challenge, but no protection was observed after 24 h. Salmeterol did not inhibit the allergen-induced changes in total number of eosinophils and their activation markers in peripheral blood. These data suggest that a single dose of salmeterol modifies allergen-induced airway responses, above all by sustained bronchodilation.

We wanted to determine whether changes in bronchial hyperresponsiveness (BHR) following allergen challenge show a time relationship with inflammatory events in the airways of allergic asthmatic subjects. Lavage was performed and endobronchial biopsies were taken via the fiberoptic bronchoscope, before, and 3 and 24 h after, allergen challenge, on separate occasions, in nine dual asthmatic responders. The numbers of activated eosinophils, identified by immunohistochemistry, using the monoclonal anti-eosinophil cationic protein antibody, EG2, were significantly increased both at 3 h and at 24 h in the submucosa and bronchial lavage. A significant negative correlation was found between the number of EG2+ cells in the submucosa and in the bronchial lavage 24 h after the allergen challenge (r = -0.70). At 24 h, the amount of eosinophil cationic protein (ECP) was increased in the bronchial lavage. A significant correlation was observed between the amount of ECP at 3 h and the log provocative dose of house dust mite producing a 20% fall in forced expiratory volume in one second (PD20 HDM) (r = -0.63). The results suggest a recruitment of activated eosinophils to the submucosa and, further, to the epithelial lining, followed by degranulation. This process has already started 3 h after allergen challenge, and lasts for at least 24 h, which may result in mucosal damage and subsequent allergen-induced increase in BHR, before and after the late asthmatic reaction.

Bronchial hyperresponsiveness to adenosine 5'-monophosphate (AMP) was studied after allergen challenge in allergic asthmatic patients. Measurements were made with and without nedocromil sodium pretreatment. Nedocromil sodium inhibited both the early and late asthmatic reactions (P.01). After allergen challenge a significant decrease in PC20 AMP from 12.2 mg/mL to 4.47 mg/mL (P.05) at three hours was found, returning almost to baseline values: 10.85 mg/mL (P.05) at 24 hours. Nedocromil sodium, 6 mg, given before allergen challenge prevented the increased responsiveness to AMP at three hours [PC20 10.12 mg/mL (P.05)], but caused a decrease in PC20 AMP at 24 hours to 6.32 mg/mL (P.05). Desensitization of the adenosine receptor during the late asthmatic reaction, which is prevented by nedocromil sodium, may explain the lack of increased responsiveness at 24 hours. AMP may play a physiologic role in allergen-induced late phase reactions.

An otherwise healthy 44-yr-old man experienced a serious attack of bronchial obstruction after working with resins and hardeners, releasing fumes of a mixture of an alipathic and a cycloaliphatic diamine hardener. Eight hours after deliberate challenge with the hardener a large increase of airway resistance was found. Seventy-two hours after challenge, eosinophilia in the bronchoalveolar lavage (BAL) fluid together with a decrease of peripheral eosinophils was seen. After cessation of contact with this hardener, no more acute episodes occurred, although maintenance treatment with a topical corticosteroid and a beta 2-agonist remained necessary. A BAL performed 1 yr later showed a normal cell distribution. The results suggest that these aliphatic and cycloaliphatic diamine hardeners may be occupational hazards. Eosinophil inflammation may play a causal role.

Rationale We hypothesized that a once-daily base dose of budesonide/formoterol in a single inhaler (Symbicort ® ), plus additional doses as needed to provide improved control and immediate relief of symptoms (Single inhaler Therapy), would reduce the risk of severe exacerbations compared with a higher fixed dose of budesonide plus as-needed terbutaline. Methods This was a 12-month, randomized, double-blind, parallel-group study. Symptomatic patients (n=1890; mean age 43 [range 11-80] years, mean baseline FEV 1 70% predicted normal, mean ICS dose 746μg/day) received either a daily base dose of budesonide/formoterol (160/4.5μg, 2 inhalations once daily) with additional inhalations (=10/day) as needed for relief of symptoms, or budesonide (160μg, 2 inhalations twice daily) plus as-needed terbutaline 0.4mg. We assessed the risk of severe exacerbations (defined as hospitalization/emergency room [ER] treatment, oral steroids due to asthma worsening, or morning PEF=70% of baseline on 2 consecutive days), as-needed medication use, and tolerability. Results The budesonide/formoterol group had a 39% lower risk of a severe exacerbation compared with the budesonide group (p Conclusions Single inhaler Therapy with a once-daily base dose of budesonide/formoterol plus additional inhalations as needed significantly reduces the risk of severe exacerbations compared with a higher fixed dose of budesonide plus terbutaline.