Relationship between FEV1 change and patient-reported outcomes in randomised trials of inhaled bronchodilators for stable COPD: a systematic review.

BACKGROUND: Interactions between spirometry and patient-reported outcomes in COPD are not well understood. This systematic review and study-level analysis investigated the relationship between changes in FEV1 and changes in health status with bronchodilator therapy. METHODS: Six databases (to October 2009) were searched to identify studies with long-acting bronchodilator therapy reporting FEV1 and health status, dyspnoea or exacerbations. Mean and standard deviations of treatment effects were extracted for each arm of each study. Relationships between changes in trough FEV1 and outcomes were assessed using correlations and random-effects regression modelling. The primary outcome was St George's Respiratory Questionnaire (SGRQ) total score. RESULTS: Thirty-six studies (≥ 3 months) were included. Twenty-two studies (23,654 patients) with 49 treatment arms each contributing one data point provided SGRQ data. Change in trough FEV1 and change in SGRQ total score were negatively correlated (r = -0.46, p < 0.001); greater increases in FEV1 were associated with greater reductions (improvements) in SGRQ. The correlation strengthened with increasing study duration from 3 to 12 months. Regression modelling indicated that 100 mL increase in FEV1 (change at which patients are more likely to report improvement) was associated with a statistically significant reduction in SGRQ of 2.5 (95% CI 1.9, 3.1), while a clinically relevant SGRQ change (4.0) was associated with 160.6 (95% CI 129.0, 211.6) mL increase in FEV1. The association between change in FEV1 and other patient-reported outcomes was generally weak. CONCLUSIONS: Our analyses indicate, at a study level, that improvement in mean trough FEV1 is associated with proportional improvements in health status

Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease

BACKGROUND: The long-term efficacy and safety of aclidinium bromide, a novel, long-acting muscarinic antagonist, were investigated in patients with moderate to severe chronic obstructive pulmonary disease (COPD). METHODS: In two double-blind, 52-week studies, ACCLAIM/COPD I (n=843) and II (n=804), patients were randomised to inhaled aclidinium 200 μg or placebo once-daily. Patients were required to have a post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio of ≤70% and FEV1<80% of the predicted value. The primary endpoint was trough FEV1 at 12 and 28 weeks. Secondary endpoints were health status measured by St George's Respiratory Questionnaire (SGRQ) and time to first moderate or severe COPD exacerbation. RESULTS: At 12 and 28 weeks, aclidinium improved trough FEV1 versus placebo in ACCLAIM/COPD I (by 61 and 67 mL; both p<0.001) and ACCLAIM/COPD II (by 63 and 59 mL; both p<0.001). More patients had a SGRQ improvement≥4 units at 52 weeks with aclidinium versus placebo in ACCLAIM/COPD I (48.1% versus 39.5%; p=0.025) and ACCLAIM/COPD II (39.0% versus 32.8%; p=0.074). The time to first exacerbation was significantly delayed by aclidinium in ACCLAIM/COPD II (hazard ratio [HR] 0.7; 95% confidence interval [CI] 0.55 to 0.92; p=0.01), but not ACCLAIM/COPD I (HR 1.0; 95% CI 0.72 to 1.33; p=0.9). Adverse events were minor in both studies. CONCLUSION: Aclidinium is effective and well tolerated in patients with moderate to severe COPD

Melatonin promoted chemotaxins expression in lung epithelial cell stimulated with TNF-α

BACKGROUND: Patients with asthma demonstrate circadian variations in the airway inflammation and lung function. Pinealectomy reduces the total inflammatory cell number in the asthmatic rat lung. We hypothesize that melatonin, a circadian rhythm regulator, may modulate the circadian inflammatory variations in asthma by stimulating the chemotaxins expression in the lung epithelial cell. METHODS: Lung epithelial cells (A549) were stimulated with melatonin in the presence or absence of TNF-α(100 ng/ml). RANTES (Regulated on Activation Normal T-cells Expressed and Secreted) and eotaxin expression were measured using ELISA and real-time RT-PCR, eosinophil chemotactic activity (ECA) released by A549 was measured by eosinophil chemotaxis assay. RESULTS: TNF-α increased the expression of RANTES (307.84 ± 33.56 versus 207.64 ± 31.27 pg/ml of control, p = 0.025) and eotaxin (108.97 ± 10.87 versus 54.00 ± 5.29 pg/ml of control, p = 0.041). Melatonin(10(-10 )to 10(-6)M) alone didn't change the expression of RNATES (204.97 ± 32.56 pg/ml) and eotaxin (55.28 ± 6.71 pg/ml). However, In the presence of TNF-α (100 ng/ml), melatonin promoted RANTES (410.88 ± 52.03, 483.60 ± 55.37, 559.92 ± 75.70, 688.42 ± 95.32, 766.39 ± 101.53 pg/ml, treated with 10(-10), 10(-9), 10(-8), 10(-7),10(-6)M melatonin, respectively) and eotaxin (151.95 ± 13.88, 238.79 ± 16.81, 361.62 ± 36.91, 393.66 ± 44.89, 494.34 ± 100.95 pg/ml, treated with 10(-10), 10(-9), 10(-8), 10(-7), 10(-6)M melatonin, respectively) expression in a dose dependent manner in A549 cells (compared with TNF-α alone, P < 0.05). The increased release of RANTES and eotaxin in A549 cells by above treatment were further confirmed by both real-time RT-PCR and the ECA assay. CONCLUSION: Taken together, our results suggested that melatonin might synergize with pro-inflammatory cytokines to modulate the asthma airway inflammation through promoting the expression of chemotaxins in lung epithelial cell

Does tiotropium lower exacerbation and hospitalization frequency in COPD patients: results of a meta-analysis

<p>Abstract</p> <p>Background</p> <p>International guidelines recommend long-acting bronchodilators in patients who remain symptomatic despite adequate treatment with short-acting bronchodilators. The purpose of this study is to estimate the effect of tiotropium, a long-acting anticholinergic inhalant, on exacerbation and hospitalisation frequency.</p> <p>Methods</p> <p>Electronic databases (Medline, Embase, INAHTA, CRD databases, and the Cochrane Library) were searched for randomised controlled trials, comparing tiotropium to placebo, or other bronchodilators. Outcomes were the exacerbation frequency and hospitalisation frequency. Data were pooled using the generic inverse variance method for continuous outcomes.</p> <p>Results</p> <p>Nine studies reported comparisons with placebo (n = 8), ipratropium (short-acting anticholinergic inhalant, n = 1), and salmeterol (long-acting β₂-agonist inhalant, n = 1). Only two studies reported adequate concealment of allocation. Tiotropium reduces the number of exacerbations per patient year by 0.31 (95% CI 0.46- 0.17) compared to placebo, and by 0.23 (95% CI 0.31- 0.15) compared to ipratropium. A significant difference in exacerbation frequency between tiotropium and salmeterol was found (-0.16; 95% CI -0.29 - -0.03) based on approximations of the results of one study.</p> <p>The number of hospitalisations is reduced by 0.04 (95% CI 0.08- 0.01) per patient year compared to placebo and by 0.06 (95% CI -0.09 - -0.03) per patient year compared to ipratropium.</p> <p>Conclusions</p> <p>Statistically significant but clinically small effects were found for tiotropium compared to placebo and ipratropium. The comparison with salmeterol is significant for exacerbation frequency but not for hospitalisation frequency. Publication bias may be present.</p

Blood neutrophil activation markers in severe asthma: lack of inhibition by prednisolone therapy

BACKGROUND: Neutrophils are increased in the airways and in induced sputum of severe asthma patients. We determined the expression of activation markers from circulating neutrophils in severe asthma, and their supressibility by corticosteroids. METHODS: We compared blood neutrophils from mild, moderate-to-severe and severe steroid-dependent asthma, and non-asthmatics (n = 10 each). We examined the effect of adding or increasing oral prednisolone (30 mg/day;1 week). RESULTS: Flow cytometric expression of CD35 and CD11b, but not of CD62L or CD18, was increased in severe asthma. F-met-leu-phe increased CD11b, CD35 and CD18 and decreased CD62L expression in all groups, with a greater CD35 increase in severe asthma. In severe steroid-dependent asthma, an increase in prednisolone dose had no effect on neutrophil markers particularly CD62L, but reduced CD11b and CD62L on eosinophils. Phorbol myristate acetate-stimulated oxidative burst and IL-8 release by IL-1β, lipopolysaccharide and GM-CSF in whole blood from mild but not severe asthmatics were inhibited after prednisolone. There were no differences in myeloperoxidase or neutrophil elastase release from purified neutrophils. CONCLUSION: Because blood neutrophils in severe asthma are activated and are not inhibited by oral corticosteroids, they may be important in the pathogenesis of severe asthma

Aspergillus antigen induces robust Th2 cytokine production, inflammation, airway hyperreactivity and fibrosis in the absence of MCP-1 or CCR2

BACKGROUND: Asthma is characterized by type 2 T-helper cell (Th2) inflammation, goblet cell hyperplasia, airway hyperreactivity, and airway fibrosis. Monocyte chemoattractant protein-1 (MCP-1 or CCL2) and its receptor, CCR2, have been shown to play important roles in the development of Th2 inflammation. CCR2-deficient mice have been found to have altered inflammatory and physiologic responses in some models of experimental allergic asthma, but the role of CCR2 in contributing to inflammation and airway hyperreactivity appears to vary considerably between models. Furthermore, MCP-1-deficient mice have not previously been studied in models of experimental allergic asthma. METHODS: To test whether MCP-1 and CCR2 are each required for the development of experimental allergic asthma, we applied an Aspergillus antigen-induced model of Th2 cytokine-driven allergic asthma associated with airway fibrosis to mice deficient in either MCP-1 or CCR2. Previous studies with live Aspergillus conidia instilled into the lung revealed that MCP-1 and CCR2 play a role in anti-fungal responses; in contrast, we used a non-viable Aspergillus antigen preparation known to induce a robust eosinophilic inflammatory response. RESULTS: We found that wild-type C57BL/6 mice developed eosinophilic airway inflammation, goblet cell hyperplasia, airway hyperreactivity, elevations in serum IgE, and airway fibrosis in response to airway challenge with Aspergillus antigen. Surprisingly, mice deficient in either MCP-1 or CCR2 had responses to Aspergillus antigen similar to those seen in wild-type mice, including production of Th2 cytokines. CONCLUSION: We conclude that robust Th2-mediated lung pathology can occur even in the complete absence of MCP-1 or CCR2

House dust mite-induced airway changes in hu-SCID mice.

A