Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD

Clinical manifestations of chronic obstructive pulmonary disease (COPD), including airflow limitation, dyspnea, and activity limitation, ultimately lead to impaired health-related quality of life (HRQoL). This 9-month, randomized, double-blind, multicenter study compared the effect of once-daily tiotropium 18 μg and placebo on HRQoL, spirometric parameters, and exacerbations in 554 patients with moderate-to-severe COPD. HRQoL was assessed using the St. George’s Respiratory Questionnaire (SGRQ) and the new 8-item Visual Simplified Respiratory Questionnaire (VSRQ), which is currently being validated. The primary efficacy endpoint was the proportion of patients achieving a reduction of at least 4 units in the SGRQ total score at study end (Month 9). Mean ± SD baseline SGRQ total score was 47.4 ± 18.1. Significantly more tiotropium-treated patients achieved a reduction of at least 4 units in the SGRQ score vs placebo at study end (59.1% vs 48.2%, respectively; p = 0.029). Tiotropium significantly improved spirometric parameters (forced expiratory volume in 1 second [FEV1]: 0.11 ± 0.02 L vs 0.01 ± 0.02 L; between-group difference: 0.10 ± 0.03 L, p = 0.0001) and reduced exacerbations vs placebo. Maintenance treatment with tiotropium provided significant and clinically relevant improvements in HRQoL, as measured by the SGRQ

IL-18 Does not Increase Allergic Airway Disease in Mice When Produced by BCG

Whilst BCG inhibits allergic airway responses in murine models, IL-18 has adversary effects depending on its environment. We therefore constructed a BCG strain producing murine IL-18 (BCG-IL-18) and evaluated its efficiency to prevent an asthma-like reaction in mice. BALB/cByJ mice were sensitized (day (D) 1 and D10) by intraperitoneal injection of ovalbumin (OVA)-alum and primary (D20–22) and secondary (D62, 63) challenged with OVA aerosols. BCG or BCG-IL-18 were intraperitonealy administered 1 hour before each immunization (D1 and D10). BCG-IL-18 and BCG were shown to similarly inhibit the development of AHR, mucus production, eosinophil influx, and local Th2 cytokine production in BAL, both after the primary and secondary challenge. These data show that IL-18 did not increase allergic airway responses in the context of the mycobacterial infection, and suggest that BCG-IL-18 and BCG are able to prevent the development of local Th2 responses and therefore inhibit allergen-induced airway responses even after restimulation

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

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

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Bronchoalveolar lavage in alcoholic liver cirrhosis. T-lymphocyte subsets and immunoglobulin concentrations.

The purpose of this study was to determine the phenotype profiles of immune effector cells and the concentrations of immunoglobulins in the lower respiratory tract of non-smoking patients with alcoholic liver cirrhosis (ALC). Nine nonsmoking patients with liver biopsy-proved ALC (grade B or C cirrhosis in Child's classification), free of clinical pulmonary symptoms, and with normal chest roentgenogram were included in the study. The control group included 12 healthy nonsmokers. Each patient had fiberoptic bronchoscopy with bronchoalveolar lavage (BAL). The number of T cells and of lymphocyte subpopulations was determined by immunofluorescence studies using monoclonal antibodies that were specific for CD3, CD4, and CD8 markers. Patients with ALC exhibited a dramatically increased percentage of CD8+ cells in BAL that induced a low CD4/CD8 ratio (0.96 +/- 0.15 vs 1.8 +/- 0.12 in healthy controls). Further characterization of lymphocyte subsets' dual immunofluorescence analysis demonstrated that most of the CD8+ alveolar lymphocytes had a phenotype of cytotoxic cells (CD8+ CD11b-; 48 percent +/- 13 in ALC vs 10 percent +/- 5 in controls). ALC was associated with an appreciable alveolar-capillary "leak" as demonstrated by a significant increase in BAL fluid albumin. In addition, the concentrations of immunoglobulins in BAL fluid were significantly greater in ALC than in controls. However, the relative (to albumin) coefficient of excretion of IgG, A, and M in and alpha 2-macroglobulin BAL fluid was not significantly different between controls and ALC. Our results indicate that increased proportions of CB8+ and especially of CD8+ CD11b- cells are a common feature in the lower respiratory tract of nonsmoking patients with ALC. These changes may be of potential functional importance in the regulation of the local pulmonary immune response in ALC