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Introduction: Treatment management and patient outcomes could be improved by identifying patients with severe COPD who are at increased risk of exacerbations. Aim: To identify factors associated with exacerbation risk using a multivariate analysis of data from the WISDOM study. Methods: In WISDOM (NCT00975195; 12-month, randomised, parallel-group study), patients with severe to very severe COPD and a history of exacerbations received 18 µg tiotropium, 100 µg salmeterol and 1000 µg fluticasone propionate daily for 6 weeks, then continued or reduced inhaled corticosteroids (ICS) for 12 weeks. This post hoc multivariate analysis of time to first moderate or severe exacerbation used a stepwise selection process for candidate variables. Results: For the overall study period, the analysis was based on 2291 patients. Factors associated with a significantly increased risk of exacerbation were taking ICS at screening and ≥2 previous courses of antibiotics or steroids (Figure). Higher baseline FEV 1 , GOLD C vs GOLD D and taking xanthines at screening were associated with a significantly decreased risk of exacerbation. A backwards elimination variable selection process confirmed these results. Conclusions: Several factors were significantly associated with exacerbation risk in WISDOM. An increased risk was found in patients with prior ICS treatment and an exacerbation history. Funding: Boehringer Ingelheim.

Introduction: Tiotropium (T), a once-daily long-acting muscarinic antagonist, is a well-established first-line maintenance treatment in chronic obstructive pulmonary disease (COPD); olodaterol (O) is a once-daily long-acting β 2 -agonist that has recently gained approval in several countries. Two Phase III replicate pivotal studies assessed the efficacy and safety of fixed-dose combinations of T and O (T+O) delivered via Respimat Soft Mist inhaler in patients with GOLD Stage 2–4 COPD. Methods: Two 52-week, double-blind, parallel-group studies randomised 5162 patients to O 5 µg, T 2.5 µg, T 5 µg, T+O 2.5/5 µg or T+O 5/5 µg. Primary efficacy end points were trough FEV 1 response (ie change from baseline), FEV 1 area under the curve from 0–3 hours and SGRQ total score after 24 weeks. Pooled data from the two studies are presented here; lung function from the individual studies will subsequently be provided. Results: All treatments resulted in clinically relevant improvements in lung function, with significant increases with both T+O doses over the individual components (p 1 responses were 0.055 L (O 5 µg), 0.073 L (T 2.5 µg), 0.080 L (T 5 µg), 0.118 L (T+O 2.5/5 µg) and 0.140 L (T+O 5/5 µg). SGRQ total scores improved by 5.1 (O 5 µg), 5.7 (T 2.5 µg), 5.6 (T 5 µg), 6.2 (T+O 2.5/5 µg) and 6.8 points (T+O 5/5 µg); differences between T+O 5/5 µg and O 5 µg and T 5 µg were statistically significant (p Conclusions: T+O 5/5 µg significantly improved lung function and provided symptomatic benefit over O 5 µg and T 5 µg. Funding: Boehringer Ingelheim.

Background: Although guidance recommends ICS for prevention of recurrent COPD exacerbations, there is still uncertainty about the benefits of ICS. Objective: To evaluate the effects of stepwise withdrawal of ICS in patients (pts) with GOLD 3–4 COPD and a history of exacerbation who are treated with LAMA+LABA. Methods: WISDOM ([NCT00975195][1]) was a 12-month, double-blind, parallel-group, active-controlled study in which all pts received triple therapy (tiotropium 18 µg QD, salmeterol 50 µg BID and fluticasone 500 µg BID) for a 6-week run-in period. Pts were randomised 1:1 to continue triple therapy or stepwise withdrawal of ICS over 12 weeks (dose reduction every 6 weeks). Primary end point (time to first moderate or severe on-treatment exacerbation) is reported here. Results: 2485 pts were treated (2049 male); mean age was 63.8 years and mean baseline FEV1 was 0.975 L (34.2% predicted). ![Figure][2] ICS withdrawal was non-inferior to continued ICS for time to first moderate or severe on-treatment COPD exacerbation (hazard ratio 1.058; upper limit of the 95% CI below the pre-specified non-inferiority margin of 1.2 [0.941, 1.189]). No significant safety signals were identified. Conclusions : In pts with GOLD 3–4 COPD receiving dual bronchodilation, exacerbation risk is non-inferior with ICS withdrawal compared to ICS therapy. Funding: Boehringer Ingelheim. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00975195&atom=%2Ferj%2F44%2FSuppl_58%2F1890.atom [2]: pending:yes

Haptoglobin is a long known acute phase protein involved in hemoglobin breakdown, which was thought to be from the liver. The discovery of pHp was achieved by applying transcriptome analysis to human lung tissues which were subjected to a short term culture and infected or not infected with Haemophilus influenzae. These tissues were fixed and paraffin-embedded by the HOPE-technique. First, RT-PCR and RNA-in situ hybridization was used to confirm the pulmonary derivation of pHp. Immunohistochemistry was performed and showed expression of haptoglobin in Alveolar Epithelial Cells type II (AECII), macrophages (MA), and bronchial epithelia. Interestingly, pHp is expressed in adenocarcinomas but not in squamous cells carcinomas of the lungs; it even can be used as an additional diagnostic marker for routine purposes. In a large series of tissues we analyzed the regulation of pHp and its receptor CD163 and found an up-regulation in response to LPS, PAM3, Il6 and dexamethasone on the protein- and RNA-level. The analyses were carried out with lung tissues, A549 cells, and BALs. We found that pHp and CD 163 get rapidly secreted upon stimulation in comparably large amounts. Further experiments showed that pHp up-regulates Il8 and MCP-1 in A549 cells and TNF-α, Il6 and MCP-1 in monocyte derived macrophages, indicating a functional role in immuno-regulatory events in the human lung. pHp and its receptor act as native local pulmonary defense elements within the human respiratory system. Further studies are underway to elucidate the role of pHp in the course of different diseases of the lungs.