The sputum transcriptome better predicts COPD exacerbations after the withdrawal of inhaled corticosteroids than sputum eosinophils.

INTRODUCTION: Continuing inhaled corticosteroid (ICS) use does not benefit all patients with COPD, yet it is difficult to determine which patients may safely sustain ICS withdrawal. Although eosinophil levels can facilitate this decision, better biomarkers could improve personalised treatment decisions. METHODS: We performed transcriptional profiling of sputum to explore the molecular biology and compared the predictive value of an unbiased gene signature versus sputum eosinophils for exacerbations after ICS withdrawal in COPD patients. RNA-sequencing data of induced sputum samples from 43 COPD patients were associated with the time to exacerbation after ICS withdrawal. Expression profiles of differentially expressed genes were summarised to create gene signatures. In addition, we built a Bayesian network model to determine coregulatory networks related to the onset of COPD exacerbations after ICS withdrawal. RESULTS: In multivariate analyses, we identified a gene signature (LGALS12, ALOX15, CLC, IL1RL1, CD24, EMR4P) associated with the time to first exacerbation after ICS withdrawal. The addition of this gene signature to a multiple Cox regression model explained more variance of time to exacerbations compared to a model using sputum eosinophils. The gene signature correlated with sputum eosinophil as well as macrophage cell counts. The Bayesian network model identified three coregulatory gene networks as well as sex to be related to an early versus late/nonexacerbation phenotype. CONCLUSION: We identified a sputum gene expression signature that exhibited a higher predictive value for predicting COPD exacerbations after ICS withdrawal than sputum eosinophilia. Future studies should investigate the utility of this signature, which might enhance personalised ICS treatment in COPD patients.

Concurrent gemcitabine and 3D radiotherapy in patients with stage III unresectable non-small cell lung cancer.

BACKGROUND: Stage III unresectable non-small cell lung cancer (NSCLC) is preferably treated with concurrent schedules of chemoradiotherapy, but none is clearly superior Gemcitabine is a radiosensitizing cytotoxic drug that has been studied in phase 1 and 2 studies in this setting. The aim of this study was to describe outcome and toxicity of low-dose weekly gemcitabine combined with concurrent 3-dimensional conformal radiotherapy (3D-CRT). PATIENTS & METHODS: Treatment consisted of two cycles of a cisplatin and gemcitabine followed by weekly gemcitabine 300 mg/m2 during 5 weeks of 3D-CRT, 60 Gy in 5 weeks (hypofractionated-accelerated). Overall survival (OS), progression-free survival (PFS), and treatment related toxicity according to Common Toxicity Criteria of Adverse Events (CTCAE) version 3.0 were assessed. RESULTS: Between February 2002 and August 2008, 318 patients were treated. Median age was 64 years (range 36-86); 72% were male, WHO PS 0/1/2 was 44/53/3%. Median PFS was 15.5 months (95% confidence interval [CI], 12.9-18.1) and median OS was 24.6 months (95% CI., 21.0-28.1). Main toxicity (CTCAE grade ≥3) was dysphagia (12.6%), esophagitis (9.6%), followed by radiation pneumonitis (3.0%). There were five treatment related deaths (1.6%), two due to esophagitis and three due to radiation pneumonitis. CONCLUSION: Concurrent low-dose gemcitabine and 3D-CRT provides a comparable survival and toxicity profile to other available treatment schemes for unresectable stage III.

Sputum inflammation predicts exacerbations after cessation of inhaled corticosteroids in COPD.

INTRODUCTION: The GOLD guidelines advocate not to institute inhaled corticosteroids (ICS) in patients with mild-to-moderate COPD. However, many patients do use ICS and in some patients, withdrawal is associated with deteriorating lung function and increased exacerbation rates. Unfortunately, physicians do not know in which patients they can stop ICS treatment safely. AIM: To identify predictors of COPD exacerbations after ICS withdrawal. METHODS: During ICS treatment, post-bronchodilator spirometry, body plethysmography, and health status assessment were performed in 68 COPD patients using ICS. Additionally, sputum cell differentials, supernatant leukotriene B(4), eosinophilic cationic protein, and myeloperoxidase, serum C-reactive protein and soluble intracellular adhesion molecule, and urinary desmosine were assessed. Sputum was also analysed for mRNA levels of haemoxygenase-1, tumour necrosis factor-α, RANTES, interleukin 5(IL-5), IL-10, IL-12, IL-13, transforming growth factor-ß, and interferon-γ. STATISTICS: Cox regression analyses were performed using time to exacerbation as outcome variable to identify significant hazards for a COPD exacerbation after ICS withdrawal. RESULTS: Higher sputum % eosinophils, higher sputum MPO/neutrophil level, longer duration of COPD symptoms, <40 packyears smoking, and ICS withdrawal in November, December or January were significant hazards (all p<0.05) for experiencing a COPD exacerbation after ICS withdrawal in a monovariate model. In a multivariate model, all factors proved independent predictors except for sputum MPO/neutrophil level. CONCLUSIONS: Decisions on whether or not inhaled corticosteroids can be safely withdrawn in mild-to-moderate COPD can be facilitated by assessment of sputum inflammation, particularly eosinophil numbers, next to packyears smoking, season, and duration of COPD symptoms.

Reticular basement membrane in asthma and COPD: similar thickness, yet different composition.

BACKGROUND: Reticular basement membrane (RBM) thickening has been variably associated with asthma and chronic obstructive pulmonary disease (COPD). Even if RBM thickness is similar in both diseases, its composition might still differ. OBJECTIVE: To assess whether RBM thickness and composition differ between asthma and COPD. METHODS: We investigated 24 allergic asthmatics (forced expiratory volume in one second [FEV(1)] 92% predicted), and 17 nonallergic COPD patients (FEV(1) 60% predicted), and for each group a control group of similar age and smoking habits (12 and 10 persons, respectively). Snap-frozen sections of bronchial biopsies were stained with hematoxylin/eosin and for collagen I, III, IV, V, laminin and tenascin. RBM thickening was assessed by digital image analysis. Relative staining intensity of each matrix component was determined. RESULTS: Mean (SD) RBM thickness was not significantly different between asthma and COPD 5.5 (1.3) vs 6.0 (1.8) microm, but significantly larger than in their healthy counterparts, ie, 4.7 (0.9) and 4.8 (1.2) microm, respectively. Collagen I and laminin stained significantly stronger in asthma than in COPD. Tenascin stained stronger in asthma than in healthy controls of similar age, and stronger in COPD controls than in asthma controls (p < 0.05). CONCLUSION: RBM thickening occurs both in asthma and COPD. We provide supportive evidence that its composition differs in asthma and COPD.

Change in inflammation in out-patient COPD patients from stable phase to a subsequent exacerbation.

BACKGROUND: Inflammation increases during exacerbations of COPD, but only a few studies systematically assessed these changes. Better identification of these changes will increase our knowledge and potentially guide therapy, for instance by helping with quicker distinction of bacterially induced exacerbations from other causes. AIM: To identify which inflammatory parameters increase during COPD exacerbations compared to stable disease, and to compare bacterial and non-bacterial exacerbations. METHODS: In 45 COPD patients (37 male/8 female, 21 current smokers, mean age 65, FEV(1) 52% predicted, pack years 38) sputum was collected during a stable phase and subsequently during an exacerbation. RESULTS: Sputum total cell counts (9.0 versus 7.9 x 10(6)/mL), eosinophils (0.3 versus 0.2 x 10(6)/mL), neutrophils (6.1 versus 5.8 x 10(6)/mL), and lymphocytes (0.07 versus 0.02 x 10(6)/mL) increased significantly during an exacerbation compared to stable disease. A bacterial infection was demonstrated by culture in 8 sputum samples obtained during an exacerbation. These exacerbations had significantly increased sputum total cell and neutrophil counts, leukotriene-B4, myeloperoxidase, interleukin-8 and interleukin-6, and tumor necrosis factor-alpha (TNF-alpha) levels, and were also associated with more systemic inflammation compared to exacerbations without a bacterial infection. Sputum TNF-alpha level during an exacerbation had the best test characteristics to predict a bacterial infection. CONCLUSION: Sputum eosinophil, neutrophil, and lymphocyte counts increase during COPD exacerbations. The increase in systemic inflammation during exacerbations seems to be limited to exacerbations caused by bacterial infections of the lower airways. Sputum TNF-alpha is a candidate marker for predicting airway bacterial infection.

Anti-inflammatory effects of combined budesonide/formoterol in COPD exacerbations.

Systemic corticosteroids and additional short-acting beta2-agonists are commonly used in exacerbations of chronic obstructive pulmonary disease (COPD). In this double-blind study, the combination of a high-dose inhaled corticosteroid with a rapid-onset long-acting beta2-agonist was evaluated in the treatment of out-patient COPD exacerbations. The primary aim was to compare 14-day treatment effects of budesonide/formoterol to placebo on sputum eosinophils and, secondarily, on other indices of inflammation, forced expiratory flow in one second (FEV(1)), symptoms, health status, and adverse events. Forty-five patients not using steroids (37 male, 21/24 current/ex smoker, median packyears 38, age 65 years, FEV(1) 61% predicted), experiencing a COPD exacerbation, were treated at home with budesonide/formoterol (320/9 microg 4 times daily), prednisolone (30 mg daily), or placebo for 14 days. Sputum eosinophils were significantly reduced by budesonide/formoterol (-57%) compared to placebo (+24%) (p = 0.01). Budesonide/formoterol reduced total symptom scores significantly (p = 0.01) compared to placebo. The increase in FEV(1) by 2 weeks of treatment with budesonide/formoterol (125 ml) was not significantly different from that of placebo (43 ml) (p = 0.07). Budesonide/ formoterol treatment did not suppress morning serum cortisol compared to placebo (-16%; p = 0.50). In conclusion, budesonide/formoterol reduces sputum eosinophils and improves symptoms in the treatment of out-patient COPD exacerbations.

Cognitive performance in patients with COPD.

BACKGROUND: Hypoxemic patients with Chronic Obstructive Pulmonary Disease (COPD) have impaired cognitive performance. These neuropsychological impairments are related to the degree of hypoxemia. So far, cognitive performance has not been tested in non-hypoxemic patients with COPD. METHODS: We recruited patients with stable COPD and PaO2 > 8.0 kPa (60 mmHg), as well as healthy subjects, who were matched for age, intelligence quotient (IQ), and level of education. Cognitive performance was studied by Stroop Colour Word Test, Trailmaking, digit-symbol of the Wechsler Adult Intelligence Scale, addition subtest of the Groningen Intelligence Test, and Story Recall. RESULTS: Thirty patients with COPD (FEV1 49.8% pred, mean age 64.8 yr) and 20 healthy volunteers (65.6 yr) were enrolled. COPD patients performed significantly worse on trailmaking B, the digit-symbol test, and on the addition subtest. There was no significant correlation between the tests of cognitive performance and disease specific health status (Chronic Respiratory Questionnaire). CONCLUSIONS: We conclude that even non-hypoxemic patients with COPD show significant impairments in cognitive performance. These impairments are not associated with deteriorations in health related quality of life. Prospective evaluation of the impact of treatment on cognitive performance in non-hypoxemic patients with COPD would be a logical subsequent study.

A systematic review of the effects of bronchodilators on exercise capacity in patients with COPD.

One of the major goals of bronchodilator therapy in patients with COPD is to decrease airflow limitation in the airways and, as a consequence, improve dyspnea and exercise tolerance. The focus of this systematic review is to assess the effects of treatment with beta-agonists, anticholinergics, and theophyllines on dyspnea, and steady-state and incremental exercise capacity. Thirty-three, double-blind, randomized, placebo-controlled studies written in English were selected. This review shows that approximately half of the studies showed a significant effect of bronchodilator therapy on exercise capacity. Anticholinergic agents have significant beneficial effects in the majority of studies, especially when measured by steady-state exercise protocols. There is a trend toward a better effect of high-dose compared to low-dose anticholinergics. Short-acting beta(2)-mimetics have favorable effects on exercise capacity in more than two thirds of the studies; surprisingly, the situation is less clear for long-acting beta(2)-agents. The majority of the results of the published reports on theophyllines and their effects on exercise are negative. Direct comparisons of different classes of bronchodilators have not been made in a sufficient number of studies for a rational preference. The addition of a second bronchodilator has no proven advantage for improving exercise test results, but this has not been studied extensively and not in sufficiently large studies. The majority of studies reporting a measure of dyspnea found improvements, even in the absence of improvement in exercise capacity.