Inflammatory Biomarkers Improve Clinical Prediction of Mortality in Chronic Obstructive Pulmonary Disease. B.R. Celli, N. Locantore, J. Yates, R. Tal-Singer, B.E. Miller, P. Bakke, P. Calverley, H. Coxson, C. Crim, L.D. Edwards, D.A. Lomas, A. Duvoix, W. Macnee, S. Rennard, E. Silverman, J. Vestbo, E. Wouters, A.A. Agusti; for the ECLIPSE investigators. Am J Respir Crit Care Med. 2012 Mar 23 [Epub ahead of print].
Rationale: Accurate prediction of mortality helps select patients for interventions aimed at improving outcome.
Objectives: Because chronic obstructive pulmonary disease is characterized by low-grade systemic inflammation, we hypothesized that addition of inflammatory biomarkers to established predictive factors will improve accuracy.
Methods: 1843 patients enrolled in the ECLIPSE study were followed for 3 years. Kaplan-Meier curves, log rank analysis and Cox proportional hazards analyses determined the predictive value for mortality of clinical variables, while C-statistics assessed the added discriminative power offered by addition of biomarkers. Measurements at recruitment: we measured anthropometrics, spirometry, 6 minute walk distance, dyspnea, BODE index, history of hospitalization, co-morbidities and CT scan emphysema. White blood cell and neutrophil counts, serum or plasma levels of fibrinogen, chemokine ligand 18, surfactant protein D, C-reactive protein, Clara cell secretory protein-16, Interleukin-6 and -8 and tumor necrosis factor alpha were determined at recruitment and subsequent visits.
Main Results: 168 of the 1843 patients (9•1%) died. Non-survivors were older, had more severe airflow limitation, increased dyspnea, higher BODE score, more emphysema, and higher rates of co-morbidities and history of hospitalizations. The best predictive model for mortality using clinical variables included age, BODE and hospitalization history (C-statistic of 0•686, p < 0•001). One single biomarker (Interleukin-6) significantly improved the C statistic to 0.708, but this was further improved to 0•726, (p = 0•003) by the addition of all biomarkers. Conclusions: The addition of a panel of selected biomarkers improves the ability of established clinical variables to predict mortality in COPD.
Comments: The ECLIPSE study has been an ambitious effort to examine the potential role of biomarkers in various facets of COPD management. The current study examined the ability of biomarkers to predict mortality and found that IL-6 was the single best biomarker to add significant improvement over use of clinical variables including age, BODE, and hospitalizations. From a research perspective it remains unclear if the use of these biomarkers will be most helpful to identify subjects for studies involving interventions geared to reduce mortality or if the biomarkers may be followed serially to identify responders. The non-survivor group had clinical characteristics that intuitively would seem to be good predictors of increased mortality, hence an important question is whether or not these biomarkers have clinical utility over and above clinical parameters typically assessed to either select patients for novel therapeutic interventions and/or follow patients serially to assess response.
The Lung Tissue Microbiome in Chronic Obstructive Pulmonary Disease. M.A. Sze, P.A. Dimitriu, S. Hayashi, W.M. Elliott, J.E. McDonough, J.V. Gosselink, J. Cooper, D.D. Sin, W.W. Mohn, J.C. Hogg, Am J Respir Crit Care Med. 2012 Mar 15 [Epub ahead of print].
BACKGROUND: Based on surface brushings and BAL fluid Hilty, et al. demonstrated microbiomes in the human lung characteristic of asthma and chronic obstructive pulmonary disease (COPD), which have now been confirmed by others. The present study extends these findings to human lung tissue samples.
METHODS: DNA from lung tissue samples were obtained from non-smokers (n = 8), smokers without COPD (n = 8), very severe COPD (GOLD 4) patients (n = 8), and patients with cystic fibrosis (n = 8). The latter served as a positive control, with sterile water as a negative control. All bacterial community analyses were based on PCR amplified 16S rRNA gene fragments. Total bacterial populations were measured by quantitative PCR (QPCR) and bacterial community composition was assessed by terminal restriction fragment length polymorphism (TRFLP) analysis and pyrotag sequencing.
RESULTS: Total bacterial populations within lung tissue were small (20–1252 bacterial cells/1000 human cells) but greater in all four sample groups versus the negative control (P < 0.001). TRFLP analysis and sequencing distinguished three distinct bacterial community compositions: one common to the non-smoker and smoker groups, a second to the GOLD 4 group, and the third to the cystic fibrosis positive control group. Pyrotag sequencing identified greater than 1400 unique bacterial sequences and showed an increase in the firmicute phylum in GOLD 4 patients versus all other groups (P < 0.003) attributable to an increase in the Lactobacillus genus (P < 0.0007).
CONCLUSION: There is a detectable bacterial community within human lung tissue that changes in patients with very severe COPD.
Comments: A recent NIH funded trial reported that azithromycin reduced exacerbations in patients with COPD. The exact mechanism for this benefit remains unclear but may very well be multifactorial. Macrolides have been recognized to have intrinsic anti-inflammatory activity and recent studies have suggested they may be able to improve the phagocytic function of macrophages that has been documented to be impaired in individuals with advanced COPD. Identification of these so called microbiomes identifies an association but not necessarily cause and effect. Further study to explore whether these microbiomes trigger some of the inflammatory response or if there is any quantitative or qualitative relationship between numbers or types of organisms and exacerbation frequency and or severity would be instructive.
Relationship of obesity with respiratory symptoms and decreased functional capacity in adults without established COPD. M. Zutler, J.P. Singer, T.A. Omachi, M. Eisner, C. Iribarren, P. Katz, P.D. http://www.ncbi.nlm.nih.gov/pubmed?term = %22Blanc%20PD%22%5BAuthor%5D Prim Care Respir J. 2012 Mar 28 [Epub ahead of print].
BACKGROUND: Obesity contributes to respiratory symptoms and exercise limitation, but the relationships between obesity, airflow obstruction (AO), respiratory symptoms and functional limitation are complex.
AIMS: To determine the relationship of obesity with airflow obstruction (AO) and respiratory symptoms in adults without a previous diagnosis of chronic obstructive pulmonary disease (COPD).
METHODS: We analysed data for potential referents recruited to be healthy controls for an ongoing study of COPD. The potential referents had no prior diagnosis of COPD or healthcare utilisation attributed to COPD in the 12 months prior to recruitment. Subjects completed a structured interview and a clinical assessment including body mass index, spirometry, six-minute walk test (SMWT), and the Short Performance Physical Battery (SPPB). Multiple regression analyses were used to test the associations of obesity (body mass index >30 kg/m2) and smoking with AO (forced expiratory volume in 1s/forced vital capacity ratio <0.7). We also tested the association of obesity with respiratory symptoms and impaired functional capacity (SPPB, SMWT), adjusting for AO.
RESULTS: Of 371 subjects (aged 40–65 years), 69 (19%) had AO. In multivariate analysis, smoking was positively associated with AO (per 10 pack-years, OR 1.24; 95% CI 1.04 to 1.49) while obesity was negatively associated with AO (OR 0.54; 95% CI 0.30 to 0.98). Obesity was associated with increased odds of reporting dyspnoea on exertion (OR 3.6; 95% CI 2.0 to 6.4), productive cough (OR 2.5; 95% CI 1.1 to 6.0), and with decrements in SMWT distance (67±9m; 95% CI 50 to 84m) and SPPB score (OR 1.9; 95% CI 1.1 to 3.5). None of these outcomes was associated with AO.
CONCLUSIONS: Although AO and obesity are both common among adults without an established COPD diagnosis, obesity (but not AO) is linked to a higher risk of reporting dyspnoea on exertion, productive cough, and poorer functional capacity.
Comments: There has been an explosion of research around the relationship of obesity to asthma and COPD and indeed obesity has been deemed to potentially induce an inflammatory response. While this study selected subjects without diagnosed COPD or asthma it is instructive in illustrating that indeed (to no one's surprise I'm sure) obesity itself will contribute to dyspnea and reduced exercise intolerance independent of underlying airway disease. It is important however to recall that obese subjects may actually have mixed obstructive and non-obstructive physiology that evaluation of the FEV1/FVC ratio alone will not fully appreciate. Full PFT's would be helpful to further distinguish those who have mixed physiology or perhaps small airway obstruction. This article points out that while obesity Is known to be an independent risk factor for obstructive airway disease, the mechanisms contributing to the association could include obesity induced inflammation, lung mechanical compromise, reflux disease, deconditioning or corticosteroid induced obesity.
Combination of Roflumilast with a Beta-2 Adrenergic Receptor Agonist Inhibits Proinflammatory and Profibrotic Mediator Release from Human Lung Fibroblasts. S.L. Tannheimer, C.D. Wright, M. Salmon, Respir Res. 2012 Mar 27;13(1):28.
BACKGROUND: Small airway narrowing is an important pathology which impacts lung function in chronic obstructive pulmonary disease (COPD). The accumulation of fibroblasts and myofibroblasts contribute to inflammation, remodeling and fibrosis by production and release of mediators such as cytokines, profibrotic factors and extracellular matrix proteins. This study investigated the effects of the phosphodiesterase 4 inhibitor roflumilast, combined with the long acting beta2 adrenergic agonist indacaterol, both approved therapeutics for COPD, on fibroblast functions that contribute to inflammation and airway fibrosis.
METHODS: The effects of roflumilast and indacaterol treatment were characterized on transforming growth factor beta1 (TGFbeta1)-treated normal human lung fibroblasts (NHLF). NHLF were evaluated for expression of the profibrotic mediators endothelin-1 (ET-1) and connective tissue growth factor (CTGF), expression of the myofibroblast marker alpha smooth muscle actin, and fibronectin (FN) secretion. Tumor necrosis factor-alpha (TNF-alpha) was used to induce secretion of chemokine C-X-C motif ligand 10 (CXCL10), chemokine C-C motif ligand 5 (CCL5) and granulocyte macrophage colony-stimulating factor (GM-CSF) from NHLF and drug inhibition was assessed.
RESULTS: Evaluation of roflumilast (1–10 uM) showed no significant inhibition alone on TGFbeta1-induced ET-1 and CTGF mRNA transcripts, ET-1 and FN protein production, alpha smooth muscle expression, or TNF-alpha-induced secretion of CXCL10, CCL5 and GM-CSF. A concentration-dependent inhibition of ET-1 and CTGF was shown with indacaterol treatment, and a submaximal concentration was chosen for combination studies. When indacaterol (0.1 nM) was added to roflumilast, significant inhibition was seen on all inflammatory and fibrotic mediators evaluated, which was superior to the inhibition seen with either drug alone. Roflumilast plus indacaterol combination treatment resulted in significantly elevated phosphorylation of the transcription factor cAMP response element-binding protein (CREB), an effect that was protein kinase A-dependent. Inhibition of protein kinase A was also found to reverse the inhibition of indacaterol and roflumilast on CTGF.
CONCLUSIONS: These results demonstrate that addition of roflumilast to a LABA inhibits primary fibroblast/myofibroblast function and therapeutically this may impact lung fibroblast proinflammatory and profibrotic mediator release which contributes to small airway remodeling and airway obstruction in COPD.
Comments: There remain ongoing questions regarding the mechanism(s) by which roflumilast may exert anti-inflammatory or indeed disease modifying effects. Previous studies have demonstrated an ability of roflumilast to reduce cytokine release and inflammatory cell recruitment including neutrophils, eosinophils, and lymphocytes in induced sputum and significant reductions in eosinophil cationic protein, IL-8, neutrophil elastase, and α2-macroglobulin, a marker of microvascular leak. Questions remain as to the importance of these findings, however, as the significant differences were found compared to placebo versus other active agents. The study above adds further evidence that roflumilast may have relevant anti-inflammatory effects that are augmented by concurrent use with a long-acting beta agonist (LABA). Indeed previous studies have shown that roflumilast in addition to LABA reduced exacerbations over and above what were seen with LABA alone. These findings also raise the question as to whether earlier intervention with this combination could potentially impede airway remodeling. Obviously further studies are needed before any change in practice would be recommended.