Inflammatory and repair serum biomarker pattern. Association to clinical outcomes in COPD

BackgroundThe relationship between serum biomarkers and clinical expressions of COPD is limited. We planned to further describe this association using markers of inflammation and injury and repair.MethodsWe studied lung function, comorbidities, exercise tolerance, BODE index, and quality of life in 253 COPD patients and recorded mortality over three years. Serum levels of Interleukins 6,8 and16, tumor necrosis factor alpha (TNF α) [inflammatory panel], vascular endothelial growth factor (VEGF), and matrix metalloproteinase 9 (MMP-9) [injury and repair panel] and pulmonary and activation-regulated chemokine (PARC/CCL-18) and monocyte chemotactic protein 1 (MCP-1/CCL2) [chemoattractant panel] were measured. We related the pattern of the biomarker levels to minimal clinically important differences (MCID) using a novel visualization method [ObServed Clinical Association Results (OSCAR) plot].ResultsLevels of the inflammatory markers IL-6, TNF α were higher and those of injury and repair lower (p < 0.01) with more advanced disease (GOLD 1 vs. 4). Using the OSCAR plot, we found that patients in the highest quartile of inflammatory and lowest quartile of injury and repair biomarkers level were more clinically compromised and had higher mortality (p < 0.05).ConclusionsIn COPD, serum biomarkers of inflammation and repair are distinctly associated with important clinical parameters and survival.

[1]  W. MacNee,et al.  Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper , 2004, European Respiratory Journal.

[2]  John R Hurst,et al.  Use of plasma biomarkers at exacerbation of chronic obstructive pulmonary disease. , 2006, American journal of respiratory and critical care medicine.

[3]  W. Arap,et al.  State of the art. Cellular and molecular mechanisms of alveolar destruction in emphysema: an evolutionary perspective. , 2006, Proceedings of the American Thoracic Society.

[4]  S. Bojesen,et al.  C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease. , 2007, American journal of respiratory and critical care medicine.

[5]  J. Struck,et al.  Plasma pro-adrenomedullin but not plasma pro-endothelin predicts survival in exacerbations of COPD. , 2008, Chest.

[6]  D. Smallwood,et al.  Serum amyloid a is a biomarker of acute exacerbations of chronic obstructive pulmonary disease. , 2008, American journal of respiratory and critical care medicine.

[7]  D. Sin,et al.  Biomarkers in chronic obstructive pulmonary disease. , 2009, Proceedings of the American Thoracic Society.

[8]  D. Shale,et al.  Circulating matrix metalloproteinase-9 and osteoporosis in patients with chronic obstructive pulmonary disease , 2009, Chronic respiratory disease.

[9]  L. Edwards,et al.  Evaluation of serum CC-16 as a biomarker for COPD in the ECLIPSE cohort , 2008, Thorax.

[10]  L. Edwards,et al.  Changes in forced expiratory volume in 1 second over time in COPD. , 2011, The New England journal of medicine.

[11]  ATS statement: guidelines for the six-minute walk test. , 2002, American journal of respiratory and critical care medicine.

[12]  Ruth Tal-Singer,et al.  Fibrinogen, COPD and Mortality in a Nationally Representative U.S. Cohort , 2012, COPD.

[13]  References , 1971 .

[14]  P. Jones,et al.  Outcomes and markers in the assessment of chronic obstructive pulmonary disease , 2006, European Respiratory Journal.

[15]  Janet S. Lee,et al.  The Influence of Radiographic Phenotype and Smoking Status on Peripheral Blood Biomarker Patterns in Chronic Obstructive Pulmonary Disease , 2009, PloS one.

[16]  B. Celli,et al.  Inspiratory-to-total lung capacity ratio predicts mortality in patients with chronic obstructive pulmonary disease. , 2005, American journal of respiratory and critical care medicine.

[17]  M. Wolzt,et al.  Circulating vascular endothelial growth factor and systemic inflammatory markers in patients with stable and exacerbated chronic obstructive pulmonary disease. , 2008, Clinical science.

[18]  Y. Higashimoto,et al.  Increased serum concentrations of tissue inhibitor of metalloproteinase-1 in COPD patients , 2005, European Respiratory Journal.

[19]  W. Bailey,et al.  Editorial: Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2023 Guidelines for COPD, Including COVID-19, Climate Change, and Air Pollution , 2023, Medical science monitor : international medical journal of experimental and clinical research.

[20]  P. Jones,et al.  Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease , 1999, Thorax.

[21]  R. Rodríguez-Roisín,et al.  Toward a consensus definition for COPD exacerbations. , 2000, Chest.

[22]  J. Vestbo,et al.  Chronic obstructive pulmonary disease biomarker(s) for disease activity needed--urgently. , 2010, American Journal of Respiratory and Critical Care Medicine.

[23]  B. Make.  How Can We Assess Outcomes of Clinical Trials: The MCID Approach , 2007, COPD.

[24]  D. McAuley,et al.  Matrix metalloproteinases in acute lung injury: mediators of injury and drivers of repair , 2011, European Respiratory Journal.

[25]  T. Mineo,et al.  Variations of inflammatory mediators and alpha1-antitrypsin levels after lung volume reduction surgery for emphysema. , 2010, American journal of respiratory and critical care medicine.

[26]  L. Edwards,et al.  Serum surfactant protein D is steroid sensitive and associated with exacerbations of COPD , 2009, European Respiratory Journal.

[27]  Christopher E Brightling,et al.  Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. , 2011, American journal of respiratory and critical care medicine.

[28]  G. Fine,et al.  Tumor necrosis factor-alpha-induced synthesis of interleukin-16 in airway epithelial cells: priming for serotonin stimulation. , 2003, American Journal of Respiratory Cell and Molecular Biology.

[29]  Bartolome Celli,et al.  Profiling serum biomarkers in patients with COPD: associations with clinical parameters , 2007, Thorax.

[30]  Edwin K Silverman,et al.  Chronic obstructive pulmonary disease phenotypes: the future of COPD. , 2010, American journal of respiratory and critical care medicine.

[31]  R. Stockley.  Biomarkers in COPD: time for a deep breath , 2007, Thorax.

[32]  B. Celli,et al.  The 6‐min walk distance: change over time and value as a predictor of survival in severe COPD , 2004, European Respiratory Journal.

[33]  Y. Tohda,et al.  Serum biomarkers as predictors of lung function decline in chronic obstructive pulmonary disease. , 2009, Respiratory medicine.

[34]  L. Edwards,et al.  COPD association and repeatability of blood biomarkers in the ECLIPSE cohort , 2011, Respiratory research.

[35]  G. Turino,et al.  Matrix elastin: a promising biomarker for chronic obstructive pulmonary disease. , 2011, American journal of respiratory and critical care medicine.

[36]  C. Mackenzie,et al.  A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. , 1987, Journal of chronic diseases.

[37]  L. Edwards,et al.  Serum PARC/CCL-18 concentrations and health outcomes in chronic obstructive pulmonary disease. , 2011, American journal of respiratory and critical care medicine.

[38]  Toru Oga,et al.  Dyspnea is a better predictor of 5-year survival than airway obstruction in patients with COPD. , 2002, Chest.

[39]  B. Celli,et al.  C-reactive protein levels and survival in patients with moderate to very severe COPD. , 2008, Chest.

[40]  Courtney Crim,et al.  Persistent Systemic Inflammation is Associated with Poor Clinical Outcomes in COPD: A Novel Phenotype , 2012, PloS one.

[41]  C. Janson,et al.  Serum levels of matrix metalloproteinase‐9, tissue inhibitors of metalloproteinase‐1 and their ratio are associated with impaired lung function in the elderly: A population‐based study , 2010, Respirology.

[42]  Alvar Agusti,et al.  Immunologic aspects of chronic obstructive pulmonary disease. , 2009, The New England journal of medicine.

[43]  P. Jones,et al.  The St George's Respiratory Questionnaire. , 1991, Respiratory medicine.

[44]  D. Postma,et al.  Pulmonary biomarkers in chronic obstructive pulmonary disease. , 2006, American journal of respiratory and critical care medicine.