Systemic inflammatory markers as predictors of longitudinal outcomes in COPD : Results from the Bergen COPD Cohort Study
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Background: Chronic obstructive pulmonary disease (COPD) is major cause of morbidity and mortality worldwide. The prevalence is increasing worldwide, as a result of an increase in cigarette smoking the last decades. The main symptom of COPD is chronic and progressive dyspnea, often accompanied with cough and increased amounts of phlegm. A significant share of the patients suffers episodes with exacerbation of the disease, which may negatively impact quality of life, disease burden and survival. COPD pathophysiology is complex and consists of different disease mechanisms. Inflammation is a central component of COPD, and increased number of immune cells and cytokines are found both in the airways and in the systemic circulation. The COPD pathophysiology is incompletely understood, and there is comprehensive research on inflammatory biomarkers in order to improve diagnosis, identify patients with increased risk of adverse outcome, and to find targets for medical treatment. Aims: 1-Identify diagnostic biomarkers of stable COPD and acute exacerbation of COPD. 2 -Identify inflammatory biomarkers as predictors for longitudinal outcome using longitudinal data: a. as predictors for future exacerbations b. as predictors for change in lung function c. as predictors for mortality and cause of death d. as predictors for lung cancer Methods: The Bergen COPD cohort study (BCCS) included 433 COPD patients and 325 controls between 2006 and 2009. The COPD patients were aged between 40-76, all were former or current smokers. The COPD diagnosis was based on a clinical evaluation combined with an obstructive post-bronchodilator spirometry. Of the 433 COPD patients, 356 patients living in the vicinity of Haukeland University Hospital were also included in the Bergen COPD Exacerbation Study (BCES). All patients and controls went through an extensive examination at inclusion including medical history, physical examination, lung function testing, bioelectrical impedance measurements, HRCT, blood sampling, and microbiological testing. The patients and a selection of the controls were followed up during study visits each 6 months for 3 years, repeating lung function tests and blood sampling each 6 months, bioelectrical impedance each 12 months. In addition, patients were followed up to 9 years regarding mortality and cause of death as well as lung cancer development. Acute exacerbations of COPD (AECOPD) were registered both at each 6-month visit, in addition the patients in the BCES were telephoned each month and asked about symptoms regarding AECOPD. A selection of the patients was also examined at exacerbation where additional blood sampling was performed. The inflammatory biomarkers were evaluated at baseline and at AECOPD using both non-parametric and multiple regression models. For the analysis of the inflammatory biomarkers as predictors of future exacerbations, decline in lung function, mortality and lung cancer development, bi-level longitudinal regression models and cox-regression models were used. Results: Systemic inflammatory markers were measured in all 433 patients and 325 controls at inclusion, and in 149 patients at AECOPD. Macrophage migration inhibitory factor (MIF) was identified as potential biomarker both for stable COPD as well as AECOPD in Paper 2. Within the three years of the BCES, 350 of 403 COPD patients suffered 933 moderate and 370 severe COPD exacerbations. A history of exacerbations, female sex, chronic cough and a lower FEV1 were identified as predictors for future AECOPD in Paper 1. In Paper 3, high levels of GDF-15 were identified as a predictor for a higher future AECOPD count. The COPD patients experienced an average yearly FEV1 decline of 61 ml (1.31 %) in men and 36 ml (0.76 % women) in women. High levels of GDF-15 were identified as a predictor of a faster decline of both FEV1 and FVC in Paper 3. Other factors associated with a faster FEV1 decline were male sex and cachexia. Thirty-six COPD patients died with the first three years of follow up, 159 within 9 years. High levels of GDF-15 were identified as a predictor of a higher mortality in Paper 3. Other factors associated with a higher mortality were a low FEV1, cachexia, obesity and a high degree of comorbidity. Twenty-eight patients developed lung cancer within 9 years. COPD was significantly associated with a higher lung cancer risk. Within COPD patients, emphysema and obesity was associated with a higher lung cancer risk. Of 44 inflammatory biomarkers, only IP-10 was associated with a higher lung cancer risk, whereas systemic inflammation evaluated by a PCA-analysis did not show any correlation with lung cancer development. Conclusion: 1 Macrophage migration inhibitory factor (MIF) was identified as potential biomarker for both for stable COPD as well as AECOPD. 2 a. High levels of GDF-15 were identified as a predictor for a higher future AECOPD count in addition to several clinical characteristics. b. High levels of GDF-15 were identified as a predictor of a faster decline of both FEV1 and FVC. c. High levels of GDF-15 were identified as a predictor of all-cause mortality as well as mortality due to respiratory disease. d. IP-10 was significantly associated with a higher lung cancer risk, whereas systemic inflammation did not show any correlation with lung cancer development.
Has partsPaper 1: Husebo GR, Bakke PS, Aanerud M, Hardie JA, Ueland T, Gronseth R, Persson LJ, Aukrust P, and Eagan TM. Predictors of exacerbations in chronic obstructive pulmonary disease--results from the Bergen COPD cohort study. PLoS One 9: e109721, 2014. The article is available at: https://hdl.handle.net/1956/9799
Paper 2: Husebo GR, Bakke PS, Gronseth R, Hardie JA, Ueland T, Aukrust P, and Eagan TM. Macrophage migration inhibitory factor, a role in COPD. American Journal of Physiology Lung Cellular and Molecular Physiology 311: L1-7, 2016. The article is not available in BORA due to publisher restrictions. The published version is available at: https://doi.org/10.1152/ajplung.00461.2015
Paper 3: Husebo GR, Gronseth R, Lerner L, Gyuris J, Hardie JA, Bakke PS, and Eagan TM. Growth differentiation factor-15 is a predictor of important disease outcomes in patients with COPD. The European Respiratory Journal 49, 2017. The article is not available in BORA due to publisher restrictions. The published version is available at: https://doi.org/10.1183/13993003.01298-2016
Paper 4: Husebo GR, Nielsen R, Hardie J, Bakke PS, Lerner L, D'Alessandro-Gabazza C, Gyuris J, Gabazza E, Aukrust P, and Eagan T. Risk factors for lung cancer in COPD - results from the Bergen COPD cohort study. Respiratory Medicine 152: 81-88, 2019. The published version is available in the thesis file. The accepted version is available at: https://hdl.handle.net/1956/22102