Abstract
BackgroundChronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by multiple subtypes and variable disease progression. Blood biomarkers have been variably associated with subtype, severity, and disease progression. Just as combined clinical variables are more highly predictive of outcomes than individual clinical variables, we hypothesized that multiple biomarkers may be more informative than individual biomarkers to predict subtypes, disease severity, disease progression, and mortality.MethodsFibrinogen, C-Reactive Protein (CRP), surfactant protein D (SP-D), soluble Receptor for Advanced Glycation Endproducts (sRAGE), and Club Cell Secretory Protein (CC16) were measured in the plasma of 1465 subjects from the COPDGene cohort and 2746 subjects from the ECLIPSE cohort. Regression analysis was performed to determine whether these biomarkers, individually or in combination, were predictive of subtypes, disease severity, disease progression, or mortality, after adjustment for clinical covariates.ResultsIn COPDGene, the best combinations of biomarkers were: CC16, sRAGE, fibrinogen, CRP, and SP-D for airflow limitation (p < 10−4), SP-D, CRP, sRAGE and fibrinogen for emphysema (p < 10−3), CC16, fibrinogen, and sRAGE for decline in FEV1 (p < 0.05) and progression of emphysema (p < 10−3), and all five biomarkers together for mortality (p < 0.05). All associations except mortality were validated in ECLIPSE. The combination of SP-D, CRP, and fibrinogen was the best model for mortality in ECLIPSE (p < 0.05), and this combination was also significant in COPDGene.ConclusionThis comprehensive analysis of two large cohorts revealed that combinations of biomarkers improve predictive value compared with clinical variables and individual biomarkers for relevant cross-sectional and longitudinal COPD outcomes.
Highlights
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by multiple subtypes and variable disease progression
We evaluated the efficacy of five biomarkers soluble Receptor for Advanced Glycation Endproducts (sRAGE), surfactant protein D (SP-D), fibrinogen, Club cell secretory protein (CC16), and C-Reactive Protein (CRP) - both individually and in combination, at predicting airflow limitation, severity of emphysema, exacerbations, decline in Forced expiratory volume in the first second (FEV1), progression of emphysema, and mortality in the COPDGene and ECLIPSE cohorts
All analyses performed on the COPDGene and ECLIPSE cohorts are shown in Additional file 2: Figure S5 and S6, respectively, with the best model in each cohort highlighted in yellow
Summary
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by multiple subtypes and variable disease progression. Aside from smoking cessation and oxygen, no available therapies prolong survival or prevent disease progression, with few promising novel drugs in the pipeline [1]. Detection of subclinical disease through biomarkers could lead to interventions (e.g., smoking cessation) that could prevent the development of overt COPD. The identification of biomarkers associated with COPD subtypes or severity may stimulate basic research into the mechanisms underlying the pathogenesis of COPD and identify novel therapeutic targets
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