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Observational Study
. 2017 Mar 22;12(3):e0174063.
doi: 10.1371/journal.pone.0174063. eCollection 2017.

C-reactive Protein and N-terminal Prohormone Brain Natriuretic Peptide as Biomarkers in Acute Exacerbations of COPD Leading to Hospitalizations

Free PMC article
Observational Study

C-reactive Protein and N-terminal Prohormone Brain Natriuretic Peptide as Biomarkers in Acute Exacerbations of COPD Leading to Hospitalizations

Yu-Wei Roy Chen et al. PLoS One. .
Free PMC article


There are currently no accepted and validated blood tests available for diagnosing acute exacerbations of chronic obstructive pulmonary disease (AECOPD). In this study, we sought to determine the discriminatory power of blood C-reactive protein (CRP) and N-terminal prohormone brain natriuretic peptide (NT-proBNP) in the diagnosis of AECOPD requiring hospitalizations. The study cohort consisted of 468 patients recruited in the COPD Rapid Transition Program who were hospitalized with a primary diagnosis of AECOPD, and 110 stable COPD patients who served as controls. Logistic regression was used to build a classification model to separate AECOPD from convalescent or stable COPD patients. Performance was assessed using an independent validation set of patients who were not included in the discovery set. Serum CRP and whole blood NT-proBNP concentrations were highest at the time of hospitalization and progressively decreased over time. Of the 3 classification models, the one with both CRP and NT-proBNP had the highest AUC in discriminating AECOPD (cross-validated AUC of 0.80). These data were replicated in a validation cohort with an AUC of 0.88. A combination of CRP and NT-proBNP can reasonably discriminate AECOPD requiring hospitalization versus clinical stability and can be used to rapidly diagnose patients requiring hospitalization for AECOPD.

Conflict of interest statement

Competing Interests: YRC, VC, ZH, CJH, BMM, JMF, and RTN have nothing to disclose. JAL reports personal fees from GE Healthcare, outside the submitted work. MLD reports grants from Genome Canada, Genome British Columbia, Genome Quebec, Canadian Institutes for Health Research (CIHR), Networks of Centres of Excellence Centre of Excellence for Commercialization and Research, St. Paul's Hospital Foundation, and the Canadian Respiratory Research Network, which is funded by the Institute of Circulatory and Respiratory Health Emerging Network of CIHR, the Canadian Lung Association, the Canadian Thoracic Society, and the Canadian Respiratory Health Professionals, during the conduct of the study. DS reports grants from Genome Canada, grants from Canadian Institutes of Health Research, during the conduct of the study; grants and personal fees from Boehringer Ingelheim, grants and personal fees from AstraZeneca, personal fees from Novartis, grants from Merck, outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.


Fig 1
Fig 1. Timeline of blood collection and systemic steroids administration.
The figure displays blood sample collection time point during hospitalization to follow-up for each patient visit. Samples were collected at day 1 of hospitalization, day 3, discharge, day 30 and day 90 post-hospitalization. Systemic corticosteroids were administered on average 19±12 hours prior to the first blood sample collection after hospital admission. The day of discharge is variable, with a median of 5 days and interquartile range (IQR) of 3–8 days.
Fig 2
Fig 2. CRP and NT-proBNP time course box-plots.
A) CRP concentrations of the discovery set at five time-points for AECOPD patients and as well as stable COPD controls. The data are expressed as Tukey box-plots, in which the box represents the 25th, the median, and the 75th percentile. The whiskers extend to 1.5 times of the interquartile range on either side of the box, and the outliers plotted separately. The y-axis is displayed on a natural-log scale. B) NT-proBNP concentrations of the discovery set represented similarly to A.
Fig 3
Fig 3. Length of hospital stay versus NT-proBNP concentration.
NT-proBNP and length of stay are both plotted on natural-log scale. The linear relationship is significant (p = 0.042) from a multiple linear regression analysis. The axes are on a natural-log scale. The model has an adjusted R-squared value of 0.062 based on a sample size of 222 patients from the discovery set. The model was adjusted for age, gender and smoking status.
Fig 4
Fig 4. NT-proBNP Cox proportional hazards survival curve.
The figure shows the concentration of NT-proBNP at the time of hospitalization in predicting all-cause mortality. The x-axis represents number of days post-hospitalization and the y-axis represents the proportion of survivors. The red survival curve followed patients with high NT-proBNP concentrations (90th percentile) whereas the blue curve followed patients with low NT-proBNP concentrations (10th percentile). The curves were displayed with 95% confidence intervals as dotted lines. There was a significant hazard ratio of 1.27 [CI: 1.18–1.38] risk associated with the doubling of NT-proBNP concentration (p-value < 0.0001).
Fig 5
Fig 5. ROC curves of the 3 models from the discovery set.
ROC curve for 1) CRP, 2) NT-proBNP, and 3) CRP + NT-proBNP. The ROC curve is used in discriminating patients with AECOPD. Abbreviations: CRP = C-reactive protein, and NT-proBNP = N-terminal of the prohormone brain natriuretic peptide.

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Grant support

Funding was provided by Genome Canada, Genome British Columbia, Genome Quebec, the Canadian Institutes of Health Research, PROOF Centre of Excellence, St. Paul's Foundation, Providence Health Care Research Institute, the Canadian Respiratory Research Network, and the National Heart, Lung, and Blood Institute’s COPD Clinical Research Network (Grants U10 HL074441, U10 HL074418, U10 HL074428, U10 HL074409, U10 HL074407, U10 HL074422, U10 HL074416, U10 HL074408, U10 HL074439, U10 HL0744231, and U10 HL074424). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.