Prognostic utility of admission cell-free DNA levels in patients with chronic obstructive pulmonary disease exacerbations

Abstract

Background

Chronic obstructive pulmonary disease exacerbations (COPDEs) are associated with increased morbidity and mortality. Cell-free DNA (cfDNA) is a novel biomarker associated with clinical outcomes in several disease states but has not been studied in COPD. The objectives of this study were to assess cfDNA levels during a COPDE, to evaluate the association of cfDNA with clinical parameters and to explore the prognostic implications of cfDNA levels on long-term survival.

Methods

This was an observational study that assessed cfDNA levels in patients admitted to hospital for a COPDE. Plasma cfDNA levels of COPDE patients were compared to those of matched stable COPD patients and healthy controls. Multivariable and Cox regression analyses were used to assess the association of cfDNA levels with blood gas parameters and long-term survival.

Results

A total of 62 patients (46 males, forced expiratory volume in 1 second [FEV₁] 38%±13%) were included. The median cfDNA levels on admission for COPDE patients was 1,634 ng/mL (interquartile range [IQR] 1,016–2,319) compared to 781 ng/mL (IQR 523–855) for stable COPD patients, matched for age and disease severity, and 352 ng/mL (IQR 209–636) for healthy controls (P<0.0001, for both comparisons). cfDNA was correlated with partial arterial pressure of carbon dioxide (PaCO₂, r=0.35) and pH (r=−0.35), P=0.01 for both comparisons. In a multivariable analysis, PaCO₂ was the only independent predictor of cfDNA. Using a cfDNA level of 1,924 ng/mL (threshold for abnormal PaCO₂), those with high levels had a trend for increased 5-year mortality risk adjusted for age, sex and FEV₁% (hazard ratio 1.92, 95% confidence interval 0.93–3.95, P=0.08).

Conclusion

Plasma cfDNA might offer a novel technique to identify COPD patients at increased risk of poor outcomes, but the prognostic utility of this measurement requires further study.

Keywords:

• chronic obstructive pulmonary disease
• exacerbation
• cell-free DNA
• biomarker
• prognosis

Acknowledgments

We would like to thank Mrs. Valeria Frishman for her technical assistance.

Author contributions

Avital Avriel contributed to conception and design, data collection, analysis and interpretation of data, first draft of the article, and revision of the article critically for important intellectual content. Dmitry Rozenberg contributed to analysis and interpretation of data, and revision of the article critically for important intellectual content. Yael Raviv contributed to interpretation of data and revision of the article critically for important intellectual content. Dov Heimer contributed to data collection, and revision of the article critically for important intellectual content. Bar-Shai Amir contributed to data collection (stable COPD), interpretation of data, and revision of the article critically for important intellectual content. Rachel Gavish contributed to data collection, interpretation of data, and revision of the article critically for important intellectual content. Jony Sheynin contributed to laboratory analysis, interpretation of data, and revision of the article critically for important intellectual content. Amos Douvdevani contributed to conception and design, interpretation of data, and revision of the article critically for important intellectual content. All authors contributed toward data analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work.

Disclosure

Amos Douvdevani submitted a US Patent Application No 13/659,439 “Assay for Detecting Circulating Free Nucleic Acids.” Dmitry Rozenberg received salary support from the University of Toronto, Clinician Scientist Training program and Vanier Graduate Scholarship. The other authors report no conflicts of interest in this work.