Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype

Abstract

Background: Because chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, the identification of specific clinical phenotypes is key to developing more effective therapies. To explore if the persistence of systemic inflammation is associated with poor clinical outcomes in COPD we assessed patients recruited to the well-characterized ECLIPSE cohort (NCT00292552).

Methods and findings: Six inflammatory biomarkers in peripheral blood (white blood cells (WBC) count and CRP, IL-6, IL-8, fibrinogen and TNF-α levels) were quantified in 1,755 COPD patients, 297 smokers with normal spirometry and 202 non-smoker controls that were followed-up for three years. We found that, at baseline, 30% of COPD patients did not show evidence of systemic inflammation whereas 16% had persistent systemic inflammation. Even though pulmonary abnormalities were similar in these two groups, persistently inflamed patients during follow-up had significantly increased all-cause mortality (13% vs. 2%, p<0.001) and exacerbation frequency (1.5 (1.5) vs. 0.9 (1.1) per year, p<0.001) compared to non-inflamed ones. As a descriptive study our results show associations but do not prove causality. Besides this, the inflammatory response is complex and we studied only a limited panel of biomarkers, albeit they are those investigated by the majority of previous studies and are often and easily measured in clinical practice.

Conclusions: Overall, these results identify a novel systemic inflammatory COPD phenotype that may be the target of specific research and treatment.

Conflict of interest statement

Competing Interests: BRC: Received consulting fees from Altana, AstraZeneca, Boehringer-Ingelheim and GlaxoSmithKline; speaking fees from Altana, AstraZeneca, Boehringer-Ingelheim and GlaxoSmithKline; and grant support from Boehringer-Ingelheim and GlaxoSmithKline. NL, JY, RT-S, BEM, CC, RJM and LDE: Full-time employees of GlaxoSmithKline and hold stock or stock options in GlaxoSmithKline. PB: Received lecture fees from AstraZeneca, GlaxoSmithKline and NycoMed; has participated in clinical research studies sponsored by GlaxoSmithKline, Pfizer and Boehringer-Ingelheim; is currently member of the Steering Committee and the Scientific Committee of the ECLIPSE study which is sponsored by GlaxoSmithKline PC: Received fees for serving on advisory boards for GlaxoSmithKline, AstraZeneca, Nycomed, Novartis and Boehringer Ingelheim, for expert testimony for Forest/Nycomed, and has received speaker fees from GlaxoSmithKline and Nycomed; has received travel assistance from GlaxoSmithKline to attend ECLIPSE study meetings and from Boehringer Ingelheim to attend a scientific conference. HC: Received an honorarium for serving on the steering committee for the ECLIPSE project for GlaxoSmithKline; was the co-investigator on two multi-center studies sponsored by GlaxoSmithKline and has received travel expenses to attend meetings related to the project; has three contract service agreements with GlaxoSmithKline to quantify the CT scans in subjects with COPD and a service agreement with Spiration Inc to measure changes in lung volume in subjects with severe emphysema; was the co-investigator (D Sin PI) on a Canadian Institutes of Health – Industry (Wyeth) partnership grant; has received a fee for speaking at a conference and related travel expenses from AstraZeneca (Australia); was the recipient of a GSK Clinical Scientist Award (06/2010-07/2011). DAL: Received grant support, honoraria and consultancy fees from GlaxoSmithKline. WM: Received travel assistance from GlaxoSmithKline to attend ECLIPSE study meetings. SR: Received fees for serving on advisory boards, consulting or honoraria from Almirall, APT Pharma, Aradigm, Argenta, AstraZeneca, Boehringer Ingelheim, Chiesi, Dey, Forest, GlaxoSmitkKlein, HoffmanLaRoche, MedImmune, Mpex, Novartis, Nycomed, Oriel, Otsuka, Pearl, Pfizer, Pharmaxis, Merck and Talecris. ES: Received an honorarium for a talk on COPD genetics, grant support for two studies of COPD genetics, and consulting fees from GlaxoSmithKline; honoraria for talks and consulting fees from AstraZeneca. JV: Received fees for serving on advisory boards for GlaxoSmithKline, AstraZeneca, Nycomed and Boehringer Ingelheim, and has received speaker fees from GlaxoSmithKline, AstraZeneca, Pfizer, Boehringer-Ingelheim, Chiesi, Novartis and Nycomed; has received travel assistance from GlaxoSmithKline to attend ECLIPSE study meetings; his wife has previously worked in pharmaceutical companies, including GSK and AstraZeneca. EW: Serves on an advisory board for Nycomed; has received lecture fees from GlaxoSmithKline, AstraZeneca and Novartis, and has received research grants from GlaxoSmithKline and AstraZeneca. AA: Received travel assistance from GlaxoSmithKline to attend ECLIPSE study meetings and honorarium for speaking at conferences and participating in advisory boards from Almirall, Astra-Zeneca, Boheringer-Ingelheim, Chiesi, Esteve, GSK, Medimmune, Novartis, Nycomed, Pfizer, Roche and Procter & Gamble.

Figures

Figure 1. Box plot (log scale) of the different biomarkers determined at baseline in COPD patients, smokers with normal lung function and nonsmokers.

For further explanations, see text.

Figure 2. Network layout of the systemic inflammatory response (inflammome) in non-smokers (n = 202), smokers with normal lung function (n = 297) and COPD patients (n = 1755) at recruitment.

Each node of the network corresponds to one of the six inflammatory biomarkers determined in this study (see color code), and its size is proportional to the prevalence of abnormal values (>95th percentile of non-smokers) of that particular biomarker in that particular group of subjects (precise figure shown inside of each node). Two nodes are linked if more than 1% of subjects in the network share abnormal values of these two biomarkers, its width being proportional to that proportion. For further explanations, see text.

Figure 3. Proportion of patients with none, one, or two (or more) biomarkers (WBC count, CRP, IL-6 and fibrinogen) in the upper quartile of the COPD distribution, at baseline (left bars) and after one year follow up (right bars).

For further explanations, see text.