Three-Year Follow-Up of Interleukin 6 and C-Reactive Protein in Chronic Obstructive Pulmonary Disease

Renata Ferrari; Suzana E Tanni; Laura MO Caram; Corina Corrêa; Camila R Corrêa; Irma Godoy


Respiratory Research. 2013;14(24) 

In This Article

Abstract and Introduction


Background: Past studies have shown that mean values of Interleukin-6 (IL-6) and C-reactive protein (CRP) do not change significantly in COPD patients over a one-year period. However, longer period follow-up studies are still lacking. Thus, the aim of this study is to evaluate plasma CRP and IL-6 concentration over three years in COPD patients and to test the association between these inflammatory mediators and disease outcome markers.

Methods: A cohort of 77 outpatients with stable COPD was evaluated at baseline, and 53 (mean FEV1, 56% predicted) were included in the prospective study. We evaluated Interleukin-6 (IL-6), C-reactive protein (CRP), six-minute walking distance (6MWD), and body mass index (BMI) at baseline and after three years. Plasma concentration of IL-6 was measured by high sensitivity ELISA, and CRP was obtained by high sensitivity particle-enhanced immunonephelometry.

Results: IL-6 increased significantly after 3 years compared to baseline measurements [0.8 (0.5–1.3) vs 2.4 (1.3–4.4) pg/ml; p < 0.001] and was associated with worse 6MWD performance. In the Cox regression, increased IL-6 at baseline was associated with mortality [Hazard Ratio (95% CI) = 2.68 (0.13, 1.84); p = 0.02]. CRP mean values did not change [5 (1.6–7.9) vs 4.7 (1.7–10) pg/L; p = 0.84], although eleven patients (21%) presented with changes >3 mg/L in CRP after 3 years.

Conclusions: The systemic inflammatory process, evaluated by IL-6, seems to be persistent, progressive and associated with mortality and worse physical performance in COPD patients.


Chronic obstructive pulmonary disease (COPD) affects primarily the lungs; however, it is now recognized as a disease with systemic repercussions, and it is associated with chronic inflammation.[1] In fact, there is increasing evidence that systemic inflammatory mediators such as C-reactive protein (CRP) and interleukin 6 (IL-6) are increased in the peripheral blood of COPD patients.[2,3] Cross-sectional studies show that CRP levels are related to important clinical outcomes, including exercise tolerance,[4] health status[5] and the exacerbation of disease.[6] Plasma IL-6 concentration is known as a powerful promoter of CRP production in the liver,[7] and it is associated with CRP levels in COPD patients.[4,5,8] IL-6 levels also have been shown to interfere with malnutrition pathophysiology since is increased in low weight COPD patients.[9] A previous study has shown that mean values of CRP remained stable over a 17- month period;[10] in addition, Kolsum et al.[8] have shown that IL-6 did not change over one-year.

Recent study showed that systemic inflammation, when present for at least 1 year, was associated with a higher incidence of exacerbations and worse survival despite similar lung impairment in COPD patients.[11] Furthermore, survival analyses show that the addition of white blood cell counts and the systemic levels of IL-6, CRP, interleukin 8, fibrinogen, chemokine ligand 18, and surfactant protein D improve significantly the ability of clinical variables to predict mortality in COPD patients.[12] In a cohort of 253 COPD patients, the results showed that the highest levels of inflammatory markers was related to the degree of airflow obstruction, functional capacity and health status.[13] The importance of studies to evaluate the inflammatory status in COPD has increased since the launching of new drugs, such as an oralphosphodiesterase 4 (PDE4) inhibitor with systemic effects and appears to offer the potential to target the inflammatory processes underlying COPD.[14] Clinical trials have demonstrated that roflumilast improves lung function and reduces exacerbation frequency in COPD.

In summary, systemic inflammation in COPD is associated with poor outcomes and long-term follow-up studies of inflammatory mediators are needed to better understand the progression of this outcome. We hypothesized that reporting the evolution of CRP and IL-6 will provide information regarding the utility of these mediators in clinical practice and consequently to guide therapeutic interventions in COPD. Thus, the aim of this study was to evaluate plasma CRP and IL-6 concentration over three years in COPD patients and to test the association between these inflammatory mediators and nutritional status, exercise tolerance, disease exacerbations and mortality.