Three-year follow-up of Interleukin 6 and C-reactive protein in chronic obstructive pulmonary disease

Renata Ferrari, Suzana E Tanni, Laura M O Caram, Corina Corrêa, Camila R Corrêa, Irma Godoy, Renata Ferrari, Suzana E Tanni, Laura M O Caram, Corina Corrêa, Camila R Corrêa, Irma Godoy

Abstract

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.

Trial registration: No.:NCT00605540.

Figures

Figure 1
Figure 1
Diagram of patient follow up in three-year period. 6MWD = six-minute walking distance.
Figure 2
Figure 2
Plasma concentration of IL-6 and CRP at baseline and after three years. IL-6 = Interleukin 6; CRP = C-reactive protein. Data show medians with interquartile range.

References

    1. Global Initiative for Chronic Obstructive Lung Disease guideline. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease (updated 2010) Global Initiative for Chronic Obstructive Lung Disease; website. . Accessed June 15 2012.
    1. Gan WQ, Man SFP, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax. 2004;59:574–580. doi: 10.1136/thx.2003.019588.
    1. Tanni SE, Pelegrino NR, Angeleli AY, Correa C, Godoy I. Smoking and tumor necrosis factor-alpha mediated systemic inflammation in COPD patients. J Inflamm (Lond) 2010;7:29. doi: 10.1186/1476-9255-7-29.
    1. Broekhuizen R, Wouters EFM, Creutzberg EC, Schols AM. Raised CRP levels mark metabolic and functional impairment in advanced COPD. Thorax. 2007;61:17–22.
    1. Garrod R, Marshall J, Barley E, Fredericks S, Hagan G. The relationship between inflammatory markers and disability in chronic obstructive pulmonary disease. Prim Care Respir J. 2007;16:236–240. doi: 10.3132/pcrj.2007.00047.
    1. Hurst JR, Donaldson GC, Perera WR, Wilkinson TM, Bilello JA, Hagan GW, Vessey RS, Wedzicha JA. Use of plasma biomarkers at exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2006;174:867–874. doi: 10.1164/rccm.200604-506OC.
    1. Kishimoto T. The biology of interleukin-6. Blood. 1989;1989(74):1–10.
    1. Kolsum U, Roy K, Starkey C, Borrill Z, Truman N, Vestbo J, Singh D. The repeatability of interleukin-6, tumor necrosis factor-alpha, and C-reactive protein in COPD patients over one year. Int J Chron Obstruct Pulmon Dis J. 2009;4:149–156.
    1. Eid AA, Ionescu AA, Nixon LS, Lewis-Jenkins V, Matthews SB, Griffiths TL, Shale DJ. Inflammatory response and body composition in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;164:1414–1418. doi: 10.1164/ajrccm.164.8.2008109.
    1. Pinto-Plata VM, Mullerova H, Toso JF, Feudjo-Tepie M, Soriano JB, Vessey RS, Celli BR. C- reactive protein in patients with COPD, control smokers, and non-smokers. Thorax. 2006;61:23–28.
    1. Agustí A, Edwards LD, Rennard SI, MacNee W, Tal-Singer R, Miller BE, Vestbo J, Lomas DA, Calverley PM, Wouters E, Crim C, Yates JC, Silverman EK, Coxson HO, Bakke P, Mayer RJ, Celli B. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS One. 2012;7:e37483. doi: 10.1371/journal.pone.0037483.
    1. Celli BR, Locantore N, Yates J, Tal-Singer R, Miller BE, Bakke P, Calverley P, Coxson H, Crim C, Edwards LD, Lomas DA, Duvoix A, MacNee W, Rennard S, Silverman E, Vestbo J, Wouters E, Agustí A. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185:1065–1072. doi: 10.1164/rccm.201110-1792OC.
    1. Pinto-Plata V, Casanova C, Mullerova H, de Torres JP, Corado H, Varo N, Cordova E, Zeineldine S, Paz H, Baz R, Divo M, Cortopassi F, Celli BR. Inflammatory and repair serum biomarker pattern. Association to clinical outcomes in COPD. Respir Res. 2012;13:71. doi: 10.1186/1465-9921-13-71.
    1. Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br J Pharmacol. 2011;163:53–67. doi: 10.1111/j.1476-5381.2011.01218.x.
    1. Jardim JR, Oliveira JA, Nascimento O. II Consenso Brasileiro de DPOC. J Bras Pneumol. 2004;30(Suppl 5):1–42.
    1. American Thoracic Society statement. Standardization of spirometry – Update. Am Rev Respir Dis. 1987;136:1285–1298.
    1. American Thoracic Society statement. Guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166:111–117.
    1. Kovelis D, Segretti NO, Probst VS, Lareau SC, Brunetto AF, Pitta F. Validação do Modified Pulmonary Functional Status and Dyspnea Questionnaire e da escala do Medical Research Council para o uso em pacientes com doença pulmonar obstrutiva crônica no Brasil. J Bras Pneumol. 2008;34:1008–1018. doi: 10.1590/S1806-37132008001200005.
    1. Celli BR, Cote CG, Marin JM, Casanova C, Montes de Oca M, Mendez RA, Pinto Plata V, Cabral HJ. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med. 2004;350:1005–1012. doi: 10.1056/NEJMoa021322.
    1. Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a Combined Comorbidity Index. J Clin Epidemiol. 1994;47:1245–1251. doi: 10.1016/0895-4356(94)90129-5.
    1. R Development Core Team. R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2011.
    1. Ferrari R, Tanni SE, Faganello MM, Caram LM, Lucheta PA, Godoy I. Three-year follow-up study of respiratory and systemic manifestations of chronic obstructive pulmonary disease. Braz J Med Biol Res. 2011;44:46–52. doi: 10.1590/S0100-879X2010007500150.
    1. Rincon M. Interleukin-6: from an inflammatory marker to a target for inflammatory diseases. Trends Immunol. 2012;33:571–577. doi: 10.1016/j.it.2012.07.003.
    1. Mehrotra N, Freire AX, Bauer DC, Harris TB, Newman AB, Kritchevsky SB, Meibohm B. Predictors of mortality in elderly subjects with obstructive airway disease: the PILE score. Ann Epidemiol. 2010;20:223–232. doi: 10.1016/j.annepidem.2009.11.005.
    1. Waschki B, Kirsten A, Holz O, Müller KC, Meyer T, Watz H, Magnussen H. Physical activity is the strongest predictor of all-cause mortality in patients with COPD: a prospective cohort study. Chest. 2011;140:331–342. doi: 10.1378/chest.10-2521.
    1. de Torres JP, Pinto-Plata V, Casanova C, Mullerova H, Córdoba-Lanús E, Muros de Fuentes M, Aguirre-Jaime A, Celli BR. C-reactive protein levels and survival in patients with moderate to very severe COPD. Chest. 2008;133:1336–1343. doi: 10.1378/chest.07-2433.
    1. Man SFP, Connett JE, Anthonisen NR, Wise RA, Tashkin DP, Sin DD. C-reactive protein and mortality in mild to moderate chronic obstructive pulmonary disease. Thorax. 2006;61:849–853. doi: 10.1136/thx.2006.059808.
    1. Dahl M, Vestbo J, Lange P, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;175:250–255. doi: 10.1164/rccm.200605-713OC.
    1. Sin DD, Man SF. Interleukin-6: a red herring or a real catch in COPD? Chest. 2008;133:4–6. doi: 10.1378/chest.07-2085.
    1. Walter RE, Wilk JB, Larson MG, Vasan RS, Keaney JF Jr, Lipinska I, O'Connor GT, Benjamin EJ. Systemic inflammation and COPD: the Framingham Heart Study. Chest. 2008;133:19–25. doi: 10.1378/chest.07-0058.
    1. Kishimoto T. Interleukin-6: from basic science to medicine–40 years in immunology. Annu Rev Immunol. 2005;23:1–21. doi: 10.1146/annurev.immunol.23.021704.115806.
    1. Nishida H, Horio T, Suzuki Y, Iwashima Y, Tokudome T, Fumiki Yoshihara F, Nakamura S, Kawano Y. Interleukin-6 as an independent predictor of future cardiovascular events in high-risk Japanese patients: Comparison with C-reactive protein. Cytokine. 2011;53:342–346. doi: 10.1016/j.cyto.2010.12.005.
    1. Jenny NS, French B, Arnold AM, Strotmeyer ES, Cushman M, Chaves PH, Ding J, Fried LP, Kritchevsky SB, Rifkin DE, Sarnak MJ, Newman AB. Long-term assessment of inflammation and healthy aging in late life: The Cardiovascular Health Study All Stars. Gerontol A Biol Sci Med Sci. 2012;2012(67):970–976.
    1. Brinkley TE, Leng X, Miller ME, Kitzman DW, Pahor M, Berry MJ, Marsh AP, Kritchevsky SB, Nicklas BJ. Chronic inflammation is associated with low physical function in older adults across multiple comorbidities. J Gerontol A Biol Sci Med Sci. 2009;64:455–461.
    1. Yende S, Waterer GW, Tolley EA, Newman AB, Bauer DC, Taaffe DR, Jensen R, Crapo R, Rubin S, Nevitt M, Simonsick EM, Satterfield S, Harris T, Kritchevsky SB. Inflammatory markers are associated with ventilator limitation and muscle dysfunction in obstructive lung disease in well functioning elderly subjects. Thorax. 2006;61:10–16.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit