Skip to main content
Top
Published in: Journal of Inflammation 1/2015

Open Access 01-12-2015 | Research

Neutrophil-to-lymphocyte ratio, calprotectin and YKL-40 in patients with chronic obstructive pulmonary disease: correlations and 5-year mortality – a cohort study

Authors: Allan Klitgaard Sørensen, Dennis Back Holmgaard, Lone Hagens Mygind, Julia Johansen, Court Pedersen

Published in: Journal of Inflammation | Issue 1/2015

Login to get access

Abstract

Background

Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and progressive decline in pulmonary function. Neutrophil-to-lymphocyte ratio (NLR), YKL-40 and calprotectin are biomarkers of inflammation and predict mortality in patients with different inflammatory diseases. We aimed to investigate the correlation between levels of these three biomarkers and neutrophil granulocyte and lymphocyte count in patients with moderate to very severe COPD stratified by use of systemic glucocorticoids. Furthermore, we studied the ability of these biomarkers to predict all-cause mortality.

Methods

386 patients with moderate to very severe COPD were followed prospectively for 10 years. Patients were divided into two groups according to systemic glucocorticoid use at baseline. Correlations between biomarkers were assessed by Spearman’s Rho, and mortality was evaluated in uni- and multivariate Cox regression analyses with hazard ratios (HR) and 95% confidence intervals (CI).

Results

Plasma calprotectin was positively correlated with neutrophil granulocyte count and NLR. No significant association was found between plasma YKL-40 and the cellular biomarkers, irrespective of glucocorticoid treatment. In the group not treated with systemic glucocorticoids, plasma calprotectin [HR 1.002 (95% CI 1.000 – 1.004)], NLR [HR 1.090 (1.036 – 1.148)] and lymphocyte count [HR 0.667 (0.522 – 0.851)] were significantly associated with higher mortality. In the group treated with systemic glucocorticoids, higher plasma YKL-40 was significantly associated with mortality in univariate Cox regression analysis [HR 1.006 (1.003 – 1.008)].

Conclusions

Calprotectin was related to neutrophil granulocyte count and NLR in patients with moderate to very severe COPD in stable phase and not in treatment with systemic glucocorticoids. Lymphopenia, higher plasma calprotectin and higher NLR were independent predictors of increased all-cause mortality in this group. Our data also suggests that treatment with systemic glucocorticoids has a significant impact on the ability of inflammatory biomarkers to predict all-cause mortality.

Trial registration

ClinicalTrials.gov NCT00132860.
Literature
1.
go back to reference Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. European Respiratory J. 2004;23(6):932–46.CrossRef Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. European Respiratory J. 2004;23(6):932–46.CrossRef
2.
go back to reference Sinden NJ, Stockley RA. Systemic inflammation and comorbidity in COPD: a result of ‘overspill’ of inflammatory mediators from the lungs? Review Evidence Thorax. 2010;65(10):930–6. doi:10.1136/thx.2009.130260.CrossRef Sinden NJ, Stockley RA. Systemic inflammation and comorbidity in COPD: a result of ‘overspill’ of inflammatory mediators from the lungs? Review Evidence Thorax. 2010;65(10):930–6. doi:10.1136/thx.2009.130260.CrossRef
3.
go back to reference Casanova C, de Torres JP, Aguirre-Jaime A, Pinto-Plata V, Marin JM, Cordoba E, et al. The progression of chronic obstructive pulmonary disease is heterogeneous: the experience of the BODE cohort. Am J Respir Crit Care Med. 2011;184(9):1015–21. doi:10.1164/rccm.201105-0831OC.CrossRefPubMed Casanova C, de Torres JP, Aguirre-Jaime A, Pinto-Plata V, Marin JM, Cordoba E, et al. The progression of chronic obstructive pulmonary disease is heterogeneous: the experience of the BODE cohort. Am J Respir Crit Care Med. 2011;184(9):1015–21. doi:10.1164/rccm.201105-0831OC.CrossRefPubMed
4.
go back to reference Celli BR, Cote CG, Marin JM, Casanova C, Montes De Oca M, Mendez RA, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(10):1005–12. doi:10.1056/NEJMoa021322.CrossRefPubMed Celli BR, Cote CG, Marin JM, Casanova C, Montes De Oca M, Mendez RA, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(10):1005–12. doi:10.1056/NEJMoa021322.CrossRefPubMed
5.
go back to reference Agusti A, Edwards LD, Rennard SI, MacNee W, Tal-Singer R, Miller BE, et al. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS One. 2012;7(5):e37483. doi:10.1371/journal.pone.0037483.CrossRefPubMedCentralPubMed Agusti A, Edwards LD, Rennard SI, MacNee W, Tal-Singer R, Miller BE, et al. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS One. 2012;7(5):e37483. doi:10.1371/journal.pone.0037483.CrossRefPubMedCentralPubMed
6.
go back to reference Celli BR, Locantore N, Yates J, Tal-Singer R, Miller BE, Bakke P, et al. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185(10):1065–72. doi:10.1164/rccm.201110-1792OC.CrossRefPubMed Celli BR, Locantore N, Yates J, Tal-Singer R, Miller BE, Bakke P, et al. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185(10):1065–72. doi:10.1164/rccm.201110-1792OC.CrossRefPubMed
7.
go back to reference Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(26):2645–53. doi:10.1056/NEJMoa032158.CrossRefPubMed Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(26):2645–53. doi:10.1056/NEJMoa032158.CrossRefPubMed
8.
go back to reference Ergelen M, Uyarel H, Altay S, Kul S, Ayhan E, Isik T et al. Predictive value of elevated neutrophil to lymphocyte ratio in patients undergoing primary angioplasty for ST-segment elevation myocardial infarction. Clin Appl Thromb Hemost. 2013. doi:10.1177/1076029612473516. Ergelen M, Uyarel H, Altay S, Kul S, Ayhan E, Isik T et al. Predictive value of elevated neutrophil to lymphocyte ratio in patients undergoing primary angioplasty for ST-segment elevation myocardial infarction. Clin Appl Thromb Hemost. 2013. doi:10.1177/1076029612473516.
9.
go back to reference Gul M, Uyarel H, Ergelen M, Ugur M, Isik T, Ayhan E et al. Predictive value of neutrophil to lymphocyte ratio in clinical outcomes of non-ST elevation myocardial infarction and unstable angina pectoris: A 3-year follow-up. Clin Appl Thromb Hemost. 2012. doi:10.1177/1076029612465669 Gul M, Uyarel H, Ergelen M, Ugur M, Isik T, Ayhan E et al. Predictive value of neutrophil to lymphocyte ratio in clinical outcomes of non-ST elevation myocardial infarction and unstable angina pectoris: A 3-year follow-up. Clin Appl Thromb Hemost. 2012. doi:10.1177/1076029612465669
10.
go back to reference Cedres S, Torrejon D, Martinez A, Martinez P, Navarro A, Zamora E, et al. Neutrophil to lymphocyte ratio (NLR) as an indicator of poor prognosis in stage IV non-small cell lung cancer. Clinical Translational Oncol. 2012;14(11):864–9. doi:10.1007/s12094-012-0872-5.CrossRef Cedres S, Torrejon D, Martinez A, Martinez P, Navarro A, Zamora E, et al. Neutrophil to lymphocyte ratio (NLR) as an indicator of poor prognosis in stage IV non-small cell lung cancer. Clinical Translational Oncol. 2012;14(11):864–9. doi:10.1007/s12094-012-0872-5.CrossRef
11.
go back to reference Li MX, Liu XM, Zhang XF, Zhang JF, Wang WL, Zhu Y, et al. Prognostic role of neutrophil-to-lymphocyte ratio in colorectal cancer: A systematic review and meta-analysis. Int J Cancer . 2014;134(10):2403–13. doi:10.1002/ijc.28536.CrossRefPubMed Li MX, Liu XM, Zhang XF, Zhang JF, Wang WL, Zhu Y, et al. Prognostic role of neutrophil-to-lymphocyte ratio in colorectal cancer: A systematic review and meta-analysis. Int J Cancer . 2014;134(10):2403–13. doi:10.1002/ijc.28536.CrossRefPubMed
12.
go back to reference Sen BB, Rifaioglu EN, Ekiz O, Inan MU, Sen T, Sen N. Neutrophil to lymphocyte ratio as a measure of systemic inflammation in psoriasis. Cutan Ocul Toxicol. 2013. doi:10.3109/15569527.2013.834498 Sen BB, Rifaioglu EN, Ekiz O, Inan MU, Sen T, Sen N. Neutrophil to lymphocyte ratio as a measure of systemic inflammation in psoriasis. Cutan Ocul Toxicol. 2013. doi:10.3109/15569527.2013.834498
13.
go back to reference Gunay E, Sarinc Ulasli S, Akar O, Ahsen A, Gunay S, Koyuncu T et al. Neutrophil-to-lymphocyte ratio in chronic obstructive pulmonary disease: a retrospective study. Inflammation. 2013. doi:10.1007/s10753-013-9749-1. Gunay E, Sarinc Ulasli S, Akar O, Ahsen A, Gunay S, Koyuncu T et al. Neutrophil-to-lymphocyte ratio in chronic obstructive pulmonary disease: a retrospective study. Inflammation. 2013. doi:10.1007/s10753-013-9749-1.
14.
go back to reference Voganatsi A, Panyutich A, Miyasaki KT, Murthy RK. Mechanism of extracellular release of human neutrophil calprotectin complex. J Leukoc Biol. 2001;70(1):130–4.PubMed Voganatsi A, Panyutich A, Miyasaki KT, Murthy RK. Mechanism of extracellular release of human neutrophil calprotectin complex. J Leukoc Biol. 2001;70(1):130–4.PubMed
15.
go back to reference Rammes A, Roth J, Goebeler M, Klempt M, Hartmann M, Sorg C. Myeloid-related protein (MRP) 8 and MRP14, calcium-binding proteins of the S100 family, Are secreted by activated monocytes via a novel, tubulin-dependent pathway. J Biol Chem. 1997;272(14):9496–502. doi:10.1074/jbc.272.14.9496.CrossRefPubMed Rammes A, Roth J, Goebeler M, Klempt M, Hartmann M, Sorg C. Myeloid-related protein (MRP) 8 and MRP14, calcium-binding proteins of the S100 family, Are secreted by activated monocytes via a novel, tubulin-dependent pathway. J Biol Chem. 1997;272(14):9496–502. doi:10.1074/jbc.272.14.9496.CrossRefPubMed
16.
go back to reference Edgeworth J, Gorman M, Bennett R, Freemont P, Hogg N. Identification of p8,14 as a highly abundant heterodimeric calcium binding protein complex of myeloid cells. J Biological Chem. 1991;266(12):7706–13. Edgeworth J, Gorman M, Bennett R, Freemont P, Hogg N. Identification of p8,14 as a highly abundant heterodimeric calcium binding protein complex of myeloid cells. J Biological Chem. 1991;266(12):7706–13.
17.
go back to reference Hsu K, Champaiboon C, Guenther BD, Sorenson BS, Khammanivong A, Ross KF et al. ANTI-INFECTIVE PROTECTIVE PROPERTIES OF S100 CALGRANULINS. Anti-inflammatory & anti-allergy agents in medicinal chemistry. 2009;8(4):290–305. Hsu K, Champaiboon C, Guenther BD, Sorenson BS, Khammanivong A, Ross KF et al. ANTI-INFECTIVE PROTECTIVE PROPERTIES OF S100 CALGRANULINS. Anti-inflammatory & anti-allergy agents in medicinal chemistry. 2009;8(4):290–305.
18.
go back to reference Carroccio A, Rocco P, Rabitti PG, Di Prima L, Forte GB, Cefalu AB, et al. Plasma calprotectin levels in patients suffering from acute pancreatitis. Dig Dis Sci. 2006;51(10):1749–53. doi:10.1007/s10620-006-9078-4.CrossRefPubMed Carroccio A, Rocco P, Rabitti PG, Di Prima L, Forte GB, Cefalu AB, et al. Plasma calprotectin levels in patients suffering from acute pancreatitis. Dig Dis Sci. 2006;51(10):1749–53. doi:10.1007/s10620-006-9078-4.CrossRefPubMed
19.
go back to reference Gray RD, Imrie M, Boyd AC, Porteous D, Innes JA, Greening AP. Sputum and serum calprotectin are useful biomarkers during CF exacerbation. J Cystic Fibrosis. 2010;9(3):193–8. doi:10.1016/j.jcf.2010.01.005.CrossRef Gray RD, Imrie M, Boyd AC, Porteous D, Innes JA, Greening AP. Sputum and serum calprotectin are useful biomarkers during CF exacerbation. J Cystic Fibrosis. 2010;9(3):193–8. doi:10.1016/j.jcf.2010.01.005.CrossRef
20.
go back to reference Meuwis MA, Vernier-Massouille G, Grimaud JC, Bouhnik Y, Laharie D, Piver E, et al. Serum calprotectin as a biomarker for Crohn’s disease. J Crohn’s Colitis. 2013;7(12):e678–83. doi:10.1016/j.crohns.2013.06.008.CrossRef Meuwis MA, Vernier-Massouille G, Grimaud JC, Bouhnik Y, Laharie D, Piver E, et al. Serum calprotectin as a biomarker for Crohn’s disease. J Crohn’s Colitis. 2013;7(12):e678–83. doi:10.1016/j.crohns.2013.06.008.CrossRef
21.
go back to reference Andres Cerezo L, Mann H, Pecha O, Plestilova L, Pavelka K, Vencovsky J, et al. Decreases in serum levels of S100A8/9 (calprotectin) correlate with improvements in total swollen joint count in patients with recent-onset rheumatoid arthritis. Arthritis ResTherapy. 2011;13(4):R122. doi:10.1186/ar3426. Andres Cerezo L, Mann H, Pecha O, Plestilova L, Pavelka K, Vencovsky J, et al. Decreases in serum levels of S100A8/9 (calprotectin) correlate with improvements in total swollen joint count in patients with recent-onset rheumatoid arthritis. Arthritis ResTherapy. 2011;13(4):R122. doi:10.1186/ar3426.
22.
go back to reference Cury DB, Mizsputen SJ, Versolato C, Miiji LO, Pereira E, Delboni MA, et al. Serum calprotectin levels correlate with biochemical and histological markers of disease activity in TNBS colitis. Cell Immunol. 2013;282(1):66–70. doi:10.1016/j.cellimm.2013.04.004.CrossRefPubMedCentralPubMed Cury DB, Mizsputen SJ, Versolato C, Miiji LO, Pereira E, Delboni MA, et al. Serum calprotectin levels correlate with biochemical and histological markers of disease activity in TNBS colitis. Cell Immunol. 2013;282(1):66–70. doi:10.1016/j.cellimm.2013.04.004.CrossRefPubMedCentralPubMed
23.
go back to reference Holmgaard DB, Mygind LH, Titlestad I, Madsen H, Pedersen SS, Mortensen OH, et al. Calprotectin–a marker of mortality in COPD? Results from a prospective cohort study. COPD. 2013;10(5):581–7. doi:10.3109/15412555.2013.781580.CrossRefPubMed Holmgaard DB, Mygind LH, Titlestad I, Madsen H, Pedersen SS, Mortensen OH, et al. Calprotectin–a marker of mortality in COPD? Results from a prospective cohort study. COPD. 2013;10(5):581–7. doi:10.3109/15412555.2013.781580.CrossRefPubMed
24.
go back to reference Harutyunyan M, Christiansen M, Johansen JS, Kober L, Torp-Petersen C, Kastrup J. The inflammatory biomarker YKL-40 as a new prognostic marker for all-cause mortality in patients with heart failure. Immunobiology. 2012;217(6):652–6. doi:10.1016/j.imbio.2011.11.003.CrossRefPubMed Harutyunyan M, Christiansen M, Johansen JS, Kober L, Torp-Petersen C, Kastrup J. The inflammatory biomarker YKL-40 as a new prognostic marker for all-cause mortality in patients with heart failure. Immunobiology. 2012;217(6):652–6. doi:10.1016/j.imbio.2011.11.003.CrossRefPubMed
25.
go back to reference Kastrup J, Johansen JS, Winkel P, Hansen JF, Hildebrandt P, Jensen GB, et al. High serum YKL-40 concentration is associated with cardiovascular and all-cause mortality in patients with stable coronary artery disease. Eur Heart J. 2009;30(9):1066–72. doi:10.1093/eurheartj/ehp049.CrossRefPubMed Kastrup J, Johansen JS, Winkel P, Hansen JF, Hildebrandt P, Jensen GB, et al. High serum YKL-40 concentration is associated with cardiovascular and all-cause mortality in patients with stable coronary artery disease. Eur Heart J. 2009;30(9):1066–72. doi:10.1093/eurheartj/ehp049.CrossRefPubMed
26.
go back to reference Rathcke CN, Kistorp C, Raymond I, Hildebrandt P, Gustafsson F, Lip GY, et al. Plasma YKL-40 levels are elevated in patients with chronic heart failure. Scandinavian Cardiovasc J. 2010;44(2):92–9. doi:10.3109/14017430903402218.CrossRef Rathcke CN, Kistorp C, Raymond I, Hildebrandt P, Gustafsson F, Lip GY, et al. Plasma YKL-40 levels are elevated in patients with chronic heart failure. Scandinavian Cardiovasc J. 2010;44(2):92–9. doi:10.3109/14017430903402218.CrossRef
27.
go back to reference Dehn H, Hogdall EV, Johansen JS, Jorgensen M, Price PA, Engelholm SA, et al. Plasma YKL-40, as a prognostic tumor marker in recurrent ovarian cancer. Acta Obstet Gynecol Scand. 2003;82(3):287–93.CrossRefPubMed Dehn H, Hogdall EV, Johansen JS, Jorgensen M, Price PA, Engelholm SA, et al. Plasma YKL-40, as a prognostic tumor marker in recurrent ovarian cancer. Acta Obstet Gynecol Scand. 2003;82(3):287–93.CrossRefPubMed
28.
go back to reference Kazakova M, Batalov A, Deneva T, Mateva N, Kolarov Z, Sarafian V. Relationship between sonographic parameters and YKL-40 levels in rheumatoid arthritis. Rheumatol Int. 2013;33(2):341–6. doi:10.1007/s00296-012-2387-3.CrossRefPubMed Kazakova M, Batalov A, Deneva T, Mateva N, Kolarov Z, Sarafian V. Relationship between sonographic parameters and YKL-40 levels in rheumatoid arthritis. Rheumatol Int. 2013;33(2):341–6. doi:10.1007/s00296-012-2387-3.CrossRefPubMed
29.
go back to reference Johansen JS, Schultz NA, Jensen BV. Plasma YKL-40: a potential new cancer biomarker? Future oncology (London, England). 2009;5(7):1065–82. doi: 10.2217/fon.09.66. Johansen JS, Schultz NA, Jensen BV. Plasma YKL-40: a potential new cancer biomarker? Future oncology (London, England). 2009;5(7):1065–82. doi: 10.2217/fon.09.66.
30.
go back to reference Rehli M, Krause SW, Andreesen R. Molecular characterization of the gene for human cartilage gp-39 (CHI3L1), a member of the chitinase protein family and marker for late stages of macrophage differentiation. Genomics. 1997;43(2):221–5. doi:10.1006/geno.1997.4778.CrossRefPubMed Rehli M, Krause SW, Andreesen R. Molecular characterization of the gene for human cartilage gp-39 (CHI3L1), a member of the chitinase protein family and marker for late stages of macrophage differentiation. Genomics. 1997;43(2):221–5. doi:10.1006/geno.1997.4778.CrossRefPubMed
31.
go back to reference Brochner CB, Johansen JS, Larsen LA, Bak M, Mikkelsen HB, Byskov AG, et al. YKL-40 is differentially expressed in human embryonic stem cells and in cell progeny of the three germ layers. J Histochem Cytochem. 2012;60(3):188–204. doi:10.1369/0022155411433331.CrossRefPubMedCentralPubMed Brochner CB, Johansen JS, Larsen LA, Bak M, Mikkelsen HB, Byskov AG, et al. YKL-40 is differentially expressed in human embryonic stem cells and in cell progeny of the three germ layers. J Histochem Cytochem. 2012;60(3):188–204. doi:10.1369/0022155411433331.CrossRefPubMedCentralPubMed
32.
go back to reference Lee CG, Da Silva CA, Dela Cruz CS, Ahangari F, Ma B, Kang MJ, et al. Role of chitin and chitinase/chitinase-like proteins in inflammation, tissue remodeling, and injury. Annu Rev Physiol. 2011;73:479–501. doi:10.1146/annurev-physiol-012110-142250.CrossRefPubMed Lee CG, Da Silva CA, Dela Cruz CS, Ahangari F, Ma B, Kang MJ, et al. Role of chitin and chitinase/chitinase-like proteins in inflammation, tissue remodeling, and injury. Annu Rev Physiol. 2011;73:479–501. doi:10.1146/annurev-physiol-012110-142250.CrossRefPubMed
33.
go back to reference Kawada M, Seno H, Kanda K, Nakanishi Y, Akitake R, Komekado H, et al. Chitinase 3-like 1 promotes macrophage recruitment and angiogenesis in colorectal cancer. Oncogene. 2012;31(26):3111–23. doi:10.1038/onc.2011.498.CrossRefPubMedCentralPubMed Kawada M, Seno H, Kanda K, Nakanishi Y, Akitake R, Komekado H, et al. Chitinase 3-like 1 promotes macrophage recruitment and angiogenesis in colorectal cancer. Oncogene. 2012;31(26):3111–23. doi:10.1038/onc.2011.498.CrossRefPubMedCentralPubMed
34.
go back to reference Lee CG, Hartl D, Lee GR, Koller B, Matsuura H, Da Silva CA, et al. Role of breast regression protein 39 (BRP-39)/chitinase 3-like-1 in Th2 and IL-13-induced tissue responses and apoptosis. J Experimental Med. 2009;206(5):1149–66. doi:10.1084/jem.20081271.CrossRef Lee CG, Hartl D, Lee GR, Koller B, Matsuura H, Da Silva CA, et al. Role of breast regression protein 39 (BRP-39)/chitinase 3-like-1 in Th2 and IL-13-induced tissue responses and apoptosis. J Experimental Med. 2009;206(5):1149–66. doi:10.1084/jem.20081271.CrossRef
35.
go back to reference Tang H, Sun Y, Shi Z, Huang H, Fang Z, Chen J et al. YKL-40 induces IL-8 expression from bronchial epithelium via MAPK (JNK and ERK) and NF-kappaB pathways, causing bronchial smooth muscle proliferation and migration. J Immunol (Baltimore, MD: 1950). 2013;190(1):438–46. doi: 10.4049/jimmunol.1201827. Tang H, Sun Y, Shi Z, Huang H, Fang Z, Chen J et al. YKL-40 induces IL-8 expression from bronchial epithelium via MAPK (JNK and ERK) and NF-kappaB pathways, causing bronchial smooth muscle proliferation and migration. J Immunol (Baltimore, MD: 1950). 2013;190(1):438–46. doi: 10.4049/jimmunol.1201827.
36.
go back to reference Matsuura H, Hartl D, Kang MJ, Dela Cruz CS, Koller B, Chupp GL, et al. Role of breast regression protein-39 in the pathogenesis of cigarette smoke-induced inflammation and emphysema. Am J Respir Cell Mol Biol. 2011;44(6):777–86. doi:10.1165/rcmb.2010-0081OC.CrossRefPubMedCentralPubMed Matsuura H, Hartl D, Kang MJ, Dela Cruz CS, Koller B, Chupp GL, et al. Role of breast regression protein-39 in the pathogenesis of cigarette smoke-induced inflammation and emphysema. Am J Respir Cell Mol Biol. 2011;44(6):777–86. doi:10.1165/rcmb.2010-0081OC.CrossRefPubMedCentralPubMed
37.
go back to reference He CH, Lee CG, Dela Cruz CS, Lee CM, Zhou Y, Ahangari F, et al. Chitinase 3-like 1 regulates cellular and tissue responses via IL-13 receptor alpha2. Cell Reports. 2013;4(4):830–41. doi:10.1016/j.celrep.2013.07.032.CrossRefPubMedCentralPubMed He CH, Lee CG, Dela Cruz CS, Lee CM, Zhou Y, Ahangari F, et al. Chitinase 3-like 1 regulates cellular and tissue responses via IL-13 receptor alpha2. Cell Reports. 2013;4(4):830–41. doi:10.1016/j.celrep.2013.07.032.CrossRefPubMedCentralPubMed
38.
go back to reference Korthagen NM, van Moorsel CH, Barlo NP, Ruven HJ, Kruit A, Heron M, et al. Serum and BALF YKL-40 levels are predictors of survival in idiopathic pulmonary fibrosis. Respir Med. 2011;105(1):106–13. doi:10.1016/j.rmed.2010.09.012.CrossRefPubMed Korthagen NM, van Moorsel CH, Barlo NP, Ruven HJ, Kruit A, Heron M, et al. Serum and BALF YKL-40 levels are predictors of survival in idiopathic pulmonary fibrosis. Respir Med. 2011;105(1):106–13. doi:10.1016/j.rmed.2010.09.012.CrossRefPubMed
39.
go back to reference Letuve S, Kozhich A, Arouche N, Grandsaigne M, Reed J, Dombret MC, et al. YKL-40 is elevated in patients with chronic obstructive pulmonary disease and activates alveolar macrophages. J Immunol (Baltimore, Md. 2008;181(7):5167–73.CrossRef Letuve S, Kozhich A, Arouche N, Grandsaigne M, Reed J, Dombret MC, et al. YKL-40 is elevated in patients with chronic obstructive pulmonary disease and activates alveolar macrophages. J Immunol (Baltimore, Md. 2008;181(7):5167–73.CrossRef
40.
go back to reference Chupp GL, Lee CG, Jarjour N, Shim YM, Holm CT, He S, et al. A chitinase-like protein in the lung and circulation of patients with severe asthma. N Engl J Med. 2007;357(20):2016–27. doi:10.1056/NEJMoa073600.CrossRefPubMed Chupp GL, Lee CG, Jarjour N, Shim YM, Holm CT, He S, et al. A chitinase-like protein in the lung and circulation of patients with severe asthma. N Engl J Med. 2007;357(20):2016–27. doi:10.1056/NEJMoa073600.CrossRefPubMed
41.
go back to reference Holmgaard DB, Mygind LH, Titlestad IL, Madsen H, Pedersen SS, Johansen JS, et al. Plasma YKL-40 and all-cause mortality in patients with chronic obstructive pulmonary disease. BMC Pulmonary Med. 2013;13(1):77. doi:10.1186/1471-2466-13-77.CrossRef Holmgaard DB, Mygind LH, Titlestad IL, Madsen H, Pedersen SS, Johansen JS, et al. Plasma YKL-40 and all-cause mortality in patients with chronic obstructive pulmonary disease. BMC Pulmonary Med. 2013;13(1):77. doi:10.1186/1471-2466-13-77.CrossRef
42.
go back to reference Bojesen SE, Johansen JS, Nordestgaard BG. Plasma YKL-40 levels in healthy subjects from the general population. Clin Chim Acta. 2011;412(9–10):709–12. doi:10.1016/j.cca.2011.01.022. Bojesen SE, Johansen JS, Nordestgaard BG. Plasma YKL-40 levels in healthy subjects from the general population. Clin Chim Acta. 2011;412(9–10):709–12. doi:10.1016/j.cca.2011.01.022.
43.
go back to reference Babyak MA. What you see may not be what you get: a brief, nontechnical introduction to overfitting in regression-type models. Psychosom Med. 2004;66(3):411–21.PubMed Babyak MA. What you see may not be what you get: a brief, nontechnical introduction to overfitting in regression-type models. Psychosom Med. 2004;66(3):411–21.PubMed
44.
go back to reference Oudijk EJ, Nijhuis EH, Zwank MD, van de Graaf EA, Mager HJ, Coffer PJ, et al. Systemic inflammation in COPD visualised by gene profiling in peripheral blood neutrophils. Thorax. 2005;60(7):538–44. doi:10.1136/thx.2004.034009.CrossRefPubMedCentralPubMed Oudijk EJ, Nijhuis EH, Zwank MD, van de Graaf EA, Mager HJ, Coffer PJ, et al. Systemic inflammation in COPD visualised by gene profiling in peripheral blood neutrophils. Thorax. 2005;60(7):538–44. doi:10.1136/thx.2004.034009.CrossRefPubMedCentralPubMed
45.
go back to reference Yu DT, Clements PJ, Paulus HE, Peter JB, Levy J, Barnett EV. Human lymphocyte subpopulations. Effect of corticosteroids. J Clinical Invest. 1974;53(2):565–71. doi:10.1172/jci107591.CrossRef Yu DT, Clements PJ, Paulus HE, Peter JB, Levy J, Barnett EV. Human lymphocyte subpopulations. Effect of corticosteroids. J Clinical Invest. 1974;53(2):565–71. doi:10.1172/jci107591.CrossRef
46.
go back to reference Mishler JM, Emerson PM. Development of Neutrophilia by serially increasing doses of dexamethasone. Br J Haematol. 1977;36(2):249–57.CrossRefPubMed Mishler JM, Emerson PM. Development of Neutrophilia by serially increasing doses of dexamethasone. Br J Haematol. 1977;36(2):249–57.CrossRefPubMed
47.
go back to reference Vestbo J, Rennard S. Chronic obstructive pulmonary disease biomarker(s) for disease activity needed–urgently. Am J Respir Crit Care Med. 2010;182(7):863–4. doi:10.1164/rccm.201004-0602ED.CrossRefPubMed Vestbo J, Rennard S. Chronic obstructive pulmonary disease biomarker(s) for disease activity needed–urgently. Am J Respir Crit Care Med. 2010;182(7):863–4. doi:10.1164/rccm.201004-0602ED.CrossRefPubMed
48.
go back to reference de Torres JP, Pinto-Plata V, Casanova C, Mullerova H, Cordoba-Lanus E, Muros de Fuentes M, et al. C-reactive protein levels and survival in patients with moderate to very severe COPD. Chest. 2008;133(6):1336–43. doi:10.1378/chest.07-2433.CrossRefPubMed de Torres JP, Pinto-Plata V, Casanova C, Mullerova H, Cordoba-Lanus E, Muros de Fuentes M, et al. C-reactive protein levels and survival in patients with moderate to very severe COPD. Chest. 2008;133(6):1336–43. doi:10.1378/chest.07-2433.CrossRefPubMed
49.
go back to reference Moberg M, Vestbo J, Martinez G, Lange P, Ringbaek T. Prognostic value of C-reactive protein, leukocytes, and vitamin d in severe chronic obstructive pulmonary disease. TheScientificWorldJOURNAL. 2014;2014:140736. doi:10.1155/2014/140736.CrossRefPubMedCentralPubMed Moberg M, Vestbo J, Martinez G, Lange P, Ringbaek T. Prognostic value of C-reactive protein, leukocytes, and vitamin d in severe chronic obstructive pulmonary disease. TheScientificWorldJOURNAL. 2014;2014:140736. doi:10.1155/2014/140736.CrossRefPubMedCentralPubMed
50.
go back to reference Dickens JA, Miller BE, Edwards LD, Silverman EK, Lomas DA, Tal-Singer R. COPD association and repeatability of blood biomarkers in the ECLIPSE cohort. Respir Res. 2011;12:146. doi:10.1186/1465-9921-12-146.CrossRefPubMedCentralPubMed Dickens JA, Miller BE, Edwards LD, Silverman EK, Lomas DA, Tal-Singer R. COPD association and repeatability of blood biomarkers in the ECLIPSE cohort. Respir Res. 2011;12:146. doi:10.1186/1465-9921-12-146.CrossRefPubMedCentralPubMed
51.
go back to reference Le Tulzo Y, Pangault C, Gacouin A, Guilloux V, Tribut O, Amiot L, et al. Early circulating lymphocyte apoptosis in human septic shock is associated with poor outcome. Shock (Augusta, Ga). 2002;18(6):487–94.CrossRef Le Tulzo Y, Pangault C, Gacouin A, Guilloux V, Tribut O, Amiot L, et al. Early circulating lymphocyte apoptosis in human septic shock is associated with poor outcome. Shock (Augusta, Ga). 2002;18(6):487–94.CrossRef
52.
go back to reference de Jager CP, van Wijk PT, Mathoera RB, de Jongh-Leuvenink J, van der Poll T, Wever PC. Lymphocytopenia and neutrophil-lymphocyte count ratio predict bacteremia better than conventional infection markers in an emergency care unit. Crit Care. 2010;14(5):R192. doi:10.1186/cc9309.CrossRefPubMedCentralPubMed de Jager CP, van Wijk PT, Mathoera RB, de Jongh-Leuvenink J, van der Poll T, Wever PC. Lymphocytopenia and neutrophil-lymphocyte count ratio predict bacteremia better than conventional infection markers in an emergency care unit. Crit Care. 2010;14(5):R192. doi:10.1186/cc9309.CrossRefPubMedCentralPubMed
53.
go back to reference Heffernan DS, Monaghan SF, Thakkar RK, Machan JT, Cioffi WG, Ayala A. Failure to normalize lymphopenia following trauma is associated with increased mortality, independent of the leukocytosis pattern. Crit Care. 2012;16(1):R12. doi:10.1186/cc11157.CrossRefPubMedCentralPubMed Heffernan DS, Monaghan SF, Thakkar RK, Machan JT, Cioffi WG, Ayala A. Failure to normalize lymphopenia following trauma is associated with increased mortality, independent of the leukocytosis pattern. Crit Care. 2012;16(1):R12. doi:10.1186/cc11157.CrossRefPubMedCentralPubMed
54.
go back to reference Bhat T, Teli S, Rijal J, Bhat H, Raza M, Khoueiry G, et al. Neutrophil to lymphocyte ratio and cardiovascular diseases: a review. Expert Rev Cardiovasc Ther. 2013;11(1):55–9. doi:10.1586/erc.12.159.CrossRefPubMed Bhat T, Teli S, Rijal J, Bhat H, Raza M, Khoueiry G, et al. Neutrophil to lymphocyte ratio and cardiovascular diseases: a review. Expert Rev Cardiovasc Ther. 2013;11(1):55–9. doi:10.1586/erc.12.159.CrossRefPubMed
55.
go back to reference Ray-Coquard I, Cropet C, Van Glabbeke M, Sebban C, Le Cesne A, Judson I, et al. Lymphopenia as a prognostic factor for overall survival in advanced carcinomas, sarcomas, and lymphomas. Cancer Res. 2009;69(13):5383–91. doi:10.1158/0008-5472.can-08-3845.CrossRefPubMedCentralPubMed Ray-Coquard I, Cropet C, Van Glabbeke M, Sebban C, Le Cesne A, Judson I, et al. Lymphopenia as a prognostic factor for overall survival in advanced carcinomas, sarcomas, and lymphomas. Cancer Res. 2009;69(13):5383–91. doi:10.1158/0008-5472.can-08-3845.CrossRefPubMedCentralPubMed
56.
go back to reference Heimann TM, Bolnick K, Aufses Jr AH. Prognostic significance of severe preoperative lymphopenia in patients with Crohn’s disease. Ann Surg. 1986;203(2):132–5.CrossRefPubMedCentralPubMed Heimann TM, Bolnick K, Aufses Jr AH. Prognostic significance of severe preoperative lymphopenia in patients with Crohn’s disease. Ann Surg. 1986;203(2):132–5.CrossRefPubMedCentralPubMed
57.
go back to reference Ayala A, Herdon CD, Lehman DL, Ayala CA, Chaudry IH. Differential induction of apoptosis in lymphoid tissues during sepsis: variation in onset, frequency, and the nature of the mediators. Blood. 1996;87(10):4261–75.PubMed Ayala A, Herdon CD, Lehman DL, Ayala CA, Chaudry IH. Differential induction of apoptosis in lymphoid tissues during sepsis: variation in onset, frequency, and the nature of the mediators. Blood. 1996;87(10):4261–75.PubMed
58.
go back to reference Hotchkiss RS, Swanson PE, Freeman BD, Tinsley KW, Cobb JP, Matuschak GM, et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med. 1999;27(7):1230–51.CrossRefPubMed Hotchkiss RS, Swanson PE, Freeman BD, Tinsley KW, Cobb JP, Matuschak GM, et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med. 1999;27(7):1230–51.CrossRefPubMed
59.
go back to reference McNerlan SE, Alexander HD, Rea IM. Age-related reference intervals for lymphocyte subsets in whole blood of healthy individuals. Scand J Clin Lab Invest. 1999;59(2):89–92.CrossRefPubMed McNerlan SE, Alexander HD, Rea IM. Age-related reference intervals for lymphocyte subsets in whole blood of healthy individuals. Scand J Clin Lab Invest. 1999;59(2):89–92.CrossRefPubMed
60.
go back to reference Fraker PJ, Lill-Elghanian DA. The many roles of apoptosis in immunity as modified by aging and nutritional status. J Nutrition, Health Aging. 2004;8(1):56–63. Fraker PJ, Lill-Elghanian DA. The many roles of apoptosis in immunity as modified by aging and nutritional status. J Nutrition, Health Aging. 2004;8(1):56–63.
61.
go back to reference Landbo C, Prescott E, Lange P, Vestbo J, Almdal TP. Prognostic value of nutritional status in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999;160(6):1856–61. doi:10.1164/ajrccm.160.6.9902115.CrossRefPubMed Landbo C, Prescott E, Lange P, Vestbo J, Almdal TP. Prognostic value of nutritional status in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999;160(6):1856–61. doi:10.1164/ajrccm.160.6.9902115.CrossRefPubMed
62.
go back to reference Gebhardt C, Breitenbach U, Tuckermann JP, Dittrich BT, Richter KH, Angel P. Calgranulins S100A8 and S100A9 are negatively regulated by glucocorticoids in a c-Fos-dependent manner and overexpressed throughout skin carcinogenesis. Oncogene. 2002;21(27):4266–76. doi:10.1038/sj.onc.1205521.CrossRefPubMed Gebhardt C, Breitenbach U, Tuckermann JP, Dittrich BT, Richter KH, Angel P. Calgranulins S100A8 and S100A9 are negatively regulated by glucocorticoids in a c-Fos-dependent manner and overexpressed throughout skin carcinogenesis. Oncogene. 2002;21(27):4266–76. doi:10.1038/sj.onc.1205521.CrossRefPubMed
63.
go back to reference Johansen JS, Stoltenberg M, Hansen M, Florescu A, Horslev-Petersen K, Lorenzen I, et al. Serum YKL-40 concentrations in patients with rheumatoid arthritis: relation to disease activity. Rheumatol (Oxford, England). 1999;38(7):618–26.CrossRef Johansen JS, Stoltenberg M, Hansen M, Florescu A, Horslev-Petersen K, Lorenzen I, et al. Serum YKL-40 concentrations in patients with rheumatoid arthritis: relation to disease activity. Rheumatol (Oxford, England). 1999;38(7):618–26.CrossRef
64.
go back to reference Shao R, Francescone R, Ngernyuang N, Bentley B, Taylor SL, Moral L, et al. Anti-YKL-40 antibody and ionizing irradiation synergistically inhibit tumor vascularization and malignancy in glioblastoma. Carcinogenesis. 2014;35(2):373–82. doi:10.1093/carcin/bgt380.CrossRefPubMedCentralPubMed Shao R, Francescone R, Ngernyuang N, Bentley B, Taylor SL, Moral L, et al. Anti-YKL-40 antibody and ionizing irradiation synergistically inhibit tumor vascularization and malignancy in glioblastoma. Carcinogenesis. 2014;35(2):373–82. doi:10.1093/carcin/bgt380.CrossRefPubMedCentralPubMed
65.
go back to reference Man SF, 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(10):849–53. doi:10.1136/thx.2006.059808.CrossRefPubMedCentralPubMed Man SF, 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(10):849–53. doi:10.1136/thx.2006.059808.CrossRefPubMedCentralPubMed
66.
go back to reference 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(3):250–5. doi:10.1164/rccm.200605-713OC.CrossRefPubMed 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(3):250–5. doi:10.1164/rccm.200605-713OC.CrossRefPubMed
67.
go back to reference Peduzzi P, Concato J, Feinstein AR, Holford TR. Importance of events per independent variable in proportional hazards regression analysis, II. Accuracy and precision of regression estimates. J Clin Epidemiol. 1995;48(12):1503–10.CrossRefPubMed Peduzzi P, Concato J, Feinstein AR, Holford TR. Importance of events per independent variable in proportional hazards regression analysis, II. Accuracy and precision of regression estimates. J Clin Epidemiol. 1995;48(12):1503–10.CrossRefPubMed
Metadata
Title
Neutrophil-to-lymphocyte ratio, calprotectin and YKL-40 in patients with chronic obstructive pulmonary disease: correlations and 5-year mortality – a cohort study
Authors
Allan Klitgaard Sørensen
Dennis Back Holmgaard
Lone Hagens Mygind
Julia Johansen
Court Pedersen
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Inflammation / Issue 1/2015
Electronic ISSN: 1476-9255
DOI
https://doi.org/10.1186/s12950-015-0064-5

Other articles of this Issue 1/2015

Journal of Inflammation 1/2015 Go to the issue