Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Respiratory Research
Published in: Respiratory Research 1/2017

Open Access 01-12-2017 | Research

The value of blood cytokines and chemokines in assessing COPD

Authors: Eric Bradford, Sean Jacobson, Jason Varasteh, Alejandro P. Comellas, Prescott Woodruff, Wanda O’Neal, Dawn L. DeMeo, Xingnan Li, Victor Kim, Michael Cho, Peter J. Castaldi, Craig Hersh, Edwin K. Silverman, James D. Crapo, Katerina Kechris, Russell P. Bowler

Published in: Respiratory Research | Issue 1/2017

Login to get access

Abstract

Background

Blood biomarkers are increasingly used to stratify high risk chronic obstructive pulmonary disease (COPD) patients; however, there are fewer studies that have investigated multiple biomarkers and replicated in multiple large well-characterized cohorts of susceptible current and former smokers.

Methods

We used two MSD multiplex panels to measure 9 cytokines and chemokines in 2123 subjects from COPDGene and 1117 subjects from SPIROMICS. These biomarkers included: interleukin (IL)-2, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, eotaxin/CCL-11, eotaxin-3/CCL-26, and thymus and activation-regulated chemokine (TARC)/CCL-17. Regression models adjusted for clinical covariates were used to determine which biomarkers were associated with the following COPD phenotypes: airflow obstruction (forced expiratory flow at 1 s (FEV1%) and FEV1/forced vital capacity (FEV1/FVC), chronic bronchitis, COPD exacerbations, and emphysema. Biomarker-genotype associations were assessed by genome-wide association of single nucleotide polymorphisms (SNPs).

Results

Eotaxin and IL-6 were strongly associated with airflow obstruction and accounted for 3–5% of the measurement variance on top of clinical variables. IL-6 was associated with progressive airflow obstruction over 5 years and both IL-6 and IL-8 were associated with progressive emphysema over 5 years. None of the biomarkers were consistently associated with chronic bronchitis or COPD exacerbations. We identified one novel SNP (rs9302690 SNP) that was associated with CCL17 plasma measurements.

Conclusion

When assessing smoking related pulmonary disease, biomarkers of inflammation such as IL-2, IL-6, IL-8, and eotaxin may add additional modest predictive value on top of clinical variables alone.

Trial registration

COPDGene (ClinicalTrials.gov Identifier: NCT02445183).
Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS) (ClinicalTrials.​gov Identifier: NCT 01969344).
Appendix
Available only for authorised users
Literature
1.
United States. Public Health Service. Office Of The Surgeon General. The health consequences of smoking--50 years of progress : a report of the surgeon general. Rockville: U.S. Department Of Health And Human Services, Public Health Service, Office Of The Surgeon General; 2014.
2.
Vestbo J, Agusti A, Wouters E, et al. Should we view chronic obstructive pulmonary disease differently after Eclipse? A clinical perspective from the study team. Am J Respir Crit Care Med. 2014;189(9):1022–30.CrossRefPubMed
3.
4.
Faner R, Tal-Singer R, Riley JH, et al. Lessons from Eclipse: a review of COPD biomarkers. Thorax. 2014;69(7):666–72.CrossRefPubMed
5.
Agusti A, Gea J, Faner R. Biomarkers, the control panel and personalized COPD medicine. Respirology. 2016;21(1):24–33.CrossRefPubMed
6.
Dahl M, Tybjaerg-Hansen A, Vestbo J, Lange P, Nordestgaard BG. Elevated plasma fibrinogen associated with reduced pulmonary function and increased risk of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;164(6):1008–11.CrossRefPubMed
7.
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.CrossRefPubMed
8.
De Torres JP, Cordoba-Lanus E, Lopez-Aguilar C, et al. C-reactive protein levels and clinically important predictive outcomes in stable COPD patients. Eur Respir J. 2006;27(5):902–7.CrossRefPubMed
9.
Agusti A, Edwards LD, Rennard SI, et al. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS One. 2012;7(5):E37483.CrossRefPubMedPubMedCentral
10.
Celli BR, Locantore N, Yates J, 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.CrossRefPubMed
11.
Papaioannou AI, Mazioti A, Kiropoulos T, et al. Systemic and airway inflammation and the presence of emphysema in patients with COPD. Respir Med. 2010;104(2):275–82.CrossRefPubMed
12.
Duvoix A, Dickens J, Haq I, et al. Blood fibrinogen as a biomarker of chronic obstructive pulmonary disease. Thorax. 2013;68(7):670–6.CrossRefPubMed
13.
Mannino DM, Valvi D, Mullerova H, Tal-Singer R. Fibrinogen, COPD and mortality in a nationally representative U.S. cohort. COPD. 2012;9(4):359–66.CrossRefPubMed
14.
Vestbo J, Edwards LD, Scanlon PD, et al. Changes in forced expiratory volume in 1 second over time in COPD. N Engl J Med. 2011;365(13):1184–92.CrossRefPubMed
15.
Wedzicha JA, Seemungal TA, Maccallum PK, et al. Acute exacerbations of chronic obstructive pulmonary disease are accompanied by elevations of plasma fibrinogen and serum Il-6 levels. Thromb Haemost. 2000;84(2):210–5.PubMed
16.
Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363(12):1128–38.CrossRefPubMed
17.
Thomsen M, Ingebrigtsen TS, Marott JL, et al. Inflammatory biomarkers and exacerbations in chronic obstructive pulmonary disease. JAMA. 2013;309(22):2353–61.CrossRefPubMed
18.
Eagan TM, Ueland T, Wagner PD, et al. Systemic inflammatory markers in COPD: results from the Bergen COPD cohort study. Eur Respir J. 2010;35(3):540–8.CrossRefPubMed
19.
Fogarty AW, Jones S, Britton JR, Lewis SA, Mckeever TM. Systemic inflammation and decline in lung function in a general population: a prospective study. Thorax. 2007;62(6):515–20.CrossRefPubMedPubMedCentral
20.
Engstrom G, Segelstorm N, Ekberg-Aronsson M, Nilsson PM, Lindgarde F, Lofdahl CG. Plasma markers of inflammation and incidence of Hospitalisations for COPD: results from a population-based cohort study. Thorax. 2009;64(3):211–5.CrossRefPubMed
21.
Mannino DM, Tal-Singer R, Lomas DA, et al. Plasma fibrinogen as a biomarker for mortality and hospitalized exacerbations in people with COPD. Chronic Obstr Pulm Dis (Miami). 2015;2(1):23–34.CrossRef
22.
Cockayne DA, Cheng DT, Waschki B, et al. Systemic biomarkers of neutrophilic inflammation, tissue injury and repair in COPD patients with differing levels of disease severity. PLoS One. 2012;7(6):E38629.CrossRefPubMedPubMedCentral
23.
Cheng DT, Kim DK, Cockayne DA, et al. Systemic soluble receptor for advanced Glycation Endproducts is a biomarker of emphysema and associated with ager genetic variants in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2013;188(8):948–57.CrossRefPubMed
24.
Carolan BJ, Hughes G, Morrow J, et al. The association of plasma biomarkers with computed tomography-assessed emphysema phenotypes. Respir Res. 2014;15:127.CrossRefPubMedPubMedCentral
25.
Coxson HO, Dirksen A, Edwards LD, et al. The presence and progression of emphysema in COPD as determined by ct scanning and biomarker expression: a prospective analysis from the Eclipse study. Lancet Respir Med. 2013;1(2):129–36.CrossRefPubMed
26.
Smith DJ, Yerkovich ST, Towers MA, Carroll ML, Thomas R, Upham JW. Reduced soluble receptor for advanced glycation end-products in COPD. Eur Respir J. 2011;37(3):516–22.CrossRefPubMed
27.
Kobayashi H, Kanoh S, Motoyoshi K. Serum surfactant protein-A, but not surfactant protein-D or KL-6, can predict preclinical lung damage induced by smoking. Biomarkers. 2008;13(4):385–92.CrossRefPubMed
28.
Winkler C, Atochina-Vasserman EN, Holz O, et al. Comprehensive characterisation of pulmonary and serum surfactant protein D in COPD. Respir Res. 2011;12:29.CrossRefPubMedPubMedCentral
29.
Lomas DA, Silverman EK, Edwards LD, et al. Serum surfactant protein D is steroid sensitive and associated with exacerbations of COPD. Eur Respir J. 2009;34(1):95–102.CrossRefPubMed
30.
Lomas DA, Silverman EK, Edwards LD, Miller BE, Coxson HO, Tal-Singer R. Evaluation of serum Cc-16 as a biomarker for COPD in the Eclipse cohort. Thorax. 2008;63(12):1058–63.CrossRefPubMed
31.
32.
Couper D, Lavange LM, Han M, et al. Design of the subpopulations and intermediate outcomes in COPD study (Spiromics). Thorax. 2014;69(5):491–4.CrossRefPubMed
33.
Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS, Committee GS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Nhlbi/who global initiative for chronic obstructive lung disease (GOLD) workshop summary. Am J Respir Crit Care Med. 2001;163(5):1256–76.CrossRefPubMed
34.
35.
Celli BR, Cote CG, Marin JM, 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.CrossRefPubMed
36.
Puhan MA, Garcia-Aymerich J, Frey M, et al. Expansion of the prognostic assessment of patients with chronic obstructive pulmonary disease: the updated Bode index and the ado index. Lancet. 2009;374(9691):704–11.CrossRefPubMed
37.
Mcfadden D. Conditional logit analysis of qualitative choice behavior. In: Zarembka P, Ed. Frontiers in econometrics. Cambridge: Elsevier; 1974:105-142.
38.
39.
Nakagawa S, Schielzeth H. A general and simple method for obtaining R2 from generalized linear mixed-effects models. Methods Ecol Evol. 2013;4(2):133–42.CrossRef
40.
Han MK, Agusti A, Calverley PM, et al. Chronic obstructive pulmonary disease phenotypes: the future of COPD. Am J Respir Crit Care Med. 2010;182(5):598–604.CrossRefPubMed
41.
Lilly CM, Woodruff PG, Camargo CA Jr, et al. Elevated plasma eotaxin levels in patients with acute asthma. J Allergy Clin Immunol. 1999;104(4 Pt 1):786–90.CrossRefPubMed
42.
Adar T, Shteingart S, Ben Ya'acov A, Bar-Gil Shitrit A, Goldin E. From airway inflammation to inflammatory bowel disease: eotaxin-1, a key regulator of intestinal inflammation. Clin Immunol. 2014;153(1):199–208.CrossRefPubMed
43.
Bocchino V, Bertorelli G, Bertrand CP, et al. Eotaxin and Ccr3 are up-regulated in exacerbations of chronic bronchitis. Allergy. 2002;57(1):17–22.PubMed
44.
45.
Bade G, Khan MA, Srivastava AK, et al. Serum cytokine profiling and enrichment analysis reveal the involvement of immunological and inflammatory pathways in stable patients with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2014;9:759–73.PubMedPubMedCentral
46.
Liu X, Jones GW, Choy EH, Jones SA. The biology behind Interleukin-6 targeted interventions. Curr Opin Rheumatol. 2016;28(2):152–60.CrossRefPubMed
47.
Luo Y, Zheng SG. Hall of fame among pro-inflammatory cytokines: interleukin-6 gene and its transcriptional regulation mechanisms. Front Immunol. 2016;7:604.CrossRefPubMedPubMedCentral
48.
Yende S, Waterer GW, Tolley EA, et al. Inflammatory markers are associated with ventilatory limitation and muscle dysfunction in obstructive lung disease in well functioning elderly subjects. Thorax. 2006;61(1):10–6.CrossRefPubMed
49.
Walter RE, Wilk JB, Larson MG, et al. Systemic inflammation and COPD: the Framingham Heart Study. Chest. 2008;133(1):19–25.CrossRefPubMed
50.
Van Durme YM, Lahousse L, Verhamme KM, et al. Mendelian randomization study of Interleukin-6 in chronic obstructive pulmonary disease. Respiration. 2011;82(6):530–8.CrossRefPubMed
51.
Wei J, Xiong XF, Lin YH, Zheng BX, Cheng DY. Association between serum interleukin-6 concentrations and chronic obstructive pulmonary disease: a systematic review and meta-analysis. PeerJ. 2015;3:E1199.CrossRefPubMedPubMedCentral
52.
Ruwanpura SM, Mcleod L, Miller A, et al. Interleukin-6 promotes pulmonary emphysema associated with apoptosis in mice. Am J Respir Cell Mol Biol. 2011;45(4):720–30.CrossRefPubMed
53.
Miller J, Edwards LD, Agusti A, et al. Comorbidity, systemic inflammation and outcomes in the eclipse cohort. Respir Med. 2013;107(9):1376–84.CrossRefPubMed
54.
Iyer KS, Newell JD Jr, Jin D, et al. Quantitative dual-energy computed tomography supports a vascular etiology of smoking-induced inflammatory lung disease. Am J Respir Crit Care Med. 2016;193(6):652–61.CrossRefPubMedPubMedCentral
55.
Wendling D, Vidon C, Godfrin-Valnet M, Rival G, Guillot X, Prati C. Exacerbation of combined pulmonary fibrosis and emphysema syndrome during Tocilizumab therapy for rheumatoid arthritis. Joint Bone Spine. 2013;80(6):670–1.CrossRefPubMed
56.
Knobloch J, Chikosi SJ, Yanik S, Rupp J, Jungck D, Koch A. A systemic defect in toll-liken 4 signaling increases lipopolysaccharide-induced suppression of Il-2-dependent T-cell proliferation in COPD. Am J Physiol Lung Cell Mol Physiol. 2016;310(1):L24–39.CrossRefPubMed
57.
Celik H, Akpinar S, Karabulut H, et al. Evaluation of Il-8 nasal lavage levels and the effects of nasal involvement on disease severity in patients with stable chronic obstructive pulmonary disease. Inflammation. 2015;38(2):616–22.CrossRefPubMed
58.
De-Torres JP, Blanco D, Alcaide AB, et al. Smokers with ct detected emphysema and no airway obstruction have decreased plasma levels of Egf, Il-15, Il-8 and Il-1ra. PLoS One. 2013;8(4):E60260.CrossRefPubMedPubMedCentral
59.
Zhang L, Cheng Z, Liu W, Wu K. Expression of interleukin (Il)-10, Il-17a and Il-22 in serum and sputum of stable chronic obstructive pulmonary disease patients. COPD. 2013;10(4):459–65.CrossRefPubMed
60.
Ying S, O’Connor B, Ratoff J, et al. Expression and cellular provenance of thymic stromal lymphopoietin and chemokines in patients with severe asthma and chronic obstructive pulmonary disease. J Immunol. 2008;181(4):2790–8.CrossRefPubMed
61.
Saeki H, Tamaki K. Thymus and activation regulated chemokine (Tarc)/Ccl17 and skin diseases. J Dermatol Sci. 2006;43(2):75–84.CrossRefPubMed
62.
Hnatkova M, Mocikova H, Trneny M, Zivny J. The biological environment of Hodgkin’s lymphoma and the role of the chemokine Ccl17/Tarc. Prague Med Rep. 2009;110(1):35–41.PubMed
Metadata
Title
The value of blood cytokines and chemokines in assessing COPD
Authors
Eric Bradford
Sean Jacobson
Jason Varasteh
Alejandro P. Comellas
Prescott Woodruff
Wanda O’Neal
Dawn L. DeMeo
Xingnan Li
Victor Kim
Michael Cho
Peter J. Castaldi
Craig Hersh
Edwin K. Silverman
James D. Crapo
Katerina Kechris
Russell P. Bowler
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2017
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-017-0662-2

Other articles of this Issue 1/2017

Respiratory Research 1/2017 Go to the issue

Research

The predictive value of respiratory function tests for non-invasive ventilation in amyotrophic lateral sclerosis

Research

Effect of a retinoid X receptor partial agonist on airway inflammation and hyperresponsiveness in a murine model of asthma

Research

MicroRNA-181c inhibits cigarette smoke–induced chronic obstructive pulmonary disease by regulating CCN1 expression

Research

Serum bilirubin and the risk of chronic obstructive pulmonary disease exacerbations

Research

Malondialdehyde-acetaldehyde (MAA) adducted surfactant protein induced lung inflammation is mediated through scavenger receptor a (SR-A1)

Review

The roles and regulation of the actin cytoskeleton, intermediate filaments and microtubules in smooth muscle cell migration

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits