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. 2004 Jul;59(7):574–580. doi: 10.1136/thx.2003.019588

Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis

W Gan 1, S Man 1, A Senthilselvan 1, D Sin 1
PMCID: PMC1747070  PMID: 15223864

Abstract

Background: Individuals with chronic obstructive pulmonary disease (COPD) are at increased risk of cardiovascular diseases, osteoporosis, and muscle wasting. Systemic inflammation may be involved in the pathogenesis of these disorders. A study was undertaken to determine whether systemic inflammation is present in stable COPD.

Methods: A systematic review was conducted of studies which reported on the relationship between COPD, forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC), and levels of various systemic inflammatory markers: C-reactive protein (CRP), fibrinogen, leucocytes, tumour necrosis factor-α (TNF-α), and interleukins 6 and 8. Where possible the results were pooled together to produce a summary estimate using a random or fixed effects model.

Results: Fourteen original studies were identified. Overall, the standardised mean difference in the CRP level between COPD and control subjects was 0.53 units (95% confidence interval (CI) 0.34 to 0.72). The standardised mean difference in the fibrinogen level was 0.47 units (95% CI 0.29 to 0.65). Circulating leucocytes were also higher in COPD than in control subjects (standardised mean difference 0.44 units (95% CI 0.20 to 0.67)), as were serum TNF-α levels (standardised mean difference 0.59 units (95% CI 0.29 to 0.89)).

Conclusions: Reduced lung function is associated with increased levels of systemic inflammatory markers which may have important pathophysiological and therapeutic implications for subjects with stable COPD.

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Selected References

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  1. Agustí A. G. N., Noguera A., Sauleda J., Sala E., Pons J., Busquets X. Systemic effects of chronic obstructive pulmonary disease. Eur Respir J. 2003 Feb;21(2):347–360. doi: 10.1183/09031936.03.00405703. [DOI] [PubMed] [Google Scholar]
  2. Alessandri C., Basili S., Violi F., Ferroni P., Gazzaniga P. P., Cordova C. Hypercoagulability state in patients with chronic obstructive pulmonary disease. Chronic Obstructive Bronchitis and Haemostasis Group. Thromb Haemost. 1994 Sep;72(3):343–346. [PubMed] [Google Scholar]
  3. Anthonisen N. R., Connett J. E., Kiley J. P., Altose M. D., Bailey W. C., Buist A. S., Conway W. A., Jr, Enright P. L., Kanner R. E., O'Hara P. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA. 1994 Nov 16;272(19):1497–1505. [PubMed] [Google Scholar]
  4. Barnes P. J. Chronic obstructive pulmonary disease. N Engl J Med. 2000 Jul 27;343(4):269–280. doi: 10.1056/NEJM200007273430407. [DOI] [PubMed] [Google Scholar]
  5. Barnes P. J., Shapiro S. D., Pauwels R. A. Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur Respir J. 2003 Oct;22(4):672–688. doi: 10.1183/09031936.03.00040703. [DOI] [PubMed] [Google Scholar]
  6. Biskobing Diane M. COPD and osteoporosis. Chest. 2002 Feb;121(2):609–620. doi: 10.1378/chest.121.2.609. [DOI] [PubMed] [Google Scholar]
  7. Bridges R. B., Wyatt R. J., Rehm S. R. Effects of smoking on inflammatory mediators and their relationship to pulmonary dysfunction. Eur J Respir Dis Suppl. 1986;146:145–152. [PubMed] [Google Scholar]
  8. Camilli A. E., Robbins D. R., Lebowitz M. D. Death certificate reporting of confirmed airways obstructive disease. Am J Epidemiol. 1991 Apr 15;133(8):795–800. doi: 10.1093/oxfordjournals.aje.a115958. [DOI] [PubMed] [Google Scholar]
  9. Curtin François, Altman Douglas G., Elbourne Diana. Meta-analysis combining parallel and cross-over clinical trials. I: Continuous outcomes. Stat Med. 2002 Aug 15;21(15):2131–2144. doi: 10.1002/sim.1205. [DOI] [PubMed] [Google Scholar]
  10. Dahl M., Tybjaerg-Hansen A., Vestbo J., Lange P., Nordestgaard B. G. Elevated plasma fibrinogen associated with reduced pulmonary function and increased risk of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001 Sep 15;164(6):1008–1011. doi: 10.1164/ajrccm.164.6.2010067. [DOI] [PubMed] [Google Scholar]
  11. Danesh J., Collins R., Appleby P., Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA. 1998 May 13;279(18):1477–1482. doi: 10.1001/jama.279.18.1477. [DOI] [PubMed] [Google Scholar]
  12. Dentener M. A., Creutzberg E. C., Schols A. M., Mantovani A., van't Veer C., Buurman W. A., Wouters E. F. Systemic anti-inflammatory mediators in COPD: increase in soluble interleukin 1 receptor II during treatment of exacerbations. Thorax. 2001 Sep;56(9):721–726. doi: 10.1136/thorax.56.9.721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. DerSimonian R., Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986 Sep;7(3):177–188. doi: 10.1016/0197-2456(86)90046-2. [DOI] [PubMed] [Google Scholar]
  14. Di Francia M., Barbier D., Mege J. L., Orehek J. Tumor necrosis factor-alpha levels and weight loss in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1994 Nov;150(5 Pt 1):1453–1455. doi: 10.1164/ajrccm.150.5.7952575. [DOI] [PubMed] [Google Scholar]
  15. Di Napoli M., Papa F., Bocola V. Prognostic influence of increased C-reactive protein and fibrinogen levels in ischemic stroke. Stroke. 2001 Jan;32(1):133–138. doi: 10.1161/01.str.32.1.133. [DOI] [PubMed] [Google Scholar]
  16. Eid A. A., Ionescu A. A., Nixon L. S., Lewis-Jenkins V., Matthews S. B., Griffiths T. L., Shale D. J. Inflammatory response and body composition in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001 Oct 15;164(8 Pt 1):1414–1418. doi: 10.1164/ajrccm.164.8.2008109. [DOI] [PubMed] [Google Scholar]
  17. Engström G., Lind P., Hedblad B., Wollmer P., Stavenow L., Janzon L., Lindgärde F. Lung function and cardiovascular risk: relationship with inflammation-sensitive plasma proteins. Circulation. 2002 Nov 12;106(20):2555–2560. doi: 10.1161/01.cir.0000037220.00065.0d. [DOI] [PubMed] [Google Scholar]
  18. Friedman G. D., Klatsky A. L., Siegelaub A. B. Lung function and risk of myocardial infarction and sudden cardiac death. N Engl J Med. 1976 May 13;294(20):1071–1075. doi: 10.1056/NEJM197605132942001. [DOI] [PubMed] [Google Scholar]
  19. Fujii Takeshi, Hayashi Shizu, Hogg James C., Mukae Hiroshi, Suwa Tatsushi, Goto Yukinobu, Vincent Renaud, van Eeden Stephan F. Interaction of alveolar macrophages and airway epithelial cells following exposure to particulate matter produces mediators that stimulate the bone marrow. Am J Respir Cell Mol Biol. 2002 Jul;27(1):34–41. doi: 10.1165/ajrcmb.27.1.4787. [DOI] [PubMed] [Google Scholar]
  20. Gabay C., Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999 Feb 11;340(6):448–454. doi: 10.1056/NEJM199902113400607. [DOI] [PubMed] [Google Scholar]
  21. Hansell A. L., Walk J. A., Soriano J. B. What do chronic obstructive pulmonary disease patients die from? A multiple cause coding analysis. Eur Respir J. 2003 Nov;22(5):809–814. doi: 10.1183/09031936.03.00031403. [DOI] [PubMed] [Google Scholar]
  22. Hole D. J., Watt G. C., Davey-Smith G., Hart C. L., Gillis C. R., Hawthorne V. M. Impaired lung function and mortality risk in men and women: findings from the Renfrew and Paisley prospective population study. BMJ. 1996 Sep 21;313(7059):711–716. doi: 10.1136/bmj.313.7059.711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. James A. L., Knuiman M. W., Divitini M. L., Musk A. W., Ryan G., Bartholomew H. C. Associations between white blood cell count, lung function, respiratory illness and mortality: the Busselton Health Study. Eur Respir J. 1999 May;13(5):1115–1119. doi: 10.1034/j.1399-3003.1999.13e29.x. [DOI] [PubMed] [Google Scholar]
  24. Jousilahti P., Salomaa V., Rasi V., Vahtera E. Symptoms of chronic bronchitis, haemostatic factors, and coronary heart disease risk. Atherosclerosis. 1999 Feb;142(2):403–407. doi: 10.1016/s0021-9150(98)00248-2. [DOI] [PubMed] [Google Scholar]
  25. Kotler D. P. Cachexia. Ann Intern Med. 2000 Oct 17;133(8):622–634. doi: 10.7326/0003-4819-133-8-200010170-00015. [DOI] [PubMed] [Google Scholar]
  26. Lindmark E., Diderholm E., Wallentin L., Siegbahn A. Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease: effects of an early invasive or noninvasive strategy. JAMA. 2001 Nov 7;286(17):2107–2113. doi: 10.1001/jama.286.17.2107. [DOI] [PubMed] [Google Scholar]
  27. Mannino David M., Ford Earl S., Redd Stephen C. Obstructive and restrictive lung disease and markers of inflammation: data from the Third National Health and Nutrition Examination. Am J Med. 2003 Jun 15;114(9):758–762. doi: 10.1016/s0002-9343(03)00185-2. [DOI] [PubMed] [Google Scholar]
  28. Mendall M. A., Strachan D. P., Butland B. K., Ballam L., Morris J., Sweetnam P. M., Elwood P. C. C-reactive protein: relation to total mortality, cardiovascular mortality and cardiovascular risk factors in men. Eur Heart J. 2000 Oct;21(19):1584–1590. doi: 10.1053/euhj.1999.1982. [DOI] [PubMed] [Google Scholar]
  29. Pauwels R. A., Buist A. S., Calverley P. M., Jenkins C. R., Hurd S. S., GOLD Scientific Committee 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 Apr;163(5):1256–1276. doi: 10.1164/ajrccm.163.5.2101039. [DOI] [PubMed] [Google Scholar]
  30. Pradhan Aruna D., Manson JoAnn E., Rossouw Jacques E., Siscovick David S., Mouton Charles P., Rifai Nader, Wallace Robert B., Jackson Rebecca D., Pettinger Mary B., Ridker Paul M. Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women's Health Initiative observational study. JAMA. 2002 Aug 28;288(8):980–987. doi: 10.1001/jama.288.8.980. [DOI] [PubMed] [Google Scholar]
  31. Raisz L. G. Physiology and pathophysiology of bone remodeling. Clin Chem. 1999 Aug;45(8 Pt 2):1353–1358. [PubMed] [Google Scholar]
  32. Ridker P. M., Rifai N., Stampfer M. J., Hennekens C. H. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation. 2000 Apr 18;101(15):1767–1772. doi: 10.1161/01.cir.101.15.1767. [DOI] [PubMed] [Google Scholar]
  33. Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999 Jan 14;340(2):115–126. doi: 10.1056/NEJM199901143400207. [DOI] [PubMed] [Google Scholar]
  34. Salvi S., Blomberg A., Rudell B., Kelly F., Sandström T., Holgate S. T., Frew A. Acute inflammatory responses in the airways and peripheral blood after short-term exposure to diesel exhaust in healthy human volunteers. Am J Respir Crit Care Med. 1999 Mar;159(3):702–709. doi: 10.1164/ajrccm.159.3.9709083. [DOI] [PubMed] [Google Scholar]
  35. Schols A. M., Buurman W. A., Staal van den Brekel A. J., Dentener M. A., Wouters E. F. Evidence for a relation between metabolic derangements and increased levels of inflammatory mediators in a subgroup of patients with chronic obstructive pulmonary disease. Thorax. 1996 Aug;51(8):819–824. doi: 10.1136/thx.51.8.819. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Schols Annemie M. W. J. Pulmonary cachexia. Int J Cardiol. 2002 Sep;85(1):101–110. doi: 10.1016/s0167-5273(02)00238-3. [DOI] [PubMed] [Google Scholar]
  37. Schünemann H. J., Dorn J., Grant B. J., Winkelstein W., Jr, Trevisan M. Pulmonary function is a long-term predictor of mortality in the general population: 29-year follow-up of the Buffalo Health Study. Chest. 2000 Sep;118(3):656–664. doi: 10.1378/chest.118.3.656. [DOI] [PubMed] [Google Scholar]
  38. Sin Don D., Man S. F. Paul. Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inflammation in chronic obstructive pulmonary disease. Circulation. 2003 Mar 25;107(11):1514–1519. doi: 10.1161/01.cir.0000056767.69054.b3. [DOI] [PubMed] [Google Scholar]
  39. Takabatake N., Nakamura H., Abe S., Hino T., Saito H., Yuki H., Kato S., Tomoike H. Circulating leptin in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999 Apr;159(4 Pt 1):1215–1219. doi: 10.1164/ajrccm.159.4.9806134. [DOI] [PubMed] [Google Scholar]
  40. Takabatake N., Nakamura H., Abe S., Inoue S., Hino T., Saito H., Yuki H., Kato S., Tomoike H. The relationship between chronic hypoxemia and activation of the tumor necrosis factor-alpha system in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000 Apr;161(4 Pt 1):1179–1184. doi: 10.1164/ajrccm.161.4.9903022. [DOI] [PubMed] [Google Scholar]
  41. Tan W. C., Qiu D., Liam B. L., Ng T. P., Lee S. H., van Eeden S. F., D'Yachkova Y., Hogg J. C. The human bone marrow response to acute air pollution caused by forest fires. Am J Respir Crit Care Med. 2000 Apr;161(4 Pt 1):1213–1217. doi: 10.1164/ajrccm.161.4.9904084. [DOI] [PubMed] [Google Scholar]
  42. Vernooy Juanita H., Kükaycan Mehmet, Jacobs Jan A., Chavannes Niels H., Buurman Wim A., Dentener Mieke A., Wouters Emiel F. Local and systemic inflammation in patients with chronic obstructive pulmonary disease: soluble tumor necrosis factor receptors are increased in sputum. Am J Respir Crit Care Med. 2002 Nov 1;166(9):1218–1224. doi: 10.1164/rccm.2202023. [DOI] [PubMed] [Google Scholar]
  43. Wedzicha J. A., Seemungal T. A., MacCallum P. K., Paul E. A., Donaldson G. C., Bhowmik A., Jeffries D. J., Meade T. W. Acute exacerbations of chronic obstructive pulmonary disease are accompanied by elevations of plasma fibrinogen and serum IL-6 levels. Thromb Haemost. 2000 Aug;84(2):210–215. [PubMed] [Google Scholar]
  44. Yasuda N., Gotoh K., Minatoguchi S., Asano K., Nishigaki K., Nomura M., Ohno A., Watanabe M., Sano H., Kumada H. An increase of soluble Fas, an inhibitor of apoptosis, associated with progression of COPD. Respir Med. 1998 Aug;92(8):993–999. doi: 10.1016/s0954-6111(98)90343-2. [DOI] [PubMed] [Google Scholar]
  45. Yeung M. C., Buncio A. D. Leukocyte count, smoking, and lung function. Am J Med. 1984 Jan;76(1):31–37. doi: 10.1016/0002-9343(84)90741-1. [DOI] [PubMed] [Google Scholar]
  46. Yudkin J. S., Kumari M., Humphries S. E., Mohamed-Ali V. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? Atherosclerosis. 2000 Feb;148(2):209–214. doi: 10.1016/s0021-9150(99)00463-3. [DOI] [PubMed] [Google Scholar]
  47. de Godoy I., Donahoe M., Calhoun W. J., Mancino J., Rogers R. M. Elevated TNF-alpha production by peripheral blood monocytes of weight-losing COPD patients. Am J Respir Crit Care Med. 1996 Feb;153(2):633–637. doi: 10.1164/ajrccm.153.2.8564110. [DOI] [PubMed] [Google Scholar]
  48. van Eeden S. F., Tan W. C., Suwa T., Mukae H., Terashima T., Fujii T., Qui D., Vincent R., Hogg J. C. Cytokines involved in the systemic inflammatory response induced by exposure to particulate matter air pollutants (PM(10)). Am J Respir Crit Care Med. 2001 Sep 1;164(5):826–830. doi: 10.1164/ajrccm.164.5.2010160. [DOI] [PubMed] [Google Scholar]

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