Acute Exacerbations of Chronic Obstructive Pulmonary Disease Are Accompanied by Elevations of Plasma Fibrinogen and Serum IL-6 Levels

Jadwiga A. Wedzicha; Terence A. R. Seemungal; Peter K. MacCallum; Elizabeth A. Paul; Gavin C. Donaldson; Angshu Bhowmik; Donald J. Jeffries; Thomas W. Meade

doi:10.1055/s-0037-1613998

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2000; 84(02): 210-215
DOI: 10.1055/s-0037-1613998

Review Article

Schattauer GmbH

Acute Exacerbations of Chronic Obstructive Pulmonary Disease Are Accompanied by Elevations of Plasma Fibrinogen and Serum IL-6 Levels

Jadwiga A. Wedzicha

¹From the Department of Academic Respiratory Medicine, London, UK

,

Terence A. R. Seemungal

¹From the Department of Academic Respiratory Medicine, London, UK

,

Peter K. MacCallum

⁵Department of Medical Research Council Epidemiology and Medical Care Unit, Wolfson Institute of Preventive Medicine, London, UK

,

Elizabeth A. Paul

⁴Department of Statistics, St Bartholomew’s and Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, London, UK

,

Gavin C. Donaldson

³Department of Physiology, London, UK

,

Angshu Bhowmik

¹From the Department of Academic Respiratory Medicine, London, UK

,

Donald J. Jeffries

²Department of Virology, London, UK

,

Thomas W. Meade

⁵Department of Medical Research Council Epidemiology and Medical Care Unit, Wolfson Institute of Preventive Medicine, London, UK

› Author Affiliations

Abstract

Summary

Background

Respiratory tract infections may acutely increase risk from coronary heart disease (CHD), though the mechanisms have not been defined. Patients with chronic obstructive pulmonary disease (COPD) are prone to repeated exacerbations that are often associated with respiratory infections. These patients also have increased cardiovascular morbidity and mortality. We hypothesized that transient acute increases in plasma fibrinogen, an independent risk factor for CHD, could occur at COPD exacerbation (mediated through a rise in IL6) and thereby provide a mechanism linking respiratory infection to risk of coronary heart disease.

Methods

93 COPD patients [mean (SD) age 66.8 (8.1) years] were followed regularly over one year, with daily diary card monitoring of respiratory symptoms and peak expiratory flow rate (PEFR); 67 patients [mean FEV1 1.06 (0.44) l, FVC 2.43 (0.79) l] were seen during 120 exacerbations. At each visit spirometry was measured and blood samples taken for plasma fibrinogen and Interleukin-6 (IL-6) levels.

Result

At baseline, the mean (SD) plasma fibrinogen was elevated at 3.9 (0.67) g/l in the 67 patients with exacerbations during the study and the median (IQR) IL-6 at 4.3 (2.4 to 6.8) pg/ml. Plasma fibrinogen increased by 0.36 (0.74) g/l at exacerbation (p <0.001), with IL-6 levels rising by 1.10 (−2.73 to 6.95) pg/ml (p = 0.008). There was a relation between the changes in fibrinogen at exacerbation and IL-6 levels (r = 0.348, p <0.001). Multiple regression revealed significantly greater rises in fibrinogen when exacerbations were associated with purulent sputum (b = 0.34 g/l; p = 0.03), increased cough (b = 0.31 g/l, p = 0.019) and symptomatic colds (b = 0.228; p = 0.024).

Conclusions

Plasma fibrinogen levels were elevated in stable patients with COPD and may contribute to the increased cardiovascular morbidity and mortality in these patients. COPD exacerbations increased serum IL-6 levels, leading to a rise in plasma fibrinogen. Thus acute rather than chronic infection may have a role in predisposing to coronary heart disease or stroke.

Keywords

Exacerbations - fibrinogen - IL-6 - COPD - cardiovascular risk

Full Text

References

References
1 Spodick DH, Flessas AP, Johnson MM. Association of acute respiratory symptoms with onset of acute myocardial infarction: Prospective investigation of 150 consecutive patients and matched control patients. Am J Cardiol 1984; 53: 481-2.
2 Meier CR, Jick SS, Derby LE, Vasilakis C, Jick H. Acute respiratory tract infections and risk of first-time acute myocardial infarction. Lancet 1998; 351: 1467-71.
3 Syrjanen J, Valtonen VV, Iivanainen M, Kaste M, Huttunen JK. Preceding infection as an important risk factor for ischaemic brain infarction in young and middle aged patients. BMJ 1988; 296: 1156-60.
4 Curwen M. Excess winter mortality: a British phenomenon?. Health trends 1991; 04: 169-75.
5 Meade TW, Ruddock V, Stirling Y, Chakrabarti R, Miller GJ. Fibrinolytic activity, clotting factors and long term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet 1993; 324: 1076-9.
6 Woodhouse PR, Khaw KT, Plummer M, Fokey A, Meade TW. Seasonal variations of plasma fibrinogen and factor VII activity in the elderly: winter infections and death from cardiovascular disease. Lancet 1994; 343: 435-39.
7 Fletcher C, Peto R, Tinker C, Speizer FE. The Natural History of Chronic Bronchitis and Emphysema. Oxford University Press; 1976
8 Seemungal TAR, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157: 1418-22.
9 Jousilahti P, Vartiainen E, Tuomilehto J, Puska P. Symptoms of chronic bronchitis and the risk of coronary disease. Lancet 1996; 348: 567-72.
10 Haider AW, Larson MG, O’Donnell CJ, Evans JC, Wilson PWF, Levy D. The association of chronic cough with the risk of myocardial infarction: the Framingham Heart Study. Am J Med 1999; 106: 279-84.
11 Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995; 152: S78-83.
12 Pitkin AD, Roberts CM, Wedzicha JA. Arterialised ear lobe blood gas analysis: an underused technique. Thorax 1994; 49: 364-66.
13 Anthonisen NR, Manfreda J, Warren CPW, Hershfield ES, Harding GKM, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987; 106: 196-204.
14 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol (Basel) 1957; 17: 237-46.
15 Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin or leukocyte count with coronary heart disease. JAMA 1998; 279: 1477-82.
16 Meade TW. Fibrinogen in ischaemic heart disease. Eur Heart J 1995; 16 (Suppl A): 31-35.
17 Wedzicha JA, Syndercombe-Court D, Tan KC. Increased platelet aggregate formation in patients with chronic airflow obstruction and hypoxaemia. Thorax 1991; 46: 504-7.
18 Davi G, Basili S, Vieri M. et al Enhanced thromboxane biosynthesis in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1997; 156: 1794-9.
19 Alessandri C, Basili S, Violi F, Ferroni P, Gazzaniga PP, Cordova C. Hypercoagulability state in patients with chronic obstructive pulmonary disease. Thromb Haemost 1994; 72: 343-6.
20 Jousilahti P, Salomaa V, Rasi V, Vahtera E. Symptoms of chronic bronchitis, haemostatic factors, and coronary heart disease risk. Atherosclorosis 1999; 142: 403-7.
21 Stanescu D, Sanna A, Veriter C, Kostianev S, Calcagni PG, Fabbri LM, Maestrelli P. Airways obstruction, chronic expectoration, and rapid decline of FEV1 in smokers are associated with increased levels of sputum neutrophils. Thorax 1996; 51: 267-71.
22 Saikku P, Mattila K, Nieminen MS. et al. Serological evidence of an association of a novel chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet 1988; ii: 983-5.
23 Murray LJ, Bamford KB, O’Reilly DPJ, McCrum EE, Evans EE. Helicobacter pylori infection: relation with cardiovascular risk factors, ischaemic heart disease and social class. Br Heart J 1995; 74: 497-501.
24 Melnick JL, Dreesman GR, McCollum CH, Petrie BL, Burek J, Debakey ME. Cytomegalovirus antigen within human arterial smooth muscle cells. Lancet 1983; ii: 644-7.
25 Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: is there a link?. Lancet 1997; 350: 430-6.
26 Toss H, Gnarpe J, Gnarpe H, Siegbahn A, Lindahl B, Wallentin L. Inreased fibrinogen levels are associated with persistent Chlamydia pneumoniae infection in unstable coronary artery disease. Eur Heart J 1998; 19: 570-7.
27 Gurfinkel E, Bozovich G, Daroca A, Beck E, Mautner B. Randomized trial of roxithromycin in non-Q-wave coronary syndromes: ROXIS pilot study. Lancet 1997; 350: 404-7.
28 Gupta S, Leatham EW, Carrington D. et al. The effect of azithromycin in post-myocardial infarction patients with elevated Chlamydia pneumoniae antibody titres. J Am Coll Cardiol 1997; 29 (suppl A): 209A.
29 Castell JV, Gomez-Lechon MJ, David M, Andus T, Geiger T, Trullenque R, Fabra R, Heinrich PC. Interleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes. FEBS Letters 1989; 242: 237-39.
30 Akira S, Kishimoto T. IL-6 and NF-IL-6 in acute phase response and viral infection. Immunological reviews 1992; 127: 25-50.
31 Subauste MC, Jacoby DB, Richards SM, Proud D. Infection of a human respiratory epithelial cell line with rhinovirus. J Clin Invest 1995; 96: 549-57.