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DOI: 10.1055/s-0038-1656310
Granulocyte Elastase, Tumor Necrosis Factor-α and Urokinase Levels as Prognostic Markers in Severe Infection
Publication History
Received 24 May 1991
Accepted after revision 17 February 1992
Publication Date:
03 July 2018 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/199201/lookinside/thumbnails/10-1055-s-0038-1656310-1.jpg)
Summary
We have examined the prognostic value of the levels in the blood of granulocyte elastase-α1-proteinase inhibitor (E-α1-PI) complex, tumor necrosis factor-α (TNF-α) and urokinase-type plasminogen activator (u-PA) in 35 patients with severe infection upon admission to an Intensive Care Unit. Fourteen patients died.
No differences for E-α1-PI complex were found between survivors and nonsurvivors, but in all patients the levels on admission were eight-fold higher than the reference value.
TNF-α levels, measured by immunoassay, on admission were four times higher in the nonsurvivors than in the survivors (p = 0.0003) and correlated with the severity of the disease (APACHE II score, r = 0.43, p <0.05). TNF-α was not detectable by bioassay.
Total u-PA antigen (u-PA Ag), plasmin-activatable single-chain u-PA (scu-PA) and inactive, nonactivatable u-PA (u-PA#) were on admission all two-fold higher in the nonsurvivors (p = 0.0006, 0.003 and 0.0003, respectively), while normal in the survivors. In both, survivors and nonsurvivors, the ratio between scu-PA and u-PA Ag was significantly decreased (p <0.001, compared to a reference group of healthy volunteers), indicative for enhanced conversion of scu-PA to active two-chain u-PA (tcu-PA) and inactive u-PA# during severe infectious disease. tcu-PA was detected in nine of the 35 patients, while virtually undetectable in controls. scu-PA correlated with the Child-Pugh score on admission (r = 0.42, p <0.05). TNF-α correlated with u-PA Ag (r = 0.38, p <0.05) and with u-PA# (r = 0.47, p <0.01).
In a stepwise logistic regression analysis, documentation of infection and plasma levels of u-PA Ag contributed most significantly to prediction of patient outcome. Serum levels of TNF-α did not. These results suggest that, in addition to a number of other clinical and laboratory parameters, u-PA Ag can be used as a prognostic marker in patients with severe infection admitted to an Intensive Care Unit.
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References
- 1 Teichmann AT, Arendt P, Speer CP. Premature rupture of the membranes and amniotic infections – the significance of laboratory tests. Eur J Obstet Gynecol Reprod Biol 1990; 34: 217-222
- 2 Fischbach F, Thurmayr R, Kolben M, Graeff H. Possible prediction of neonatal and puerperal infections by intrapartum determination of polymorphonuclear granulocyte elastase levels in maternal blood. Eur J Clin Microbiol Infect Dis 1988; 7: 588-589
- 3 Harm K, Bartfeld KP, Mathew T. Plasma concentrations of granulocytic elastase-α1-proteinase inhibitor complex in patients with severe head injury, multiple trauma or cerebral bleeding. Clin Biochem 1989; 22: 149-153
- 4 Kellermann W, Frentzel-Beyme R, Welte M, Jochum M. Phospholipase A in acute lung injury after trauma and sepsis: its relation to the inflammatory mediators PMN-elastase, C3a, and neopterin. Klin Wschr 1989; 67: 190-195
- 5 Speer CP, Ninjo A, Gahr M. Elastase-α1-proteinase inhibitor in early diagnosis of neonatal septicemia. J Pediatr 1986; 108: 987-990
- 6 Speer CP, Rethwilm M, Gahr M. Elastase-α1-proteinase inhibitor: An early indicator of septicemia and bacterial meningitis in children. J Pediatr 1987; 111: 667-671
- 7 Tsaka T, Herkner KR. Polymorphonuclear elastase in neonatal sepsis. Clin Chim Acta 1990; 193: 103-112
- 8 Beutler B, Cerami A. Cachectin: more than a tumor necrosis factor. N Engl J Med 1987; 316: 379-386
- 9 Waage A, Halstensen A, Espevik T. Association between tumor necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet 1987; i: 355-357
- 10 Girardin E, Grau GE, Dayer JM, Roux-Lombard P, the J5 study group Lambert P-H. Tumor necrosis factor and interleukin 1 in the serum of children with severe infectious purpura. N Engl J Med 1988; 319: 397-400
- 11 Debets JM, Kampmeyer R, van der Linden MP, Buurman WA, van der Linden CJ. Plasma tumor necrosis factor and mortality in critically ill septic patients. Crit Care Med 1989; 17: 489-494
- 12 Marks JD, Berman Marks C, Luce JM, Montgomery AB, Turner J, Metz CA, Murray JF. Plasma tumor necrosis factor in patients with septic shock. Mortality rate, incidence of adult respiratory distress syndrome and effects of methylprednisolone administration. Am Rev Respir Dis 1990; 141: 94-97
- 13 Offner F, Philippé J, Vogelaers D, Colardyn F, Baele G, Baudrihaye M, Vermeulen A, Leroux-Roels G. Serum TNF levels in patients with infectious disease and septic shock. J Clin Lab Med 1990; 116: 100-105
- 14 Sugarman BJ, Aggarwal BB, Hass PE, Figari IS, Palladino MA, Shepard MA. Recombinant tumor necrosis factor-α: effects on proliferation of normal and transformed cells in vitro. Science 1985; 230: 943-945
- 15 Bertolini DR, Nedwin GE, Bringman TS, Smith DD, Mundy GR. Stimulation of bone resorption and inhibition of bone formation in vitro by human tumor necrosis factor. Nature 1986; 319: 516-518
- 16 Bevilacqua MP, Pober JS, Majeau GR, Fiers W, Cotran RS, Gimbrone MA. Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin 1. Proc Natl Acad Sci USA 1986; 83: 4533-4537
- 17 van Hinsbergh VWM, van den Berg EA, Fiers W, Dooijewaard G. Tumor necrosis factor induces the production of urokinase-type plasminogen activator by human endothelial cells. Blood 1990; 75: 1991-1998
- 18 Gamble JR, Harlan JM, Klebanoff SJ, Vadas MA. Stimulation of the adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor. Proc Natl Acad Sci USA 1985; 82: 8667-8671
- 19 Smith CW, Rothlein BJ, Hughes BJ, Mariscalco MM, Rudloff HE, Schmalstieg FC, Anderson DC. Recognition of an endothelial determinant for CD 18-dependent human neutrophil adherence and trans-endothelial migration. J Clin Invest 1988; 82: 1746-1756
- 20 van Hinsbergh VWM, Bauer KA, Kooistra T, Kluft C, Dooijewaard G, Sherman ML, Nieuwenhuizen W. Progress of fibrinolysis during tumor necrosis factor infusions in humans. Concomitant increase in tissue-type plasminogen activator, plasminogen activator inhibitor type-1, and fibrin(ogen) degradation products. Blood 1990; 76: 2284-2289
- 21 van Deventer SJH, Büller HR, ten Cate JW, Aarden LA, Hack CE, Sturk A. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood 1990; 76: 2520-2526
- 22 Philippé J, Offner F, Declerck PJ, Leroux-Roels G, Vogelaers D, Baele G, Collen D. Fibrinolysis and coagulation in patients with infectious disease and sepsis. Thromb Haemostas 1991; 65: 291-295
- 23 Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: A severity of disease classification system. Crit Care Med 1985; 13: 818-828
- 24 Pugh RNH, Murray-Lyon IM, Dawson JL. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973; 60: 646-664
- 25 Goris RJA, te Boekhorst TPA, Nuytinck JKS, Gimbere JSF. Multiple organ failure. Generalized autodestructive inflammation? Arch Surg 1985; 120: 1109-1115
- 26 Leroux-Roels G, Offner F, Philippé J, Vermeulen A. Influence of blood-collecting systems on concentrations of tumor necrosis factor in serum and plasma. Clin Chem 1988; 34: 2373-2374
- 27 Espevik T, Nissen-Meyer J. A highly sensitive cell line, WEHI 164 clone 13, for measuring cytotoxic factor/tumor necrosis factor from human monocytes. J Immunol Methods 1986; 95: 99-105
- 28 Liang C-M, Liang S-M, Jost T, Sand A, Dougas I, Allet B. Production and characterization of monoclonal antibodies against recombinant human tumor necrosis factor/cachectin. Biochem Biophys Res Commun 1986; 137: 847-854
- 29 Binnema DJ, Van Iersel JJL, Dooijewaard G. Quantitation of urokinase antigen in plasma and culture media by use of an ELISA. Thromb Res 1986; 43: 569-577
- 30 Calandra T, Baumgartner J-D, Grau GE, Wu M-M, Lambert P-H, Schellekens J, Verhoef J, Glauser MP. and the Swiss-Dutch J5 Immunoglobulin Study Group Prognostic values of tumor necrosis factor/cachectin, interleukin-1, interferon-α, and interferon-γ in the serum of patients with septic shock. J Infect Dis 1990; 161: 982-987
- 31 Engelberts I, Stephens S, Francot GJM, Van Der Linden CJ, Buurman WA. Evidence for different effects of soluble TNF-receptors on various TNF measurements in human biological fluids. Lancet 1991; ii: 515-516
- 32 Dooijewaard G, van Iersel JJL, Brommer EJP. Quantitation of proUK, UK, and UK-Inhibitor levels in plasma of patients and healthy men. In: Abstracts of the Eighth International Congress on Fibrinolysis, Vienna 1986. Churchill Livingstone; Edinburgh: 1986: 142
- 33 Tran-Thang C, Fasel-Felley J, Pralong G, Hofstetter J-R, Bachmann F, Kruithof EKO. Plasminogen activators and plasminogen activator inhibitors in liver deficiencies caused by chronic alcoholism or infectious hepatitis. Thromb Haemostas 1989; 62: 651-653
- 34 Binnema DJ, Dooijewaard G, Turion PNC. An analysis of the activators of single-chain urokinase-type plasminogen activator (scu-PA) in the dextran sulphate euglobulin fraction of normal plasma and of plasmas deficient in factor XII and prekallikrein. Thromb Haemostas 1991; 65: 144-148
- 35 Ziegler EJ, Mc Cutchan JA, Fierer H, Glauser MP, Sadoff JC, Douglas H, Braude AI. Treatment of gram-negative bacteremia and shock with human antiserum to a mutant Escherichia coli. . N Engl J Med 1982; 307: 1225-1230
- 36 Hesselvik JF, Blomback M, Brodin B, Mailer R. Coagulation, fibrinolysis, and kallikrein systems in sepsis: relation to outcome. Crit Care Med 1989; 17: 724-733
- 37 Ichinose A, Fujikawa K, Suyama T. The activation of pro-urokinase by plasma kallikrein and its inactivation by thrombin. J Biol Chem 1986; 261: 3486-3489
- 38 Gurewich V, Pannell R. Inactivation of single-chain urokinase (pro-urokinase) by thrombin and thrombin-like enzymes: relevance of the findings to the interpretation of fibrin-binding experiments. Blood 1987; 69: 769-772
- 39 Lijnen HR, Van Hoef B, Collen D. Activation with plasmin of two-chain urokinase-type plasminogen activator derived from single-chain urokinase-type plasminogen activator by treatment with thrombin. Eur J Biochem 1987; 169: 359-364
- 40 Schmitt M, Kanayama N, Henschen A, Hollrieder A, Hafter R, Gulba D, Jänicke F, Graeff H. Elastase released from human granulocytes stimulated with N-formyl-chemotactic peptide prevents activation of tumor cell prourokinase (pro-uPA). FEBS 1989; 255: 83-88