Soluble urokinase-type plasminogen activator receptor (suPAR) – a possible biomarker for bacteremia in sepsis / Forma solubilă a receptorului pentru activatorul de plasminogen de tip urokinază (suPAR) – un biomarker posibil pentru bacteriemie în sepsis

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Abstract

Background. Validating new sepsis biomarkers can contribute to early diagnosis and initiation of therapy. The aim of this study is to evaluate the sepsis predictive capacity of soluble urokinase plasminogen receptor (suPAR) and its role in evaluating the prognosis of bloodstream infections. Material and method. We conducted a prospective pilot study on 49 systemic inflammatory response syndrome (SIRS) patients admitted to the intensive care unit (ICU), that were divided, on the basis of bacteremia in group A (SIRS with bacteremia, n=14) and group B (SIRS without bacteremia, n=35). Hemoculture and blood samples were drawn on the first day to determine suPAR, C-reactive protein (CRP) and procalcitonin (PCT). We set to identify significant cut-off values in estimating bacteremia and mortality in septic patients. Results. In group A, suPAR values were 14.3 ng/mL (range 10-45.5 ng/mL) and in group B, 9.85 ng/mL (range 3.4-48 ng/mL) p=0.008. Area under the curve (AUC) for suPAR was 0.745 (95% CI: 0.600-0.859), for CRP 0.613 (95% CI: 0.522-0.799) and for PCT 0.718 (95% CI: 0.477-0.769). Cut-off value for suPAR in bacteremia prediction was 9.885 ng/mL, with 100% sensibility and 51.43% specificity. Mortality in group A was 85.7% (12/14) and in group B 74.3% (26/39), p>0.05. Area under the curve (AUC) for suPAR was 0.750 (95% CI: 0.455-0.936), for CRP 0.613 (95% CI: 0.413-0.913) and for PCT 0.618 (95% CI: 0.373-0.888). Cut-off value of suPAR in predicting mortality was 11.5 ng/mL, with 66.67% sensibility and 100% specificity. Conclusions. In our study suPAR had a predictive capacity for bacteremia and seems to be an independent factor for mortality prognosis in septic patients.

1. Dellinger RH, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Sur-viving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013. Feb;41(2):580-637.

2. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knauss WA, et al. Defini-tions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/ Society of Critical Care Medicine. Chest. 1992 Jun;101(6):1644-55. DOI: 10.1378/chest.101.6.1644

3. Matzinger P. The danger model: a renewed sense of self. Science. 2002 Apr 12;296(5566):301-5. DOI: 10.1126/science.1071059

4. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, et al. Circulating mito-chondrial DAMPs cause inflammatory responses to injury. Nature. 2010 Mar 4;464(7285):104-7. DOI: 10.1038/nature08780

5. Jones GR, Lowes JA. The systemic inflammatory response syndrome as a predic-tor of bacteremia and outcome from sepsis. QJM.1996 Jul;89(7):515-22. DOI: 10.1093/qjmed/89.7.515

6. Bates DW, Sands K, E. Miller E, Lanken PN, Hibberd PL, Graman PS, et al. Pre-dicting bacteremia in patients with sepsis syndrome. Academic Medical Center Consortium Sepsis Project Working Group. J Infect Dis. 1997 Dec;176(6):1538-51. DOI: 10.1086/514153

7. Bauer M, Reinhart K. Molecular diagnostics of sepsis-- where are we today? Int J Med Microbiol. 2010 Aug;300(6):411-3. DOI: 10.1016/j.ijmm.2010.04.006

8. Loonen AJM, de Jager CPC, Tosserams J, Kusters R, Hilbink M, Wever PC, et al. Biomarkers and molecular analysis to improve bloodstream infection diagnostics in an emergency care unit. PLoS ONE 2014. Jan; 9(1):e87135. DOI: 10.1371/journal.pone.0087315

9. Reinhart K, Bauer M, Riedermann NC, Hartog CS. New approaches to sepsis: molecular diagnostics and biomarkers. Clin Microbiol Rev. 2012 Oct;25(4):609-34 DOI: 10.1128/CMR.00016-12

10. Pierrakos C, Vincent JL. Sepsis biomarkers: a review. Crit. Care. 2010;14(1):R15. DOI: 10.1186/cc8872

11. Riisbro R, Christensen IJ, Hogdall C, Brunner N, Hogdall E. Soluble urokinase plasminogen activator receptor measurements: influence of sample handling. Int J Biol Markers. 2001 Oct-Dec;16(4):233-9.

12. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ESICM/ACCP/ATS/ SIS International Sepsis Definitions Conference. Crit Care Med. 2003 Apr;31(4):1250-6. DOI: 10.1097/01. CCM.0000050454.01978.3B

13. Hatzistilianou M. Diagnostic and prognostic role of procalcitonin in infections. ScientificWorldJournal. 2010 Oct;10:1941-6. DOI: 10.1100/tsw.2010.181

14. Uzzan B, Cohen R, Nicolas P, Cucherat P, Perret GY. Procalcitonin as a diagnos-tic test for sepsis in critically ill adults and after surgery or trauma: a systematic re-view and meta-analysis. Crit Care Med. 2006 Jul;34(7):1996-2003. DOI: 10.1097/01. CCM.0000226413.54364.36

15. Bloos F. Clinical diagnosis of sepsis and the combined use of biomarkers and culture and non-culture-based assays. Methods Mol Biol. 2015;1237:247-60. DOI: 10.1007/978-1-4939-1776-1_19

16. Assicot M, Gendrel D, Carsin H, Raymond J, Guilbaud J, Bohuon C. High serum procalcitonin concentrations in patients with sepsis and infection. Lancet. 1993 Feb 27;341(8844):515-8. DOI: 10.1016/0140-6736(93)90277-N

17. Bopp C, Hofer S, Bouchon A, Zimmermann JB, Martin E, Weigand MA. Soluble TREM-1 is not suitable for distinguishing between systemic inflammatory re-sponse syndrome and sepsis survivors and nonsurvivors in the early stage of acute inflammation. Eur J Anaesthesiol. 2009 Jun;26(6):504-7. DOI: 10.1097/ EJA.0b013e328329afca

18. Povoa P, Teixeira-Pinto AM, Carneiro AH, Portuguese Community-Acquired Sepsis Study Group SACiUCI. C-reactive protein, an early marker of community-acquired sepsis resolution: a multi-centre prospective observational study. Crit Care. 2011 Jul;15(4):R169. DOI: 10.1186/cc10313

19. Suberviola B, Castellanos-Ortega A, Ruiz Ruiz A, Lopez- Hoyos M, Santibanez M. Hospital mortality prognostication in sepsis using the new biomarkers suPAR and proADM in a single determination on ICU admission. Intensive Care Med. 2013 Sep; 39(9):1945-52. DOI: 10.1007/s00134-013-3056-z

20. Schuetz P, Christ-Crain M, Muller B. Procalcitonin and other biomarkers to improve assessment and antibiotic stewardship in infections - hope for hype? Swiss Med Wkly. 2009 Jun;139(23-24):318-26.

21. Huttunen R, Syrjanen J, Vuento R, Hurme M, Huhtala H, Laine J, et al. Plasma level of soluble uroki nase-type plasminogen activator receptor as a predictor of disease severity and case fatality in patients with bacteremia: a prospective cohort study. J Intern Med. 2011 Jul;270(1):32-40. DOI: 10.1111/j.1365-2796.2011.02363.x

22. Georgescu AM, Azamfirei L. Cell receptors as biomarkers in sepsis pathology. J Rom Anest Terap Int. 2014 April;21(1):45-52.

23. Andersen O, Eugen-Olsen J, Kofoed K, Iversen J, Haugaard SB. Soluble urokinase plasminogen activator receptor is a marker of dysmetabolism in HIV-infected pa-tients receiving highly active antiretroviral therapy. J Med Virol. 2008 Feb; 80(2):209-16. DOI: 10.1002/ jmv.21114

24. Eugen-Olsen J, Andersen O, Linneberg A, Ladelund S, Hansen TW, Langkilde A, et al. Circulating soluble urokinase plasminogen activator receptor predicts cancer, car-diovascular disease, diabetes and mortality in the general population. J Intern Med. 2010 Sep; 268(3):296-308. DOI: 10.1111/j.1365-2796.2010.02252.x

25. Eugen-Olsen J. suPAR - a future risk marker in bacteremia. J Intern Med. 2011 Jul; 270(1):29-31. DOI: 10.1111/j.1365-2796.2011.02372.x

26. Backes Y, van der Sluijs KF, Mackie DP, Tacke F, Koch A, Tenhunen JJ. et al. Use-fulness of suPAR as a biological marker in patients with systemic inflammation or in-fection: a systematic review. Intensive Care Med. 2012 Sep; 38(9):1418-28. DOI: 10.1007/s00134-012-2613-1

27. Koch A, Voigt S, Kruschinski C, Sanson E, Dückers H, Horn A, et al. Circulating soluble urokinase plasminogen activator receptor is stably elevated during the first week of treatment in the intensive care unit and predicts mortality in critically ill pa-tients. Crit Care. 2011; 15(1):R63. DOI: 10.1186/cc10037

28. Donadello K, Scolletta S, Covajes C, Vincent JL. suPAR as a prognostic biomarker in sepsis. BMC Med. 2012 Jan;5:10:2. DOI: 10.1186/1741-7015-10-2

29. Siahanidou T, Margeli A, Tsirogianni C, Charoni S, Giannaki M, Vavourakis E, et al. Clinical value of plasma soluble urokinase-type plasminogen activator receptor levels in term neonates with infection or sepsis: a prospective study. Mediators Inflamm. 2014 May;2014:375702.

30. Donadello K, Scolletta S, Taccone FS, Covajes C, Santonocito C Cortes DO, et al. Soluble urokinase-type plasminogen activator receptor as a prognostic biomarker in critically ill patients. J Crit Care. 2014 Feb; 29(1):144-9. DOI: 10.1016/j.jcrc.2013.08.005

31. Koch A, Tacke F. Why high suPAR is not super-diagnostic prognostic and potential pathogenic properties of a novel biomarker in the ICU. Crit Care. 2011 Dec;15(6):1020. DOI: 10.1186/cc10577

32. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003 Apr;348(16):1546-54 DOI: 10.1056/NEJMoa022139

33. Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med. 2006 Feb;34(2):344-53. DOI: 10.1097/01. CCM.0000194725.48928.3A

34. Samraj RS, Zingarelli B, Wong HR. Role of biomarkers in sepsis care. Shock. 2013 Nov;40(5):358-65. DOI: 10.1097/SHK.0b013e3182a66bd6

35. Marshall JC, Reinhart K. International Sepsis Forum. Biomarkers of sepsis. Crit Care Med. 2009 Jul;37(7):2290-8. DOI: 10.1097/CCM.0b013e3181a02afc

36. Pisinger C, Ladelund S, Eugen-Olsen J. Influence of Lifestyle on suPAR Levels. The Inter99 Study; 2012 [http://suparnostic.com/images/stories/3rd_supar_symposium_2012_abstracts_program.pdf:11-11]

37. Haugaard SB, Andersen O, Hansen TW, Eugen-Olsen J, Linneberg A, Madsbad S, et al. The immune marker soluble urokinase plasminogen activator receptor is associated with new-onset diabetes in non-smoking women and men. Diabet Med. 2012 Apr;29(4):479-87. DOI: 10.1111/j.1464-5491.2011.03513.x

38. http://suparnostic.com/Result-Interpretation. [Accessed on Sep 20th, 2012].

39. Lodes U, Bohmeier B, Lippert H, Konig B, Meyer F. PCR-based rapid sepsis di-agnosis effectively guides clinical treatment in patients with new onset of SIRS. Langenbecks Arch Surg. 2012 (Mar);397(3):447-55. DOI: 10.1007/s00423-011-0870-z

40. Hoenigl M, Raggam RB, Wagner J, Valentin T, Leitner E, Seeber K, et al. Diag-nostic accuracy of soluble urokinase activator receptor (suPAR) for prediction of bacteremia in patients with systemic inflammatory response syndrome. Clin Bio-chem. 2013 Feb;46(3):225-9. DOI: 10.1016/j.clinbiochem.2012.11.004

41. Yilmaz G, Koksal I, Karahan SC, Mentese A. The diagnostic and prognostic significance of soluble urokinase plasminogen activator receptor in systemic in-flammatory response syndrome. Clin Biochem. 2011 Oct;44(14-15):1227-30. DOI: 10.1016/j.clinbiochem. 2011.07.006

42. Wittenhagen P, Kronborg G, Weis N, Nielsen H, Obel N, Pedersen SS, et al. The plasma level of soluble urokinase receptor is elevated in patients with Streptococ- cus pneumoniae bacteraemia and predicts mortality. Clin Microbiol Infect 2004 May; 10(5):409-15. DOI: 10.1111/j.1469-0691.2004.00850.x

43. Meijers B, Poesen R, Claes K, Dietrich R, Bammens B, Sprangers B, et al. Soluble urokinase receptor is a biomarker of cardiovascular disease in chronic kidney disease. Kidney Int. 2015 Jan;87(1):210-6. DOI: 10.1038/ ki.2014.197

44. Kofoed K, Eugen-Olsen J, Petersen J, Larsen K, Andersen O. Predicting mortality in patients with systemic inflammatory response syndrome: an evaluation of two prognostic models, two soluble receptors, and a macrophage migration inhibitory factor. Eur J Clin Microbiol Infect Dis. 2008 May;27(5):375-83. DOI: 10.1007/ s10096-007-0447-5

45. Kofoed K, Andersen O, Kronborg G, Tvede M, Petersen J, Eugen-Olsen J, et al. Use of plasma C-reactive protein, procalcitonin, neutrophils, macrophage migra-tion inhibitory factor, soluble urokinase-type plasminogen activator receptor, and soluble triggering receptor expressed on myeloid cells-1 in combination to diag-nose infections: a prospective study. Crit Care. 2007;11(2):R38. DOI: 10.1186/cc5723

46. Raggam RB, Wagner J, Pruller F, Grisold A, Leitner E, Zollner-Schwetz I, et al. Soluble urokinase plasminogen activator receptor predicts mortality in patients with systemic inflammatory response syndrome. J Inter Med. 2014 Mar;19. DOI: 10.1111/joim.12238

47. Molkanen T, Ruotsalainen E, Thorball CW, Jarvinen A. Elevated soluble urokinase plasminogen activator receptor (suPAR) predicts mortality in Staphylococus aure-us bacteremia. Eur J Clin Microbiol Infect Dis. 2011 Nov;30(11):1417-24. DOI: 10.1007/s10096-011-1236-8

48. Moller HJ, Moestrup SK, Weis N, Wejse C, Nielsen H, Pedersen SS, et al. Macro-phage serum markers in pneumococcal bacteremia: prediction of survival by solu-ble CD163. Crit Care Med. 2006 Oct;34(10):2561-6. DOI: 10.1097/01.CCM.0000239120.32490.AB

49. Kaya S, Köksal I, Menteşe A, Sönmez M, Sümer A, Yıldırım SS, et al. The signi-ficance of serum urokinase plasminogen activation receptor (suPAR) in the di-agnosis and follow-up of febrile neutropenic patients with hematologic malignan-cies. Int J Infect Dis. 2013 Nov;17(11):e1056-9. DOI: 10.1016/j.ijid.2013.04.004

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