Sepsis represents one the main cause of death in patients admitted to the intensive care. Biomarkers offer an alternative approach to the diagnostic and prognostic evaluation and improve the outcomes. Angiopoietin 2 (Ang-2) and Tyrosine kinase 2 (Tie-2) are biomarkers which may be involved in sepsis, Ang-2 being responsible for vascular remodelling while Tie-2 is their endothelial receptor.
The aim of the study: To assess the Ang-2, Tie-2 and Ang-2/Tie-2 ratio serum levels in septic and non-septic patients and to investigate the independent value of circulating Ang-2, Tie-2, and Ang-2/Tie-2 ratios as predictors of prognosis in critically ill medical patients.
Study design: The study included 74 adults admitted to an intensive care unit (ICU). The patients were separated in two groups: Group A [sepsis: n=40] and Group B [no-sepsis: n= 34] patients. Serum levels of Ang-2 and Tie-2 were determined in the first 12 hours after admission and were correlated with ICU severity scores, APACHE II, SOFA and SAPS and with the death rate.
Results: Group A gave significantly higher values (p=0.01), for serum Ang-2 (11.07±9.21 ng/ml) compared to Group B (6.18±5.28 ng/ml). The level of Tie-2 was also higher (11.03±5.12 ng/ml) in Group A compared to Group B (9.46±4.99 ng/ml) (p=0.19). In Group A, the Ang-2/Tie2 ratio showed higher values than Group B (p=0.02). There was a positive association between severity scores (APACHE II, SAPS, and SOFA) and Ang-2, and Ang-2/ Tie-2 ratio, but not for Tie2.
Conclusions: In our study Ang-2 and Ang-2/Tie-2 ratio serum levels had independent diagnostic value in patients with sepsis, as measured on admission.
1. Hervald H, Egesten A. Sepsis - Pro-Inflammatory and Anti-Inflammatory Responses. Contrib Microbiol. 2011; 17:1-11.
2. James D. Faix. Biomarkers of sepsis. Crit Rev Clin Lab Sci. Jan 2013;23-36.
3. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med Feb 2013; 41:580-637. DOI: 10.1097/CCM.0b013e31827e83af.
4. 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;31:1250-6.
5. Romualdo LG, Torrella PE, González MV, Sánchez RJ, Holgado AH, Freire AO, et al. Diagnostic accuracy of presepsin (soluble CD14 subtype) for prediction of bacteremia in patients with systemic inflammatory response syndrome in the Emergency Department. Clin Biochem Dec, 2014; 47:505-8. DOI: 10.1016/j.clinbiochem.2014.02.011.
6. Kibe S, Adams K, Barlow G. Diagnostic and prognostic biomarkers of sepsis in critical care. J Antimicrob Chemother. May, 2011;66:33-40. DOI: 10.1093/jac/dkq523.
7. Kopterides P, Tsangaris I. Procalcitonin and sepsis: recent data on diagnostic utility prognostic potential and therapeutic implications in critically ill patients. Minerva Anestesiol. Jul 2012;78:823-835.
8. Sridharan P, Chamberlain RS. The efficacy of procalcitonin as a biomarker in the management of sepsis: slaying dragons or tilting at windmills? Surg Infect (Larchmt). 2013; 14:489-511. DOI: 10.1089/ sur.2012.028.
9. Gucyetmez B, Atalan HK. C - reactive protein and Hemogram Parameters for the Non-Sepsis Systemic Inflammatory Response Syndrome and Sepsis: What Do They Mean? PLoS One. 2016; 11:e0148699. DOI: 10.1371/journal.pone.0148699.
10. Zou Q1, Wen W1, Zhang XC. Presepsin as a novel sepsis biomarker. World J Emerg Med. 2014;5(1):16-9. DOI: 10.5847/wjem.j.issn.1920-8642.2014.01.002.
11. Behnes M, Bertsch T, Lepiorz D, Lang S, Trinkmann F, Brueckmann M, et al. Diagnostic and prognostic utility of soluble CD 14 subtype (presepsin) for severe sepsis and septic shock during the first week of intensive care treatment. Crit Care. 2014;18(5):507. DOI: 10.1186/ s13054-014-0507-z.
12. Biron BM, Ayala A, Lomas-Neira JL Biomarkers for Sepsis: What Is and What Might Be? Biomark Insights. 2015;10(4):7-17.
13. Belloni D, Marcatti M, Ponzoni M, et al. Angiopoietin-2 in bone marrow milieu promotes multiple myeloma- associated angiogenesis. Exp Cell Res. Sep 2015;330(1):1-12. DOI: 10.1016/j.yexcr.2014.10.017.
14. Elhefny RA, Shaban MM, Shaker OG. Prognostic value of pro-inflammatory cytokine and pro-angiogenesis factor in differentiating malignant from benign exudative effusion. Clin Respir J. May, 2015. DOI: 10.1111/ crj.12302.
15. Milam KE, Parikh SM. The angiopoietin-Tie2 signaling axis in the vascular leakage of systemic inflammation. Tissue Barriers. 2014; 3:1-2.
16. Scholz A, Plate KH, Reiss Y. Angiopoietin-2: a multifaceted cytokine that functions in both angiogenesis and inflammation. Ann N Y Acad Sci. 2015;1347:45-51. DOI: 10.1111/nyas.12726.
17. Szederjesi J, Almasy E, Lazar A, Huțanu A, Georgescu AM. The Role of Angiopoietine-2 in the Diagnosis and Prognosis of Sepsis. J Crit Care Med. Jan 2015;1(1):18-23. DOI: 10.1515/jccm-2015-0004.
18. Kümpers P, Lukasz A, David S, Horn R, Hafer C, Faulhaber-Walter R, et al. Excess circulating angiopoietin-2 is a strong predictor of mortality in critically ill medical patients. Crit Care.May, 2008;12(6):R147. DOI: 10.1186/cc7130.
19. Giuliano JS Jr, Lahni PM, Harmon K, Wong HR, Doughty LA, Carcillo JA, et al. Admission angiopoietin levels in children with septic shock. Shock. May, 2007;28:650-4. DOI: 10.1097/shk.0b013e318123867b.
20. Siner JM, Bhandari V, Engle KM, Elias JA, Siegel MD. Elevated serum angiopoietin 2 levels are associated with increased mortality in sepsis. Shock. 2009 Apr;31(4):348-53. DOI: 10.1097/ SHK.0b013e318188bd06.
21. Orfanos SE, Kotanidou A, Glynos C, Athanasiou C, Tsigkos S, Dimopoulou I, et al. Angiopoietin-2 is increased in severe sepsis: correlation with inflammatory mediators. Crit Care Med. 2007Jan; 35(1):199-206. DOI: 10.1097/01.CCM.0000251640.77679.D7.
22. David S, Kümpers P, Lukasz A, Fliser D, Martens- Lobenhoffer J, Bode-Böger SM, et al. Circulating angiopoietin-2 levels increase with progress of chronic kidney disease. Nephrol Dial Transplant. Aug, 2010;25:2571-6. DOI: 10.1093/ndt/gfq060.
23. 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.
24. 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; 348:1546-54. DOI: 10.1056/NEJMoa022139.
25. Phua J, Ngerng W, See K, Tay C, Kiong T, Lim H, et al. Characteristics and outcomes of culture-negative versus culture-positive severe sepsis. Crit Care. 2013 Sep 12;17(5):R202. DOI: 10.1186/cc12896.
26. Nicolas de Prost, Keyvan Razazi, and Christian Brun- Buisson Unrevealing culture-negative severe sepsis. Crit Care. Sep, 2013; 17(5): 1001 DOI: 10.1186/ cc13022.
27. De Busk LM, Chen Y, Nishishita T, Chen J, Thomas JW, Lin PC. Tie-2 receptor tyrosine kinase, a major mediator of tumor necrosis factor alpha-induced angiogenesis in rheumatoid arthritis. Arthritis Rheum. Sep 2003;48(9):2461-71. DOI: 10.1002/art.11213.
28. Nadar SK, Blann A, Beevers DG, Lip GY. Abnormal angiopoietins 1&2, angiopoietin receptor Tie-2 and vascular endothelial growth factor levels in hypertension: relationship to target organ damage [a sub-study of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)]. J Intern Med. Oct 2005;258(4):336-43. DOI: 10.1111/j.1365-2796.2005.01550.x.
29. Schröder J, Staubach KH, Zabel P, Stüber F, Kremer B. Procalcitonin as a marker of severity in septic shock. Langenbecks Arch Surg. Feb 1999;384(1):33-8. DOI: 10.1007/s004230050170.
30. Samraj RS, Zingarelli B, Wong HR. Role of biomarkers in sepsis care. Shock. Nov 2013;40(5):358-65. DOI: 10.1097/SHK.0b013e3182a66bd6.
31. Koenig SM, Truwit JD. Ventilator-Associated Pneumonia: diagnosis, treatment, and prevention. Clin Microbiol Rev. Oct 2006;19(4):637-57. DOI: 10.1128/ CMR.00051-05.
32. Michetti CP, Fakhry SM, Ferguson PL, Cook A, Moore FO, Gross R. Ventilator-associated pneumonia rates at major trauma centers compared with a national benchmark: a multi-institutional study of the AAST. J Trauma Acute Care Surg. May 2012;72(5):1165-73. DOI: 10.1097/TA.0b013e31824d10fa.
33. Cook D. Ventilator associated pneumonia: perspectives on the burden of illness. Intensive Care Med. Apr, 2000;26(1):31-7. DOI: 10.1007/s001340051116.
34. Aslan A, Jongman RM, Moser J, Stegeman CA, van Goor H, Diepstra A, et al. The renal angiopoietin/ Tie-2 system in lethal human sepsis, Crit Care. Mar 2014;18(2):423. DOI: 10.1186/cc13806.
35. Alves BE, Montalvao SA, Aranha FJ, Siegl TF, Souza CA, Lorand-Metze I, et al. Imbalances in serum angiopoietin concentrations are early predictors of septic shock development in patients with post chemotherapy febrile neutropenia. BMC Infect Dis. May 2010;10:143. DOI: 10.1186/1471-2334-10-143.
36. De Azevedo JR, Torres OJ, Beraldi RA, Ribas CA, Malafaia O. Prognostic evaluation of severe sepsis and septic shock: procalcitonin clearance vs Δ Sequential Organ Failure Assessment. J Crit Care. 2015; 30(1):219. DOI: 10.1016/j.jcrc.2014.08.018.
37. American College of Chest Physicians/Society of Critical Care Medicine, Consensus Conference, Crit Care Med 1992 Jun;20(6):864-74.