Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Annals of Intensive Care
Published in: Annals of Intensive Care 1/2019

Open Access 01-12-2019 | Septicemia | Research

Prediction of mortality in adult patients with sepsis using six biomarkers: a systematic review and meta-analysis

Authors: Andreas Pregernig, Mattia Müller, Ulrike Held, Beatrice Beck-Schimmer

Published in: Annals of Intensive Care | Issue 1/2019

Login to get access

Abstract

Background

Angiopoietin-1 (Ang-1) and 2 (Ang-2), high mobility group box 1 (HMGB1), soluble receptor for advanced glycation endproducts (sRAGE), soluble triggering receptor expressed on myeloid cells 1 (sTREM1), and soluble urokinase-type plasminogen activator receptor (suPAR) have shown promising results for predicting all-cause mortality in critical care patients. The aim of our systematic review and meta-analysis was to assess the prognostic value of these biomarkers for mortality in adult patients with sepsis.

Methods

A systematic literature search of the MEDLINE, PubMed, EMBASE, and Cochrane Library databases, for articles in English published from 01.01.1990 onwards, was conducted. The systematic review focused exclusively on observational studies of adult patients with sepsis, any randomized trials were excluded. For the meta-analysis, only studies which provide biomarker concentrations within 24 h of admission in sepsis survivors and nonsurvivors were included. Results are presented as pooled mean differences (MD) between nonsurvivors and survivors with 95% confidence interval for each of the six biomarkers. Studies not included in the quantitative analysis were narratively summarized. The risk of bias was assessed in all included studies using the Quality in Prognosis Studies (QUIPS) tool.

Results

The systematic literature search retrieved 2285 articles. In total, we included 44 studies in the qualitative analysis, of which 28 were included in the meta-analysis. The pooled mean differences in biomarker concentration (nonsurvivors − survivors), measured at onset of sepsis, are listed as follows: (1) Ang-1: − 2.9 ng/ml (95% CI − 4.1 to − 1.7, p < 0.01); (2) Ang-2: 4.9 ng/ml (95% CI 2.6 to 7.1, p < 0.01); (3) HMGB1: 1.2 ng/ml (95% CI 0.0 to 2.4, p = 0.05); (4) sRAGE: 1003 pg/ml (95% CI 628 to 1377, p < 0.01); (5) sTREM-1: 87 pg/ml (95% CI 2 to 171, p = 0.04); (6) suPAR: 5.2 ng/ml (95% CI 4.5 to 6.0, p < 0.01).

Conclusions

Ang-1, Ang-2, and suPAR provide beneficial prognostic information about mortality in adult patients with sepsis. The further development of standardized assays and the assessment of their performance when included in panels with other biomarkers may be recommended.
Trial registration This study was recorded on PROSPERO, prospective register of systematic reviews, under the registration ID: CRD42018081226
Appendix
Available only for authorised users
Literature
1.
Reinhart K, Daniels R, Kissoon N, Machado FR, Schachter RD, Finfer S. Recognizing sepsis as a global health priority—a WHO resolution. N Engl J Med. 2017;377(5):414–7.PubMedCrossRef
2.
Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, et al. Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am J Respir Crit Care Med. 2016;193(3):259–72.PubMedCrossRef
3.
4.
5.
Vincent J-L, Teixeira L. Sepsis biomarkers. Value and limitations. Am J Respir Crit Care Med. 2014;190(10):1081–2.PubMedCrossRef
6.
7.
Erlandsson Harris H, Andersson U. Mini-review: the nuclear protein HMGB1 as a proinflammatory mediator. Eur J Immunol. 2004;34(6):1503–12.PubMedCrossRef
8.
Bopp C, Bierhaus A, Hofer S, Bouchon A, Nawroth PP, Martin E, et al. Bench-to-bedside review: the inflammation-perpetuating pattern-recognition receptor RAGE as a therapeutic target in sepsis. Crit Care. 2008;12(1):201.PubMedPubMedCentralCrossRef
9.
Bouchon A, Facchetti F, Weigand MA, Colonna M. TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature. 2001;410(6832):1103–7.CrossRefPubMed
10.
11.
Huai Q, Mazar AP, Kuo A, Parry GC, Shaw DE, Callahan J, et al. Structure of human urokinase plasminogen activator in complex with its receptor. Science. 2006;311(5761):656.PubMedCrossRef
12.
Vincent JL, Beumier M. Diagnostic and prognostic markers in sepsis. Expert Rev Anti Infect Ther. 2013;11(3):265–75.PubMedCrossRef
13.
Sandquist M, Wong HR. Biomarkers of sepsis and their potential value in diagnosis, prognosis and treatment. Expert Rev Clin Immunol. 2014;10(10):1349–56.PubMedPubMedCentralCrossRef
14.
Backes Y, Van Der Sluijs KF, Mackie DP, Tacke F, Koch A, Tenhunen JJ, et al. Usefulness of suPAR as a biological marker in patients with systemic inflammation or infection: a systematic review. Intensive Care Med. 2012;38(9):1418–28.PubMedPubMedCentralCrossRef
15.
Xing K, Murthy S, Liles WC, Singh JM. Clinical utility of biomarkers of endothelial activation in sepsis—a systematic review. Crit Care (London, England). 2012;16(1):R7.CrossRef
16.
Su L, Liu D, Chai W, Liu D, Long Y. Role of sTREM-1 in predicting mortality of infection: a systematic review and meta-analysis. BMJ Open. 2016;6(5):e010314.PubMedPubMedCentralCrossRef
17.
Ni W, Han Y, Zhao J, Cui J, Wang K, Wang R, et al. Serum soluble urokinase-type plasminogen activator receptor as a biological marker of bacterial infection in adults: a systematic review and meta-analysis. Sci Rep. 2016;6:39481.PubMedPubMedCentralCrossRef
18.
Moher D, Liberati A, Tetzlaff J, Altman DG, The PG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLOS Med. 2009;6(7):e1000097.PubMedPubMedCentralCrossRef
19.
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 2016;315(8):801–10.PubMedPubMedCentralCrossRef
20.
Hayden JA, van der Windt DA, Cartwright JL, Côté P, Bombardier C. Assessing bias in studies of prognostic factors. Ann Intern Med. 2013;158(4):280–6.PubMedCrossRef
21.
Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions. New York: Wiley; 2011.
22.
Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014;14:135.PubMedPubMedCentralCrossRef
23.
Luo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res. 2016;27(6):1785–805.PubMedCrossRef
24.
Weir CJ, Butcher I, Assi V, Lewis SC, Murray GD, Langhorne P, et al. Dealing with missing standard deviation and mean values in meta-analysis of continuous outcomes: a systematic review. BMC Med Res Methodol. 2018;18(1):25.PubMedPubMedCentralCrossRef
25.
26.
27.
Wickham H. ggplot2: elegant graphics for data analysis. New York: Springer; 2009.CrossRef
28.
Schwarzer G. meta: an R package for meta-analysis. R News. 2007;7(3):40–5.
29.
Davis JS, Yeo TW, Piera KA, Woodberry T, Celermajer DS, Stephens DP, et al. Angiopoietin-2 is increased in sepsis and inversely associated with nitric oxide-dependent microvascular reactivity. Crit Care. 2010;14(3):R89.PubMedPubMedCentralCrossRef
30.
Fang Y, Li C, Shao R, Yu H, Zhang Q, Zhao L. Prognostic significance of the angiopoietin-2/angiopoietin-1 and angiopoietin-1/Tie-2 ratios for early sepsis in an emergency department. Crit Care (London, England). 2015;19:367.CrossRef
31.
Kranidioti H, Orfanos SE, Vaki I, Kotanidou A, Raftogiannis M, Dimopoulou I, et al. Angiopoietin-2 is increased in septic shock: evidence for the existence of a circulating factor stimulating its release from human monocytes. Immunol Lett. 2009;125(1):65–71.PubMedCrossRef
32.
Lin S-M, Chung F-T, Kuo C-H, Chou P-C, Wang T-Y, Chang P-J, et al. Circulating angiopoietin-1 correlates with the clinical course of multiple organ dysfunction syndrome and mortality in patients with severe sepsis. Medicine. 2015;94(20):e878.PubMedPubMedCentralCrossRef
33.
Mikacenic C, Hahn WO, Price BL, Harju-Baker S, Katz R, Kain KC, et al. Biomarkers of endothelial activation are associated with poor outcome in critical illness. PLoS ONE. 2015;10(10):e0141251.PubMedPubMedCentralCrossRef
34.
Palud A, Parmentier-Decrucq E, Pastre J, De Freitas Caires N, Lassalle P, Mathieu D. Evaluation of endothelial biomarkers as predictors of organ failures in septic shock patients. Cytokine. 2015;73(2):213–8.PubMedCrossRef
35.
Parikh SM, Mammoto T, Schultz A, Yuan HT, Christiani D, Karumanchi SA, et al. Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans. PLoS Med. 2006;3(3):e46.PubMedPubMedCentralCrossRef
36.
Ricciuto DR, dos Santos CC, Hawkes M, Toltl LJ, Conroy AL, Rajwans N, et al. Angiopoietin-1 and angiopoietin-2 as clinically informative prognostic biomarkers of morbidity and mortality in severe sepsis. Crit Care Med. 2011;39(4):702–10.PubMedCrossRef
37.
Siner JM, Bhandari V, Engle KM, Elias JA, Siegel MD. Elevated serum angiopoietin 2 levels are associated with increased mortality in sepsis. Shock (Augusta, GA). 2009;31(4):348–53.CrossRef
38.
van der Heijden M, Pickkers P, van Nieuw Amerongen GP, van Hinsbergh VWM, Bouw MPWJM, van der Hoeven JG, et al. Circulating angiopoietin-2 levels in the course of septic shock: relation with fluid balance, pulmonary dysfunction and mortality. Intensive Care Med. 2009;35(9):1567–74.PubMedPubMedCentralCrossRef
39.
Sunden-Cullberg J, Norrby-Teglund A, Rouhiainen A, Rauvala H, Herman G, Tracey KJ, et al. Persistent elevation of high mobility group box-1 protein (HMGB1) in patients with severe sepsis and septic shock. Crit Care Med. 2005;33(3):564–73.PubMedCrossRef
40.
Gibot S, Massin F, Cravoisy A, Barraud D, Nace L, Levy B, et al. High-mobility group box 1 protein plasma concentrations during septic shock. Intensive Care Med. 2007;33(8):1347–53.PubMedCrossRef
41.
van Zoelen MA, Laterre PF, van Veen SQ, van Till JW, Wittebole X, Bresser P, et al. Systemic and local high mobility group box 1 concentrations during severe infection. Crit Care Med. 2007;35(12):2799–804.PubMedCrossRef
42.
Karlsson S, Pettila V, Tenhunen J, Laru-Sompa R, Hynninen M, Ruokonen E. HMGB1 as a predictor of organ dysfunction and outcome in patients with severe sepsis. Intensive Care Med. 2008;34(6):1046–53.PubMedCrossRef
43.
Huang LF, Yao YM, Dong N, Yu Y, He LX, Sheng ZY. Association of high mobility group box-1 protein levels with sepsis and outcome of severely burned patients. Cytokine. 2011;53(1):29–34.PubMedCrossRef
44.
Ueno T, Ikeda T, Ikeda K, Taniuchi H, Suda S, Yeung MY, et al. HMGB-1 as a useful prognostic biomarker in sepsis-induced organ failure in patients undergoing PMX-DHP. J Surg Res. 2011;171(1):183–90.PubMedCrossRef
45.
Narvaez-Rivera RM, Rendon A, Salinas-Carmona MC, Rosas-Taraco AG. Soluble RAGE as a severity marker in community acquired pneumonia associated sepsis. BMC Infect Dis. 2012;12:15.PubMedPubMedCentralCrossRef
46.
Charoensup J, Sermswan RW, Paeyao A, Promakhejohn S, Punasee S, Chularari C, et al. High HMGB1 level is associated with poor outcome of septicemic melioidosis. Int J Infect Dis. 2014;28:e111–6.CrossRef
47.
Ravetti CG, Moura AD, Vieira EL, Pedroso ERP, Teixeira AL. sTREM-1 predicts intensive care unit and 28-day mortality in cancer patients with severe sepsis and septic shock. J Crit Care. 2015;30(2):440.e7–13.CrossRef
48.
Lee K, Chang Y, Song K, Park YY, Huh JW, Hong SB, et al. Associations between single nucleotide polymorphisms of high mobility group box 1 protein and clinical outcomes in Korean sepsis patients. Yonsei Med J. 2016;57(1):111–7.PubMedCrossRef
49.
Nobre V, Ataide TB, Brant LC, Oliveira CR, Rodrigues LV, Ribeiro ALP, et al. Use of reactive hyperemia—peripheral arterial tonometry and circulating biological markers to predict outcomes in sepsis. Revista Brasileira de terapia intensiva. 2016;28(4):387–96.PubMedPubMedCentralCrossRef
50.
Bopp C, Hofer S, Weitz J, Bierhaus A, Nawroth PP, Martin E, et al. sRAGE is elevated in septic patients and associated with patients outcome. J Surg Res. 2008;147(1):79–83.PubMedCrossRef
51.
Brodska H, Malickova K, Valenta J, Fabio A, Drabek T. Soluble receptor for advanced glycation end products predicts 28-day mortality in critically ill patients with sepsis. Scand J Clin Lab Invest. 2013;73(8):650–60.PubMedPubMedCentralCrossRef
52.
Hamasaki MY, Barbeiro HV, de Souza HP, Machado MCC, da Silva FP. sRAGE in septic shock: a potential biomarker of mortality. Revista Brasileira de terapia intensiva. 2014;26(4):392–6.PubMedPubMedCentralCrossRef
53.
Gibot S, Cravoisy A, Kolopp-Sarda MN, Bene MC, Faure G, Bollaert PE, et al. Time-course of sTREM (soluble triggering receptor expressed on myeloid cells)-1, procalcitonin, and C-reactive protein plasma concentrations during sepsis. Crit Care Med. 2005;33(4):792–6.PubMedCrossRef
54.
Giamarellos-Bourboulis EJ, Zakynthinos S, Baziaka F, Papadomichelakis E, Virtzili S, Koutoukas P, et al. Soluble triggering receptor expressed on myeloid cells 1 as an anti-inflammatory mediator in sepsis. Intensive Care Med. 2006;32(2):237–43.PubMedCrossRef
55.
Phua J, Koay ESC, Zhang D, Lee KH. How well do serum sTREM-1 measurements prognosticate in septic shock? Anaesth Intensive Care. 2008;36(5):654–8.PubMedCrossRef
56.
Suárez-Santamaría M, Santolaria F, Pérez-Ramírez A, Alemán-Valls MR, Martínez-Riera A, González-Reimers E, et al. Prognostic value of inflammatory markers (notably cytokines and procalcitonin), nutritional assessment, and organ function in patients with sepsis. Eur Cytokine Netw. 2010;21(1):19–26.PubMed
57.
58.
Su L, Liu C, Li C, Jiang Z, Xiao K, Zhang X, et al. Dynamic changes in serum soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) and its gene polymorphisms are associated with sepsis prognosis. Inflammation. 2012;35(6):1833–43.CrossRefPubMed
59.
60.
Bayram H, Tünger Ö, Çivi M, Yüceyar MH, Ulman C, Dinç Horasan G, et al. Diagnostic and prognostic value of procalcitonin and sTREM-1 levels in sepsis. Turk J Med Sci. 2015;45(3):578–86.CrossRef
61.
Charles PE, Noel R, Massin F, Guy J, Bollaert PE, Quenot JP, et al. Significance of soluble triggering receptor expressed on myeloid cells-1 elevation in patients admitted to the intensive care unit with sepsis. BMC Infect Dis. 2016;16(1):559.PubMedPubMedCentralCrossRef
62.
Brenner T, Uhle F, Fleming T, Wieland M, Schmoch T, Schmitt F, et al. Soluble TREM-1 as a diagnostic and prognostic biomarker in patients with septic shock: an observational clinical study. Biomarkers. 2017;22(1):63–9.PubMedCrossRef
63.
Giamarellos-Bourboulis EJ, Norrby-Teglund A, Mylona V, Savva A, Tsangaris I, Dimopoulou I, et al. Risk assessment in sepsis: a new prognostication rule by APACHE II score and serum soluble urokinase plasminogen activator receptor. Crit Care. 2012;16(4):R149.PubMedPubMedCentralCrossRef
64.
Gustafsson A, Ljunggren L, Bodelsson M, Berkestedt I. The prognostic value of suPAR compared to other inflammatory markers in patients with severe sepsis. Biomark Insights. 2012;7:39–44.PubMedPubMedCentralCrossRef
65.
Hoenigl M, Raggam RB, Wagner J, Valentin T, Leitner E, Seeber K, et al. Diagnostic accuracy of soluble urokinase plasminogen activator receptor (suPAR) for prediction of bacteremia in patients with systemic inflammatory response syndrome. Clin Biochem. 2013;46(3):225–9.PubMedCrossRef
66.
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;39(11):1945–52.PubMedCrossRef
67.
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;29(1):144–9.PubMedCrossRef
68.
Khater WS, Salah-Eldeen NN, Khater MS, Saleh AN. Role of suPAR and lactic acid in diagnosing sepsis and predicting mortality in elderly patients. Eur J Microbiol Immunol. 2016;6(3):178–85.CrossRef
69.
Liu X, Shen Y, Li Z, Fei A, Wang H, Ge Q, et al. Prognostic significance of APACHE II score and plasma suPAR in Chinese patients with sepsis: a prospective observational study. BMC Anesthesiol. 2016;16(1):46.PubMedPubMedCentralCrossRef
70.
Shan L, Shan F, Li J, Li X, Sun YB. Association of circulating suPAR with disease severity and clinical outcomes in patients with ARDS induced by intra-abdominal infections: a prospective observational study. Int J Clin Exp Med. 2016;9(7):12788–95.
71.
Tsirigotis P, Chondropoulos S, Frantzeskaki F, Stamouli M, Gkirkas K, Bartzeliotou A, et al. Thrombocytopenia in critically ill patients with severe sepsis/septic shock: prognostic value and association with a distinct serum cytokine profile. J Crit Care. 2016;32:9–15.PubMedCrossRef
72.
Zeng M, Chang M, Zheng H, Li B, Chen Y, He W, et al. Clinical value of soluble urokinase-type plasminogen activator receptor in the diagnosis, prognosis, and therapeutic guidance of sepsis. Am J Emerg Med. 2016;34(3):375–80.PubMedCrossRef
73.
Arora S, Singh P, Singh PM, Trikha A. procalcitonin levels in survivors and nonsurvivors of sepsis: systematic review and meta-analysis. Shock. 2015;43(3):212–21.PubMedCrossRef
74.
Liu D, Su L, Han G, Yan P, Xie L. Prognostic value of procalcitonin in adult patients with sepsis: a systematic review and meta-analysis. PLoS ONE. 2015;10(6):e0129450.PubMedPubMedCentralCrossRef
75.
Raith EP, Udy AA, Bailey M, McGloughlin S, MacIsaac C, Bellomo R, et al. Prognostic accuracy of the SOFA score, SIRS criteria, and qSOFA score for in-hospital mortality among adults with suspected infection admitted to the intensive care unit. JAMA. 2017;317(3):290–300.PubMedCrossRef
76.
Jabaudon M, Blondonnet R, Pereira B, Cartin-Ceba R, Lichtenstern C, Mauri T, et al. Plasma sRAGE is independently associated with increased mortality in ARDS: a meta-analysis of individual patient data. Intensive Care Med. 2018;44(9):1388–99.PubMedPubMedCentralCrossRef
77.
Bland M. Estimating mean and standard deviation from the sample size, three quartiles, minimum, and maximum. Int J Stat Med Res. 2015;4(1):57–64.CrossRef
78.
Cohen J, Vincent JL, Adhikari NK, Machado FR, Angus DC, Calandra T, et al. Sepsis: a roadmap for future research. Lancet Infect Dis. 2015;15(5):581–614.PubMedCrossRef
Metadata
Title
Prediction of mortality in adult patients with sepsis using six biomarkers: a systematic review and meta-analysis
Authors
Andreas Pregernig
Mattia Müller
Ulrike Held
Beatrice Beck-Schimmer
Publication date
01-12-2019
Publisher
Springer International Publishing
Published in
Annals of Intensive Care / Issue 1/2019
Electronic ISSN: 2110-5820
DOI
https://doi.org/10.1186/s13613-019-0600-1

Other articles of this Issue 1/2019

Annals of Intensive Care 1/2019 Go to the issue

Research

Association between post-procedural hyperoxia and poor functional outcome after mechanical thrombectomy for ischemic stroke: an observational study

Research

Determinants of left ventricular ejection fraction and a novel method to improve its assessment of myocardial contractility

Research

Driving pressure during proportional assist ventilation: an observational study

Research

Risk factors for progression toward brain death after out-of-hospital cardiac arrest

Research

Estimated dead space fraction and the ventilatory ratio are associated with mortality in early ARDS

Research

Impact of natural light exposure on delirium burden in adult patients receiving invasive mechanical ventilation in the ICU: a prospective study