Sepsis biomarkers: an omics perspective

Abstract

Sepsis is a common cause of death in hospitalized patients worldwide. The early detection of sepsis remains a great challenge for clinicians, and delayed diagnosis frequently undermines treatment efforts, thereby contributing to high mortality. Omics technologies allow high-throughput screening of sepsis biomarkers. This review describes currently available and novel sepsis biomarkers in the context of genomics, transcriptomics, proteomics, and metabolomics. The combination of these technologies can help refine the diagnosis of sepsis. This review paper serves as a reference for future studies that employ an integrated, multi-omics approach to disease identification.

Keywords

sepsis / biomarker / genomics / transcriptomics / proteomics / metabolomics

References

[1] Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, Suppes R, Feinstein D, Zanotti S, Taiberg L, Gurka D, Kumar A, Cheang M. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med2006; 34(6): 1589–1596

[2] Reinhart K, Bauer M, Riedemann NC, Hartog CS. New approaches to sepsis: molecular diagnostics and biomarkers. Clin Microbiol Rev2012; 25(4): 609–634

[3] Cohen J. The immunopathogenesis of sepsis. Nature2002; 420(6917): 885–891

[4] Harbarth S, Holeckova K, Froidevaux C, Pittet D, Ricou B, Grau GE, Vadas L, Pugin J; Geneva Sepsis Network.. Diagnostic value of procalcitonin, interleukin-6, and interleukin-8 in critically ill patients admitted with suspected sepsis. Am J Respir Crit Care Med2001; 164(3): 396–402

[5] Simon L, Gauvin F, Amre DK, Saint-Louis P, Lacroix J. Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect Dis2004; 39(2): 206–217

[6] Bozza FA, Salluh JI, Japiassu AM, Soares M, Assis EF, Gomes RN, Bozza MT, Castro-Faria-Neto HC, Bozza PT. Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis. Crit Care2007; 11(2): R49

[7] Vaschetto R, Nicola S, Olivieri C, Boggio E, Piccolella F, Mesturini R, Damnotti F, Colombo D, Navalesi P, Della Corte F, Dianzani U, Chiocchetti A. Serum levels of osteopontin are increased in SIRS and sepsis. Intensive Care Med2008; 34(12): 2176–2184

[8] Brenner T, Rosenhagen C, Steppan J, Lichtenstern C, Weitz J, Bruckner T, Martin EO, Hoffmann U, Weigand MA, Hofer S. Redox responses in patients with sepsis: high correlation of thioredoxin-1 and macrophage migration inhibitory factor plasma levels. Mediators Inflamm2010; 2010: 985614

[9] Bae JS. Role of high mobility group box 1 in inflammatory disease: focus on sepsis. Arch Pharm Res2012; 35(9): 1511–1523

[10] Wu Y, Wang F, Fan X, Bao R, Bo L, Li J, Deng X. Accuracy of plasma sTREM-1 for sepsis diagnosis in systemic inflammatory patients: a systematic review and meta-analysis. Crit Care2012; 16(6): R229

[11] Backes Y, van der Sluijs KF, Mackie DP, Tacke F, Koch A, Tenhunen JJ, Schultz MJ. Usefulness of suPAR as a biological marker in patients with systemic inflammation or infection: a systematic review. Intensive Care Med2012; 38(9): 1418–1428

[12] Cohen J. The immunopathogenesis of sepsis. Nature2002; 420(6917): 885–891

[13] Lobo SM, Lobo FR, Bota DP, Lopes-Ferreira F, Soliman HM, Mélot C, Vincent JL. C-reactive protein levels correlate with mortality and organ failure in critically ill patients. Chest2003; 123(6): 2043–2049

[14] Komiya K, Ishii H, Teramoto S, Takahashi O, Yamamoto H, Oka H, Umeki K, Kadota J.Plasma C-reactive protein levels are associated with mortality in elderly with acute lung injury. J Crit Care2012; 27(5): 524 e521–526

[15] Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G; SCCM/ESICM/ACCP/ATS/SIS. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med2003; 31(4): 1250–1256

[16] Wacker C, Prkno A, Brunkhorst FM, Schlattmann P. Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet Infect Dis2013; 13(5): 426–435

[17] Kofoed K, Andersen O, Kronborg G, Tvede M, Petersen J, Eugen-Olsen J, Larsen K. Use of plasma C-reactive protein, procalcitonin, neutrophils, macrophage migration inhibitory factor, soluble urokinase-type plasminogen activator receptor, and soluble triggering receptor expressed on myeloid cells-1 in combination to diagnose infections: a prospective study. Crit Care 2007; 11(2): R38

[18] Xiong C, McKeel DW, Jr., Miller JP, Morris JC. Combining correlated diagnostic tests: application to neuropathologic diagnosis of Alzheimer's disease. Medical decision making: an international journal of the Society for Medical Decision Making, 2004, 24(6): 659–669

[19] Gibot S, Béné MC, Noel R, Massin F, Guy J, Cravoisy A, Barraud D, De Carvalho Bittencourt M, Quenot JP, Bollaert PE, Faure G, Charles PE. Combination biomarkers to diagnose sepsis in the critically ill patient. Am J Respir Crit Care Med2012; 186(1): 65–71

[20] Wong HR. Genetics and genomics in pediatric septic shock. Crit Care Med2012; 40(5): 1618–1626

[21] Sutherland AM, Walley KR, Manocha S, Russell JA. The association of interleukin 6 haplotype clades with mortality in critically ill adults. Arch Intern Med2005; 165(1): 75–82

[22] Thompson CM, Holden TD, Rona G, Laxmanan B, Black RA, O’Keefe GE, Wurfel MM. Toll-like receptor 1 polymorphisms and associated outcomes in sepsis after traumatic injury: a candidate gene association study. Ann Surg2014; 259(1): 179–185

[23] Cornell TT, Wynn J, Shanley TP, Wheeler DS, Wong HR. Mechanisms and regulation of the gene-expression response to sepsis. Pediatrics2010; 125(6): 1248–1258

[24] de Aguiar BB, Girardi I, Paskulin DD, de Franca E, Dornelles C, Dias FS, Bonorino C, Alho CS. CD14 expression in the first 24h of sepsis: effect of –260C→T CD14 SNP. Immunol Invest2008; 37(8): 752–769

[25] Fallavena PR, Borges TJ, Paskulin DD, Paludo FJO, Goetze TB, de Oliveira JR, Nóbrega OT, Dias FS, Alho CS. The influences of CD14 –260C→T polymorphism on survival in ICU critically ill patients. Immunol Invest2009; 38(8): 797–811

[26] Heesen M, Bloemeke B, Schade U, Obertacke U, Majetschak M. The –260 C→T promoter polymorphism of the lipopolysaccharide receptor CD14 and severe sepsis in trauma patients. Intensive Care Med2002; 28(8): 1161–1163

[27] Barber RC, Aragaki CC, Rivera-Chavez FA, Purdue GF, Hunt JL, Horton JW. TLR4 and TNF-α polymorphisms are associated with an increased risk for severe sepsis following burn injury. J Med Genet2004; 41(11): 808–813

[28] Barber RC, Aragaki CC, Rivera-Chavez FA, Purdue GF, Hunt JL, Horton JW. TLR4 and TNF-α polymorphisms are associated with an increased risk for severe sepsis following burn injury. J Med Genet2004; 41(11): 808–813

[29] Zeng L, Gu W, Zhang AQ, Zhang M, Zhang LY, Du DY, Huang SN, Jiang JX. A functional variant of lipopolysaccharide binding protein predisposes to sepsis and organ dysfunction in patients with major trauma. Ann Surg2012; 255(1): 147–157

[30] Cardinal-Fernández P, Ferruelo A, El-Assar M, Santiago C, Gómez-Gallego F, Martín-Pellicer A, Frutos-Vivar F, Peñuelas O, Nin N, Esteban A, Lorente JA. Genetic predisposition to acute kidney injury induced by severe sepsis. J Crit Care2013; 28(4): 365–370

[31] Baier RJ, Loggins J, Yanamandra K. IL-10, IL-6 and CD14 polymorphisms and sepsis outcome in ventilated very low birth weight infants. BMC Med2006; 4(1): 10

[32] Jilma B, Marsik C, Kovar F, Wagner OF, Jilma-Stohlawetz P, Endler G. The single nucleotide polymorphism Ser128Arg in the E-selectin gene is associated with enhanced coagulation during human endotoxemia. Blood2005; 105(6): 2380–2383

[33] Geishofer G, Binder A, Müller M, Zöhrer B, Resch B, Müller W, Faber J, Finn A, Endler G, Mannhalter C, Zenz W; Central European Meningococcal Genetic Study Group. 4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene in children with systemic meningococcaemia. Eur J Pediatr2005; 164(8): 486–490

[34] Gunderson KL, Steemers FJ, Lee G, Mendoza LG, Chee MS. A genome-wide scalable SNP genotyping assay using microarray technology. Nat Genet2005; 37(5): 549–554

[35] Hoffmann TJ, Kvale MN, Hesselson SE, Zhan Y, Aquino C, Cao Y, Cawley S, Chung E, Connell S, Eshragh J, Ewing M, Gollub J, Henderson M, Hubbell E, Iribarren C, Kaufman J, Lao RZ, Lu Y, Ludwig D, Mathauda GK, McGuire W, Mei G, Miles S, Purdy MM, Quesenberry C, Ranatunga D, Rowell S, Sadler M, Shapero MH, Shen L, Shenoy TR, Smethurst D, Van den Eeden SK, Walter L, Wan E, Wearley R, Webster T, Wen CC, Weng L, Whitmer RA, Williams A, Wong SC, Zau C, Finn A, Schaefer C, Kwok PY, Risch N. Next generation genome-wide association tool: design and coverage of a high-throughput European-optimized SNP array. Genomics2011; 98(2): 79–89

[36] Arcaroli J, Fessler MB, Abraham E. Genetic polymorphisms and sepsis. Shock2005; 24(4): 300–312

[37] Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes Dev2009; 23(7): 781–783

[38] Delcuve GP, Rastegar M, Davie JR. Epigenetic control. J Cell Physiol2009; 219(2): 243–250

[39] Wen H, Dou Y, Hogaboam CM, Kunkel SL. Epigenetic regulation of dendritic cell-derived interleukin-12 facilitates immunosuppression after a severe innate immune response. Blood2008; 111(4): 1797–1804

[40] Bierne H, Hamon M, Cossart P. Epigenetics and bacterial infections. Cold Spring Harb Perspect Med2012; 2(12): a010272

[41] Laudanski K. Adoptive transfer of naïve dendritic cells in resolving post-sepsis long-term immunosuppression. Med Hypotheses2012; 79(4): 478–480

[42] Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, Bricker TL, Jarman SD 2nd, Kreisel D, Krupnick AS, Srivastava A, Swanson PE, Green JM, Hotchkiss RS. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA2011; 306(23): 2594–2605

[43] Carson WF, Cavassani KA, Dou Y, Kunkel SL. Epigenetic regulation of immune cell functions during post-septic immunosuppression. Epigenetics2011; 6(3): 273–283

[44] Wang X, Wang Y, Peng D, Huang W, Zhou X, Fu G. Changes in the inositol lipid signal system and effects on the secretion of TNF-α by macrophages in severely scalded mice. Burns2011; 37(8): 1378–1385

[45] Wang Y, Peng D, Huang W, Zhou X, Liu J, Fang Y. Mechanism of altered TNF-α expression by macrophage and the modulatory effect of Panax notoginseng saponins in scald mice. Burns2006; 32(7): 846–852

[46] Liu Y, Lin JD, Xiao XJ, Zhang BL, Lin H. An investigation of changes in gene expression profile of heart tissue in a rat sepsis model. Chin Crit Care Med (Zhongguo Wei Zhong Bing Ji Jiu Yi Xue)2009; 21(3): 155–159 (in Chinese)

[47] Li ZJ, Li YP, Gai HR, Xue YL, Feng XZ. Research of gene expression profile of liver tissue in rat sepsis model. Chin Crit Care Med (Zhongguo Wei Zhong Bing Ji Jiu Yi Xue)2007; 19(3): 156–159 (in Chinese)

[48] Cobb JP, Laramie JM, Stormo GD, Morrissey JJ, Shannon WD, Qiu Y, Karl IE, Buchman TG, Hotchkiss RS. Sepsis gene expression profiling: murine splenic compared with hepatic responses determined by using complementary DNA microarrays. Crit Care Med2002; 30(12): 2711–2721

[49] Li L, Wang XP, Wu K. Change of gene expression spectra of leucocyte in sepsis mice. Chin J Emerg Med (Zhongguo Ji Zhen Yi Xue Za Zhi)2005; 14(2): 122–126 (in Chinese)

[50] Lukaszewski RA, Yates AM, Jackson MC, Swingler K, Scherer JM, Simpson AJ, Sadler P, McQuillan P, Titball RW, Brooks TJ, Pearce MJ. Presymptomatic prediction of sepsis in intensive care unit patients. Clin Vaccine Immunol2008; 15(7): 1089–1094

[51] Sutherland A, Thomas M, Brandon RA, Brandon RB, Lipman J, Tang B, McLean A, Pascoe R, Price G, Nguyen T, Stone G, Venter D. Development and validation of a novel molecular biomarker diagnostic test for the early detection of sepsis. Crit Care2011; 15(3): R149

[52] Johnson SB, Lissauer M, Bochicchio GV, Moore R, Cross AS, Scalea TM. Gene expression profiles differentiate between sterile SIRS and early sepsis. Ann Surg2007; 245(4): 611–621

[53] Wong HR. Clinical review: Sepsis and septic shock- the potential of gene arrays. Crit Care2012; 16(1): 204

[54] Reid G, Kirschner MB, van Zandwijk N. Circulating microRNAs: association with disease and potential use as biomarkers. Crit Rev Oncol Hematol2011; 80(2): 193–208

[55] Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, Guo J, Zhang Y, Chen J, Guo X, Li Q, Li X, Wang W, Zhang Y, Wang J, Jiang X, Xiang Y, Xu C, Zheng P, Zhang J, Li R, Zhang H, Shang X, Gong T, Ning G, Wang J, Zen K, Zhang J, Zhang CY. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res2008; 18(10): 997–1006

[56] Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O’Briant KC, Allen A, Lin DW, Urban N, Drescher CW, Knudsen BS, Stirewalt DL, Gentleman R, Vessella RL, Nelson PS, Martin DB, Tewari M. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA2008; 105(30): 10513–10518

[57] Lawrie CH, Gal S, Dunlop HM, Pushkaran B, Liggins AP, Pulford K, Banham AH, Pezzella F, Boultwood J, Wainscoat JS, Hatton CS, Harris AL. Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Br J Haematol2008; 141(5): 672–675

[58] Hu Z, Chen X, Zhao Y, Tian T, Jin G, Shu Y, Chen Y, Xu L, Zen K, Zhang C, Shen H. Serum microRNA signatures identified in a genome-wide serum microRNA expression profiling predict survival of non-small-cell lung cancer. J Clin Oncol2010; 28(10): 1721–1726

[59] Zhang Y, Liao Y, Wang D, He Y, Cao D, Zhang F, Dou K. Altered expression levels of miRNAs in serum as sensitive biomarkers for early diagnosis of traumatic injury. J Cell Biochem2011; 112(9): 2435–2442

[60] Lorenzen JM, Kielstein JT, Hafer C, Gupta SK, Kümpers P, Faulhaber-Walter R, Haller H, Fliser D, Thum T. Circulating miR-210 predicts survival in critically ill patients with acute kidney injury. Clin J Am Soc Nephrol2011; 6(7): 1540–1546

[61] Kong XY, Du YQ, Li L, Liu JQ, Wang GK, Zhu JQ, Man XH, Gong YF, Xiao LN, Zheng YZ, Deng SX, Gu JJ, Li ZS. Plasma miR-216a as a potential marker of pancreatic injury in a rat model of acute pancreatitis. World J Gastroenterol2010; 16(36): 4599–4604

[62] Cermelli S, Ruggieri A, Marrero JA, Ioannou GN, Beretta L. Circulating microRNAs in patients with chronic hepatitis C and non-alcoholic fatty liver disease. PLoS ONE2011; 6(8): e23937

[63] Vasilescu C, Rossi S, Shimizu M, Tudor S, Veronese A, Ferracin M, Nicoloso MS, Barbarotto E, Popa M, Stanciulea O, Fernandez MH, Tulbure D, Bueso-Ramos CE, Negrini M, Calin GA. MicroRNA fingerprints identify miR-150 as a plasma prognostic marker in patients with sepsis. PLoS ONE2009; 4(10): e7405

[64] Zeng XL, Zhang SY, Zhang JF, Li FM, Ma XL, Mi YH. Expression of microRNA-150 in peripheral blood leukocytes in sepsis patients and its clinical significance. Chin J Respir Crit Care Med (Zhongguo Hu Xi Yu Wei Zhong Jian Hu Za Zhi)2011; 4(10): 360–364 (in Chinese)

[65] Zeng XL, Zhang SY, Zhang JF, Yuan H, Wang Y. Expression of microRNA-143 in sepsis and its clinical significance. J Chin Pract Diag Ther (Zhonghua Shi Yong Zhen Duan Yu Zhi Liao Za Zhi)2011; 11: 1063–1066 (in Chinese)

[66] Wang H, Meng K, Chen W, Feng D, Jia Y, Xie L. Serum miR-574-5p: a prognostic predictor of sepsis patients. Shock2012; 37(3): 263–267

[67] Wang JF, Yu ML, Yu G, Bian JJ, Deng XM, Wan XJ, Zhu KM. Serum miR-146a and miR-223 as potential new biomarkers for sepsis. Biochem Biophys Res Commun2010; 394(1): 184–188

[68] Peng X, Gralinski L, Armour CD, Ferris MT, Thomas MJ, Proll S, Bradel-Tretheway BG, Korth MJ, Castle JC, Biery MC, Bouzek HK, Haynor DR, Frieman MB, Heise M, Raymond CK, Baric RS, Katze MG. Unique signatures of long noncoding RNA expression in response to virus infection and altered innate immune signaling. MBio2010; 1(5): e00206-10, e00206-18

[69] Siqueira-Batista R, de Mendonça EG, Patrícia Gomes A, Roger Vitorino R, Miyadahira R, Alvarez-Perez MC, de Almeida Oliveira MG. Proteomic updates on sepsis. Rev Assoc Med Bras2012; 58(3): 376–382

[70] Zeng JZ, Zhang PH, Li LL, Ren LC, Liang PF, Huang XY. Proteomic study of peripheral blood lymphocytes of rabbits with severe burn and Pseudomonas aeruginosa sepsis. Chin Crit Care Med (Zhongguo Wei Zhong Bing Ji Jiu Yi Xue)2009; 21(8): 455–459 (in Chinese)

[71] He XD, Zou Q, Chen ZD, Yan PE. Proteomic analysis of neutrophils of rats with Acinetobacter baumannii sepsis. Chin J Microbiol Immunol (Zhonghua Wei Sheng Wu Xue He Mian Yi Xue Za Zhi)2012; 32(5): 385–394 (in Chinese)

[72] Hattori N, Oda S, Sadahiro T, Nakamura M, Abe R, Shinozaki K, Nomura F, Tomonaga T, Matsushita K, Kodera Y, Sogawa K, Satoh M, Hirasawa H. YKL-40 identified by proteomic analysis as a biomarker of sepsis. Shock2009; 32(4): 393–400

[73] Paugam-Burtz C, Albuquerque M, Baron G, Bert F, Voitot H, Delefosse D, Dondero F, Sommacale D, Francoz C, Hanna N, Belghiti J, Ravaud P, Bedossa P, Mantz J, Paradis V. Plasma proteome to look for diagnostic biomarkers of early bacterial sepsis after liver transplantation: a preliminary study. Anesthesiology2010; 112(4): 926–935

[74] Xu PB, Lin ZY, Meng HB, Yan SK, Yang Y, Liu XR, Li JB, Deng XM, Zhang WD. A metabonomic approach to early prognostic evaluation of experimental sepsis. J Infect2008; 56(6): 474–481

[75] Izquierdo-García JL, Nin N, Ruíz-Cabello J, Rojas Y, de Paula M, López-Cuenca S, Morales L, Martínez-Caro L, Fernández-Segoviano P, Esteban A, Lorente JA. A metabolomic approach for diagnosis of experimental sepsis. Intensive Care Med2011; 37(12): 2023–2032

[76] Lehmann LE, Hunfeld KP, Emrich T, Haberhausen G, Wissing H, Hoeft A, Stüber F. A multiplex real-time PCR assay for rapid detection and differentiation of 25 bacterial and fungal pathogens from whole blood samples. Med Microbiol Immunol (Berl)2008; 197(3): 313–324

[77] Kim J, Gao L, Tan K. Multi-analyte network markers for tumor prognosis. PLoS ONE2012; 7(12): e52973

Acknowledgements

This review was supported by grants from the Supporting Program for Science and Technology Research of China (2009BAI87B03), the Medical Project of the Ministry of Health of China (201202002), and the Open Program Fund of State Key Laboratory of Trauma, Burns, and Combined Injury (SKLKF201311).

Compliance with ethics guidelines

Xiao Liu, Hui Ren, and Daizhi Peng declare that they have no conflicts of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg