A Molecular Host Response Assay to Discriminate Between Sepsis and Infection-Negative Systemic Inflammation in Critically Ill Patients: Discovery and Validation in Independent Cohorts

PLoS Medicine

Volumn 12, Issue 12, 2015, Pages

  McHugh, Leo ^a   Seldon, Therese A ^a   Brandon, Roslyn A ^a   Kirk, James T ^a   Rapisarda, Antony ^a   Sutherland, Allison J ^b   Presneill, Jeffrey J ^c   Venter, Deon J ^c,d   Lipman, Jeffrey ^d,e   Thomas, Mervyn R ^f   Klein Klouwenberg, Peter M C ^g   van Vught, Lonneke ^h   Scicluna, Brendon ^h   Bonten, Marc ^g   Cremer, Olaf L ^g   Schultz, Marcus J ^h   van der Poll, Tom ^h   Yager, Thomas D ^a   Brandon, Richard B ^a  

^a Immunexpress   (United States)

^b Biosurgical Ingenuity   (Australia)

^c MATER HOSPITAL   (Australia)

^d UNIVERSITY OF QUEENSLAND   (Australia)

^e ROYAL BRISBANE AND WOMEN'S HOSPITAL   (Australia)

^f Emphron Informatics   (Australia)

^g UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

^h ACADEMIC MEDICAL CENTER   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

BIOLOGICAL MARKER; C REACTIVE PROTEIN; PROCALCITONIN;

ADULT; AGED; APACHE; AREA UNDER THE CURVE; ARTICLE; BLOOD ANALYSIS; CONTROLLED STUDY; DATA PROCESSING; DIAGNOSTIC ERROR; DISEASE SEVERITY; FEMALE; GENE EXPRESSION; GENETIC ANALYSIS; HUMAN; IMMUNE RESPONSE; INFECTION RISK; INFLAMMATION; INFORMATION PROCESSING; INTENSIVE CARE UNIT; MAJOR CLINICAL STUDY; MALE; MEASUREMENT ACCURACY; MICROARRAY ANALYSIS; MOLECULAR DIAGNOSIS; OBSERVATIONAL STUDY; RECEIVER OPERATING CHARACTERISTIC; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; RNA ANALYSIS; RNA PURIFICATION; SENSITIVITY AND SPECIFICITY; SEPSIS; SEPTICYTE LAB ASSAY; SEQUENTIAL ORGAN FAILURE ASSESSMENT SCORE; VALIDATION PROCESS; AUSTRALIA; CASE CONTROL STUDY; COHORT ANALYSIS; CRITICAL ILLNESS; DEVICES; DIAGNOSTIC PROCEDURE; MIDDLE AGED; NETHERLANDS; STANDARDS; VALIDATION STUDY; VERY ELDERLY; YOUNG ADULT;

ADULT; AGED; AGED, 80 AND OVER; BIOMARKERS; CASE-CONTROL STUDIES; COHORT STUDIES; CRITICAL ILLNESS; DIAGNOSTIC TECHNIQUES AND PROCEDURES; FEMALE; HUMANS; INFLAMMATION; INTENSIVE CARE UNITS; MALE; MIDDLE AGED; NETHERLANDS; QUEENSLAND; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; ROC CURVE; SEPSIS; YOUNG ADULT;

EID: 84953790265     PISSN: 15491277     EISSN: 15491676     Source Type: Journal    
DOI: 10.1371/journal.pmed.1001916     Document Type: Article

References (85)

1. Hsu AA, Fenton K, Weinstein S, Carpenter J, Dalton H, Bell MJ, Neurological injury markers in children with septic shock. Pediatr Crit Care Med. 2008;9:245–251. doi: 10.1097/PCC.0b013e3181727b22 18446104
2. Winters BD, Eberlein M, Leung J, Needham DM, Pronovost PJ, Sevransky JE, Long-term mortality and quality of life in sepsis: a systematic review. Crit Care Med. 2010;38:1276–1283. doi: 10.1097/CCM.0b013e3181d8cc1d 20308885
3. Bauer M, Reinhart K, Molecular diagnostics of sepsis—where are we today? Int J Med Microbiol. 2010;300:411–413. doi: 10.1016/j.ijmm.2010.04.006 20510650
4. Calandra T, Cohen J, The International Sepsis Forum consensus conference on definitions of infection in the intensive care unit. Crit Care Med. 2005;33:1538–1548. 16003060
5. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock. Crit Care Med. 2008;36:296–327. 18158437
6. 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. Intensive Care Med. 2013;39:165–228. doi: 10.1007/s00134-012-2769-8 23361625
7. Coburn B, Morris AM, Tomlinson G, Detsky AS, Does this adult patient with suspected bacteremia require blood cultures? JAMA 2012;308:502–511. doi: 10.1001/jama.2012.8262 22851117
8. Angus DC, van der Poll T, Severe sepsis and septic shock. N Engl J Med. 2013;369:840–851. doi: 10.1056/NEJMra1208623 23984731
9. Forner L, Larsen T, Kilian M, Holmstrup P, Incidence of bacteremia after chewing, tooth brushing and scaling in individuals with periodontal inflammation. J Clin Periodontol. 2006;33:401–407. 16677328
10. Lamy B, Roy P, Carret G, Flandrois J- P, Delignette-Muller ML, What is the relevance of obtaining multiple blood samples for culture? A comprehensive model to optimize the strategy for diagnosing bacteremia. Clin Infect Dis. 2002;35:842–850. 12228821
11. Aronson MD, Bor DH, Blood cultures. Ann Intern Med. 1987;106:246–253. 3541726
12. Uzzan B, Cohen R, Nicolas P, Cucherat M, Perret G-Y, Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysis. Crit Care Med. 2006;34:1996–2003. 16715031
13. Meynaar IA, Droog W, Batstra M, Vreede R, Herbrink P, In critically ill patients, serum procalcitonin is more useful in differentiating between sepsis and SIRS than CRP, Il-6, or LBP. Crit Care Res Pract. 2011;2011:594645. doi: 10.1155/2011/594645 21687569
14. Tang BM, McLean AS, Dawes IW, Huang SJ, Lin RC, The use of gene-expression profiling to identify candidate genes in human sepsis. Am J Respir Crit Care Med. 2007;176:676–684. 17575094
15. Cruciani M, Meta-analyses of diagnostic tests in infectious diseases: how helpful are they in the intensive care setting? HSR Proc Intensive Care Cardiovasc Anesth. 2011;3:103–108. 23439607
16. Hoenigl M, Raggam RB, Wagner J, Prueller F, Grisold AJ, Leitner E, et al. Procalcitonin fails to predict bacteremia in SIRS patients: a cohort study. Int J Clin Pract. 2014;68:1278–1281. doi: 10.1111/ijcp.12474 24898888
17. Reinhart K, Bauer M, Riedemann NC, Hartog CS, New approaches to sepsis: molecular diagnostics and biomarkers. Clin Microbiol Rev. 2012;25:609–634. doi: 10.1128/CMR.00016-12 23034322
18. Shapiro NI, Trzeciak S, Hollander JE, Birkhahn R, Otero R, Osborn TM, et al. A prospective, multicenter derivation of a biomarker panel to assess risk of organ dysfunction, shock, and death in emergency department patients with suspected sepsis. Crit Care Med. 2009;37:96–104. doi: 10.1097/CCM.0b013e318192fd9d 19050610
19. Gibot S, Bene MC, Noel R, Massin F, Guy J, Cravoisy A, et al. Combination biomarkers to diagnose sepsis in the critically ill patient. Am J Resp Crit Care Med. 2012;186:65–71. doi: 10.1164/rccm.201201-0037OC 22538802
20. Venter D, Thomas M, Lipman J, Tang B, McLean A, Pascoe R, et al. A novel molecular biomarker diagnostic for the early detection of sepsis. Crit Care 2010;14 (Suppl 2):P9. doi: 10.1186/cc9112
21. Sutherland A, Thomas M, Brandon RA, Brandon RB, Lipman J, Tang B, et al. Development and validation of a novel molecular biomarker diagnostic test for the early detection of sepsis. Crit Care 2011;15:R149. doi: 10.1186/cc10274 21682927
22. Brandon RB, Thomas M, Brandon RA, Venter D, Presneill J, Lipman J, et al. A limited set of molecular biomarkers may provide superior diagnostic outcomes to procalcitonin in sepsis. Crit Care 2012;16 (Suppl 3):P40. doi: 10.1186/cc11727
23. 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;31:1250–1256. 12682500
24. Klein Klouwenberg PM, Ong DS, Bos LD, de Beer FM, van Hooijdonk RT, Huson MA, et al. Interobserver agreement of centers for disease control and prevention criteria for classifying infections in critically ill patients. Crit Care Med. 2013;41:2373–2378. doi: 10.1097/CCM.0b013e3182923712 23921277
25. Klein Klouwenberg PM, van Mourik MS, Ong DS, Horn J, Schultz MJ, Cremer OL, et al. Electronic implementation of a novel surveillance paradigm for ventilator-associated events. Feasibility and validation. Am J Respir Crit Care Med. 2014;189:947–955. doi: 10.1164/rccm.201307-1376OC 24498886
26. Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM, CDC definitions for nosocomial infections, 1988. Am J Infect Control 1988;16:128–140. 2841893
27. Lockstone HE, Exon array data analysis using Affymetrix power tools and R statistical software. Brief Bioinform. 2011;12.6:634–644. 21498550
28. Huber PJ, Robust statistics. New York: John Wiley and Sons; 1981.
29. Guyon I, Weston J, Barnhill S, Vapnik V, Gene selection for cancer classification using support vector machines. Mach Learn. 2002;46:389–422. doi: 10.1023/A:1012487302797
30. Díaz-Uriarte R, Alvarez de Andrés S, Gene selection and classification of microarray data using random forest. BMC Bioinformatics 2006;7:3. 16398926
31. Helm D, Labischinski H, Schallehn G, Naumann D, Classification and identification of bacteria by Fourier-transform infrared spectroscopy. J Gen Microbiol. 1991;137:69–79. 1710644
32. Clinical and Laboratory Standards InstituteAssessment of the diagnostic accuracy of laboratory tests using receiver operating characteristic curves; approved guideline. 2nd edition. EP24-A2. Wayne (Pennsylvania): Clinical and Laboratory Standards Institute; 2011.
33. Huang SH, Dimensionality reduction in automatic knowledge acquisition: a simple greedy search approach. IEEE Trans Knowl Data Eng. 2003;15.6:1364–1373. doi: 10.1109/TKDE.2003.1245278
34. Venkatraman ES, A permutation test to compare receiver operating characteristic curves. Biometrics 2000;56:1134–1138. 11129471
35. Robin X, Turck N, Hainard A, Tiberti N, Lisacek F, Sanchez J-C, et al. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics 2011;12:77–93. doi: 10.1186/1471-2105-12-77 21414208
36. DeLong ER, DeLong DM, Clarke-Pearson DL, Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988;44:837–845. 3203132
37. Gustafson P, Le Nhu D, Comparing the effects of continuous and discrete covariate mismeasurement, with emphasis on the dichotomization of mismeasured predictors. Biometrics 2002;58:878–887. 12495142
38. Royston P, Altman DG, Sauerbrei W, Dichotomizing continuous predictors in multiple regression: a bad idea. Stat Med. 2006;25:127–141. 16217841
39. Naggara O, Raymond J, Guilbert F, Roy D, Weill A, Altman DG, Analysis by categorizing or dichotomizing continuous variables is inadvisable: an example from the natural history of unruptured aneurysms. Am J Neuroradiol. 2011;32:437–440. doi: 10.3174/ajnr.A2425 21330400
40. Caille A, Leyrat C, Giraudeau B, Dichotomizing a continuous outcome in cluster randomized trials: impact on power. Stat Med. 2012;31:2822–2832. doi: 10.1002/sim.5409 22733454
41. Gu W, Pepe MS, Estimating the capacity for improvement in risk prediction with a marker. Biostatistics 2009;10:172–186. doi: 10.1093/biostatistics/kxn025 18714084
42. Pencina MJ, D’Agostino RB, SrD’Agostino RB, JrVasan RS, Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med. 2008;27:157–172. 17569110
43. Kerr KF, Wang Z, Janes H, McClelland RL, Psaty BM, Pepe MS, Net reclassification indices for evaluating risk prediction instruments: a critical review. Epidemiology 2014;25:114–121. doi: 10.1097/EDE.0000000000000018 24240655
44. Leisenring W, Alonzo T, Pepe MS, Comparisons of predictive values of binary medical diagnostic tests for paired designs. Biometrics 2000;56:345–351. 10877288
45. Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig LM, et al. Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative. Clin Chem. 2003;49:1–6. 12507953
46. Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig LM, et al. The STARD statement for reporting studies of diagnostic accuracy: explanation and elaboration. Clin Chem. 2003;49:7–18. 12507954
47. Takahashi W, Watanabe E, Fujimura L, Watanabe-Takano H, Yoshidome H, Swanson PE, et al. Kinetics and protective role of autophagy in a mouse cecal ligation and puncture-induced sepsis. Crit Care 2013;17:R160. doi: 10.1186/cc12839 23883625
48. Huynh KK, Eskelinen EL, Scott CC, Malevanets A, Saftig P, Grinstein S, LAMP proteins are required for fusion of lysosomes with phagosomes. EMBO J 2007;26:313–324. 17245426
49. Lin L, Ayala P, Larson J, Mulks M, Fukuda M, Carlsson SR, et al. The Neisseria type 2 IgA1 protease cleaves LAMP1 and promotes survival of bacteria within epithelial cells. Mol Microbiol. 1997;24:1083–1094. 9220014
50. Endo S, Inada K, Yamashita H, Takakuwa T, Nakae H, Kasai T, et al. Platelet-activating factor (PAF) acetylhydrolase activity, type II phospholipase A2, and cytokine levels in patients with sepsis. Res Commun Chem Pathol Pharmacol. 1994;83:289–295. 8008978
51. Yang J, Xu J, Chen X, Zhang Y, Jiang X, Guo X, et al. Decrease of plasma platelet-activating factor acetylhydrolase activity in lipopolysaccharide induced Mongolian gerbil sepsis model. PLoS ONE 2010;5:e9190. doi: 10.1371/journal.pone.0009190 20169191
52. Gomes RN, Bozza FA, Amancio RT, Japiassu AM, Vianna RC, Larangeira AP, et al. Exogenous platelet-activating factor acetylhydrolase reduces mortality in mice with systemic inflammatory response syndrome and sepsis. Shock 2006;26:41–49. 16783197
53. Takakuwa T, Endo S, Nakae H, Suzuki T, Inada K, Yoshida M, et al. Relationships between plasma levels of type-II phospholipase A2, PAF-acetylhydrolase, leukotriene B4, complements, endothelin-1, and thrombomodulin in patients with sepsis. Res Commun Chem Pathol Pharmacol. 1994;84:271–281. 7938901
54. Schuster DP, Metzler M, Opal S, Lowry S, Balk R, Abraham E, et al. Recombinant platelet-activating factor acetylhydrolase to prevent acute respiratory distress syndrome and mortality in severe sepsis: phase IIb, multicenter, randomized, placebo-controlled, clinical trial. Crit Care Med. 2003;31:1612–1619. 12794395
55. Opal S, Laterre P-F, Abraham E, Francois B, Wittebole X, Lowry S, et al. Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial. Crit Care Med. 2004;32:332–341. 14758145
56. Pankla R, Buddhisa S, Berry M, Blankenship DM, Bancroft GJ, Banchereau J, et al. Genomic transcriptional profiling identifies a candidate blood biomarker signature for the diagnosis of septicemic melioidosis. Genome Biol. 2009;10:R127. doi: 10.1186/gb-2009-10-11-r127 19903332
57. Ledford JG, Kovarova M, Koller BH, Impaired host defense in mice lacking ONZIN. J Immunol. 2007;178:5132–5143. 17404296
58. Johnson RM, Kerr MS, Slaven JE, Perforin is detrimental to controlling C. muridarum replication in vitro, but not in vivo. PLoS ONE 2013;8:e63340. doi: 10.1371/journal.pone.0063340 23691028
59. Johnson RM, Kerr MS, Slaven JE, Plac8-dependent and inducible NO synthase-dependent mechanisms clear Chlamydia muridarum infections from the genital tract. J Immunol. 2012;188:1896–1904. doi: 10.4049/jimmunol.1102764 22238459
60. Wieland S, Thimme R, Purcell RH, Chisari FV, Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci U S A 2004;101:6669–6674. 15100412
61. Kuroki M, Arakawa F, Matsuo Y, Oikawa S, Misumi Y, Nakazato H, et al. Molecular cloning of nonspecific cross-reacting antigens in human granulocytes. J Biol Chem. 1991;266:11810–11817. 2050678
62. Tascón JD, Adrian J, Kopp K, Scholz P, Tschan MP, Kuespert K, et al. The granulocyte orphan receptor CEACAM4 is able to trigger phagocytosis of bacteria. J Leukocyte Biol. 2015;97:521–531. doi: 10.1189/jlb.2AB0813-449RR 25567962
63. Bos MP, Grunert F, Belland RJ, Differential recognition of members of the carcinoembryonic antigen family by Opa variants of Neisseria gonorrhoeae. Infect Immun. 1997;65:2353–2361. 9169774
64. Klein SL, Sex differences in prophylaxis and therapeutic treatments for viral diseases. Handb Exp Pharmacol. 2012;214:499–522. doi: 10.1007/978-3-642-30726-3_22 23027464
65. Pennell LM, Galligan CL, Fish EN, Sex affects immunity. J Autoimmun. 2012;38:J282–J291. doi: 10.1016/j.jaut.2011.11.013 22225601
66. Gelfand EW, Development of asthma is determined by the age-dependent host response to respiratory virus infection: therapeutic implications. Curr Opin Immunol. 2012;24:713–719. doi: 10.1016/j.coi.2012.08.011 22981683
67. Stoecklein VM, Osuka A, Lederer JA, Trauma equals danger—damage control by the immune system. J Leukocyte Biol. 2012;92:539–551. doi: 10.1189/jlb.0212072 22654121
68. Lang PO, Aspinall R, Immunosenescence and herd immunity: with an ever increasing aging population do we need to rethink vaccine schedules? Expert Rev Vaccines 2012;11:167–176. doi: 10.1586/erv.11.187 22309666
69. Fulop T, Larbi A, Kotb R, de Angelis AF, Pawelec G, Aging, immunity, and cancer. Discov Med 2011;11:537–550. 21712020
70. Ransohoff DF, Feinstein AR, Problems of spectrum and bias in evaluating the efficacy of diagnostic tests. N Engl J Med. 1978;299:926–930. 692598
71. Lijmer JG, Mol BW, Heisterkamp S, Bonsel GJ, Prins MH, van der Meulen JH, et al. Empirical evidence of design-related bias in studies of diagnostic tests. J Am Med Assoc. 1999;282:1061–1066. 10493205
72. Mulherin SA, Miller WC, Spectrum bias or spectrum effect? Subgroup variation in diagnostic test evaluation. Ann Intern Med. 2002;137:598–602. 12353947
73. Willis BH, Spectrum bias—why clinicians need to be cautious when applying diagnostic test studies. Fam Pract. 2008;25:390–396. doi: 10.1093/fampra/cmn051 18765409
74. Castelli GP, Pognani C, Meisner M, Stuani A, Bellomi D, Sgarbi L, Procalcitonin and C-reactive protein during systemic inflammatory response syndrome, sepsis and organ dysfunction. Crit Care. 2004;8:R234–R242. doi: 10.1186/cc2877 15312223
75. Luzzani A, Polati E, Dorizzi R, Rungatscher A, Pavan R, Merlini A, Comparison of procalcitonin and C-reactive protein as markers of sepsis. Crit Care Med. 2003;31:1737–1741. 12794413
76. Rey C, Los Arcos M, Concha A, Medina A, Prieto S, Martinez P, et al. Procalcitonin and C-reactive protein as markers of systemic inflammatory response syndrome severity in critically ill children. Intensive Care Med. 2007;33:477–484. 17260130
77. van Gestel A, Bakker J, Veraart CP, van Hout BA, Prevalence and incidence of severe sepsis in Dutch intensive care units. Crit Care. 2004;8:R153–R162. doi: 10.1186/cc2858 15312213
78. Pewsner D, Battaglia M, Minder C, Marx A, Bucher HC, Egger M, Ruling a diagnosis in or out with “SpPIn” and “SnNOut”: a note of caution. BMJ. 2004;329:209–213. 15271832
79. Knaus WA, Wagner DP, Draper EA, Zimmerman JE, Bergner M, Bastos PG, et al. The APACHE III prognostic system. Risk prediction of hospital mortality for critically ill hospitalized adults. Chest 1991;100:1619–1636. 1959406
80. Moreno R, Vincent J-L, Matos R, Mendonca A, Cantraine F, Thijs L, et al. The use of maximum SOFA score to quantify organ dysfunction/failure in intensive care. Results of a prospective, multicentre study. Working Group on Sepsis related Problems of the ESICM. Intensive Care Med. 1999;25:686–696. 10470572
81. Cook R, Cook DJ, Tilley J, Lee K, Marshall J, Multiple organ dysfunction: baseline and serial component scores. Crit Care Med. 2001;29:2046–2050. 11700393
82. Braykov NP, Morgan DJ, Schweizer ML, Uslan DZ, Kelesidis T, Weisenberg SA, et al. Assessment of empirical antibiotic therapy optimisation in six hospitals: an observational cohort study. Lancet Infect Dis. 2014;14:1220–1227. doi: 10.1016/S1473-3099(14)70952-1 25455989
83. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AA, Knaus WA, et al. Definitions 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;101:1644–1655. 1303622
84. Nathan C, Points of control in inflammation. Nature 2002;420:846–852. 12490957
85. Nathan C, Ding A, Non-resolving inflammation. Cell 2010;140:871–882. doi: 10.1016/j.cell.2010.02.029 20303877