Diagnostic for Sepsis

Abstract

A method of diagnosing severe sepsis prior to definitive clinical diagnosis. A pattern of gene expression that correlates strongly with a future diagnosis of severe sepsis and organ failure was identified in patients who had their blood drawn at first clinical presentation. The methods comprise identifying a pattern of two or more polynucleotides, whereby the altered expression of these polynucleotides correlates with prospective and actual sepsis. Also methods of identifying agents for treating sepsis based on the characteristics of this gene expression pattern are provided.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows: 
     
         1 . A method for diagnosing sepsis in a subject, comprising determining in a biological sample obtained from the subject a level of expression for each of a plurality of Endotoxin Tolerance Signature genes to provide a sample gene signature, and comparing the sample gene signature with a reference gene signature, wherein the reference gene signature represents a standard level of expression of each of the plurality of genes; wherein a difference between the sample gene signature and the reference gene signature indicates that the subject has sepsis. 
     
     
         2 . The method according to  claim 1 , wherein the sepsis is severe sepsis. 
     
     
         3 . A method for identifying a subject at risk of developing severe sepsis, comprising determining in a biological sample obtained from the subject a level of expression for each of a plurality of Endotoxin Tolerance Signature genes to provide a sample gene signature, and comparing the sample gene signature with a reference gene signature, wherein the reference gene signature represents a standard level of expression of each of the plurality of genes; wherein a difference between the sample gene signature and the reference gene signature indicates that the subject is at risk of developing severe sepsis. 
     
     
         4 . A method for identifying a subject at risk of organ failure, comprising determining in a biological sample obtained from the subject a level of expression for each of a plurality of Endotoxin Tolerance Signature genes to provide a sample gene signature, and comparing the sample gene signature with a reference gene signature, wherein the reference gene signature represents a standard level of expression of each of the plurality of genes; wherein a difference between the sample gene signature and the reference gene signature indicates that the subject is at risk of organ failure 
     
     
         5 . The method according to any one of  claims 1  to  4 , wherein the subject is suspected of having sepsis. 
     
     
         6 . The method according to any one of  claims 1  to  4 , wherein the subject has been diagnosed as having sepsis by standard procedures. 
     
     
         7 . The method according to any one of  claims 1  to  6 , wherein the plurality of genes is selected from ADAM15, ADAMDEC1, ALCAM, ALDH1A1, ANKRD1, C19orf59, CA12, CAMP, CCL1, CCL19, CCL22, CCL24, CCL7, CD14, CD300LF, CD93, CDK5RAP2, CPVL, CST3, CST6, CTSK, CXCL10, CYP1B1, CYP27B1, DDIT4, DHRS9, DPYSL3, EGR2, EMR1, EMR3, FBP1, FCER1G, FCER2, FPR1, FPR2, GK, GPNMB, GPR137B, HBEGF, HIST1H1C, HIST2H2AA3, HIST2H2AC, HK2, HK3, HPSE, HSD11B1, HTRA1, IL18BP, IL3RA, ITGB8, KIAA1199, LILRA3, LILRA5, LIPA, LY86, MARCO, MGST1, MMP7, MT1F, MT1G, MT1H, MT1M, MT1X, MXD1, MYADM, NEFH, NQO1, NRIP3, OLIG2, PANX2, PAPLN, PDLIM7, PLAUR, PLD3, PPBP, PROCR, PSTPIP2, PTGES, PTGR1, RAB13, RARRES1, RETN, RHBDD2, RNASE1, S100A12, S100A4, S100A8, S100A9, SERPINA1, SERPINB7, SLC16A10, SLC7A11, TGM2, TLR7, TMEM158, TREM1, TSPAN4, UPP1 and VCAN. 
     
     
         8 . A method for diagnosing endotoxin tolerance in a subject, the method comprising:
 a) determining in a biological sample obtained from the subject a level of expression for each of a plurality of genes selected from ADAM15, ADAMDEC1, ALCAM, ALDH1A1, ANKRD1, C19orf59, CA12, CAMP, CCL1, CCL19, CCL22, CCL24, CCL7, CD14, CD300LF, CD93, CDK5RAP2, CPVL, CST3, CST6, CTSK, CXCL10, CYP1B1, CYP27B1, DDIT4, DHRS9, DPYSL3, EGR2, EMR1, EMR3, FBP1, FCER1G, FCER2, FPR1, FPR2, GK, GPNMB, GPR137B, HBEGF, HIST1H1C, HIST2H2AA3, HIST2H2AC, HK2, HK3, HPSE, HSD11B1, HTRA1, IL18BP, IL3RA, ITGB8, KIAA1199, LILRA3, LILRA5, LIPA, LY86, MARCO, MGST1, MMP7, MT1F, MT1G, MT1H, MT1M, MT1X, MXD1, MYADM, NEFH, NQO1, NRIP3, OLIG2, PANX2, PAPLN, PDLIM7, PLAUR, PLD3, PPBP, PROCR, PSTPIP2, PTGES, PTGR1, RAB13, RARRES1, RETN, RHBDD2, RNASE1, S100A12, S100A4, S100A8, S100A9, SERPINA1, SERPINB7, SLC16A10, SLC7A11, TGM2, TLR7, TMEM158, TREM1, TSPAN4, UPP1 and VCAN to provide a sample gene signature, and   b) comparing the sample gene signature with a reference gene signature, wherein the reference gene signature represents a standard level of expression of each of the plurality of genes;   wherein a difference between the sample gene signature and the reference gene signature indicates that the subject has endotoxin tolerance.   
     
     
         9 . The method according to  claim 8 , wherein the subject has or is suspected of having sepsis. 
     
     
         10 . The method according to  claim 8  or  9 , further comprising identifying the subject as being at risk of severe sepsis and/or organ failure if there is a difference between the sample gene signature and the reference gene signature. 
     
     
         11 . The method according to any one of  claims 7  to  10 , wherein the difference between the sample gene signature and the reference gene signature is defined by a difference in expression of at least two of the plurality of genes in an expression change direction. 
     
     
         12 . The method according to  claim 11 , wherein the difference between the sample gene signature and the reference gene signature is defined by a difference in expression of at least 5 of the plurality of genes in an expression change direction. 
     
     
         13 . The method according to  claim 11 , wherein the difference between the sample gene signature and the reference gene signature is defined by a difference in expression of at least 10 of the plurality of genes in an expression change direction. 
     
     
         14 . The method according to  claim 11 , wherein the difference between the sample gene signature and the reference gene signature is defined by a difference in expression of at least 15 of the plurality of genes in an expression change direction. 
     
     
         15 . The method according to  claim 11 , wherein the difference between the sample gene signature and the reference gene signature is defined by a difference in expression of at least 20 of the plurality of genes in an expression change direction. 
     
     
         16 . The method according to  claim 11 , wherein the difference between the sample gene signature and the reference gene signature is defined by a difference in expression of at least 25 of the plurality of genes in an expression change direction. 
     
     
         17 . The method according to  claim 11 , wherein the difference between the sample gene signature and the reference gene signature is defined by a difference in expression of at least 30 of the plurality of genes in an expression change direction. 
     
     
         18 . The method according to  claim 11 , wherein the difference between the sample gene signature and the reference gene signature is defined by a difference in expression of at least 31 of the plurality of genes in an expression change direction. 
     
     
         19 . The method according to any one of  claims 11  to  18 , wherein the expression change direction is upregulation if the gene is ADAMDEC1, ANKRD1, C19orf59, CA12, CCL1, CCL19, CCL22, CCL24, CCL7, CD14, CD300LF, CD93, CDK5RAP2, CYP1B1, CYP27B1, DDIT4, DPYSL3, EGR2, EMR1, EMR3, FBP1, FCER1G, FCER2, FPR1, FPR2, GK, GPR137B, HBEGF, HIST1H1C, HIST2H2AA3, HIST2H2AC, HK2, HK3, HPSE, HSD11B1, IL3RA, ITGB8, KIAA1199, LILRA3, LILRA5, MARCO, MGST1, MMP7, MT1F, MT1G, MT1H, MT1M, MT1X, MXD1, MYADM, NEFH, NRIP3, OLIG2, PANX2, PAPLN, PDLIM7, PLAUR, PPBP, PROCR, PTGES, PTGR1, RAB13, REIN, RHBDD2, S100A12, S100A8, S100A9, SERPINA1, SERPINB7, SLC16A10, SLC7A11, TGM2, TMEM158, TREM1, UPP1 or VCAN, and downregulation if the gene is ADAM15, ALCAM, ALDH1A1, CAMP, CPVL, CST3, CST6, CTSK, CXCL10, DHRS9, GPNMB, HTRA1, IL18BP, LIPA, LY86, NQO1, PLD3, PSTPIP2, RARRES1, RNASE1, S100A4, TLR7 or TSPAN4. 
     
     
         20 . The method according to any one of  claims 7  to  19 , wherein the plurality of genes are selected from C19orf59, CCL22, CD14, CD300LF, CYP1B1, DHRS9, FCER1G, FPR1, FPR2, GK, HISTH2H2AA3, HK2, HK3, HPSE, LILRA5, MGST1, PDLIM7, PLAUR, PSTPIP2, RAB13, RETN, RHBDD2, S100A4, S100A9, S100A12, SERPINA1, UPP1, CPVL, CST3, LY86 and PROCR. 
     
     
         21 . The method according to any one of  claims 7  to  19 , wherein the plurality of genes comprises C19orf59, CCL22, CD14, CD300LF, CYP1B1, DHRS9, FCER1G, FPR1, FPR2, GK, HISTH2H2AA3, HK2, HK3, HPSE, LILRA5, MGST1, PDLIM7, PLAUR, PSTPIP2, RAB13, RETN, RHBDD2, S100A4, S100A9, S100A12, SERPINA1, UPP1, CPVL, CST3, LY86 and PROCR. 
     
     
         22 . The method according to any one of  claims 1  to  21 , wherein determining the level of expression comprises detecting nucleic acids encoded by each of the plurality of genes. 
     
     
         23 . The method according to  claim 22 , wherein determining the level of expression comprises one or more of a polymerase chain reaction (PCR) amplification method, a non-PCR based amplification method, reverse transcriptase-(RT) PCR, Q-beta replicase amplification, ligase chain reaction, signal amplification (Ampliprobe), light cycling, differential display, Northern analysis, hybridization, microarray analysis, DNA sequencing, Ref-Seq, MassArray analysis and MALDI-TOF mass spectrometry. 
     
     
         24 . The method according to  claim 22 , wherein detecting the nucleic acids comprises contacting the biological sample with a microarray comprising a plurality of polynucleotide probes capable of hybridizing to the nucleic acids encoded by each of the plurality of genes. 
     
     
         25 . The method according to  claim 22 , wherein determining the level of expression comprises isolating mRNA from the biological sample, reverse transcribing the mRNA to generate cDNA products and contacting the cDNA products with a microarray comprising a plurality of polynucleotide probes capable of hybridizing to a plurality of cDNAs that are complementary to a plurality of mRNAs expressed from the plurality of genes. 
     
     
         26 . The method according to any one of  claims 1  to  25 , further comprising a step of obtaining the biological sample from the subject. 
     
     
         27 . The method according to any one of  claims 1  to  26 , wherein the biological sample comprises blood, plasma, serum, tissue, amniotic fluid, saliva, urine, stool, bronchoalveolar lavage fluid, cerebrospinal fluid or skin cells. 
     
     
         28 . The method according to any one of  claims 1  to  26 , wherein the biological sample comprises blood. 
     
     
         29 . A method for treating sepsis comprising administering an effective amount of one or more antibiotics to a subject who has been diagnosed as having sepsis by the method according to  claim 1 . 
     
     
         30 . A method for treating sepsis in a subject, the method comprising:
 a) determining whether the subject has sepsis or is at risk of developing sepsis by:
 (i) determining in a biological sample obtained from the subject a level of expression for each of a plurality of genes selected from ADAM15, ADAMDEC1, ALCAM, ALDH1A1, ANKRD1, C19orf59, CA12, CAMP, CCL1, CCL19, CCL22, CCL24, CCL7, CD14, CD300LF, CD93, CDK5RAP2, CPVL, CST3, CST6, CTSK, CXCL10, CYP1B1, CYP27B1, DDIT4, DHRS9, DPYSL3, EGR2, EMR1, EMR3, FBP1, FCER1G, FCER2, FPR1, FPR2, GK, GPNMB, GPR137B, HBEGF, HIST1H1C, HIST2H2AA3, HIST2H2AC, HK2, HK3, HPSE, HSD11B1, HTRA1, IL18BP, IL3RA, ITGB8, KIAA1199, LILRA3, LILRA5, LIPA, LY86, MARCO, MGST1, MMP7, MT1F, MT1G, MT1H, MT1M, MT1X, MXD1, MYADM, NEFH, NQO1, NRIP3, OLIG2, PANX2, PAPLN, PDLIM7, PLAUR, PLD3, PPBP, PROCR, PSTPIP2, PTGES, PTGR1, RAB13, RARRES1, RETN, RHBDD2, RNASE1, S100A12, S100A4, S100A8, S100A9, SERPINA1, SERPINB7, SLC16A10, SLC7A11, TGM2, TLR7, TMEM158, TREM1, TSPAN4, UPP1 and VCAN to provide a sample gene signature, and 
 (ii) comparing the sample gene signature with a reference gene signature, wherein the reference gene signature represents a standard level of expression of each of the plurality of genes, and wherein a difference between the sample gene signature and the reference gene signature indicates that the subject has sepsis or is at risk of developing sepsis, and 
   b) if the subject has sepsis or is at risk of developing sepsis, administering to the subject an effective amount of one or more antibiotics.   
     
     
         31 . The method according to  claim 30 , wherein the sepsis is severe sepsis. 
     
     
         32 . The method according to any one of  claims 29  to  31 , wherein the one or more antibiotics is one or a combination of a glycopeptide, a ceflasporin, a beta-lactam, a beta-lactamase inhibitor, a carbapenem, a quinolone, a fluoroquinolone, an aminoglycoside, a macrolide and a monobactam. 
     
     
         33 . A method for decreasing the risk of organ failure in a subject comprising administering an effective amount of one or more antibiotics to a subject who has been diagnosed as having sepsis or being at risk of developing severe sepsis by the method according to any one of  claims 1  to  3 . 
     
     
         34 . A method for decreasing the risk of organ failure in a subject, the method comprising:
 a) determining whether the subject is at risk of organ failure by:
 (i) determining in a biological sample obtained from the subject a level of expression for each of a plurality of genes selected from ADAM15, ADAMDEC1, ALCAM, ALDH1A1, ANKRD1, C19orf59, CA12, CAMP, CCL1, CCL19, CCL22, CCL24, CCL7, CD14, CD300LF, CD93, CDK5RAP2, CPVL, CST3, CST6, CTSK, CXCL10, CYP1B1, CYP27B1, DDIT4, DHRS9, DPYSL3, EGR2, EMR1, EMR3, FBP1, FCER1G, FCER2, FPR1, FPR2, GK, GPNMB, GPR137B, HBEGF, HIST1H1C, HIST2H2AA3, HIST2H2AC, HK2, HK3, HPSE, HSD11B1, HTRA1, IL18BP, IL3RA, ITGB8, KIAA1199, LILRA3, LILRA5, LIPA, LY86, MARCO, MGST1, MMP7, MT1F, MT1G, MT1H, MT1M, MT1X, MXD1, MYADM, NEFH, NQO1, NRIP3, OLIG2, PANX2, PAPLN, PDLIM7, PLAUR, PLD3, PPBP, PROCR, PSTPIP2, PTGES, PTGR1, RAB13, RARRES1, RETN, RHBDD2, RNASE1, S100A12, S100A4, S100A8, S100A9, SERPINA1, SERPINB7, SLC16A10, SLC7A11, TGM2, TLR7, TMEM158, TREM1, TSPAN4, UPP1 and VCAN to provide a sample gene signature, and 
 (ii) comparing the sample gene signature with a reference gene signature, wherein the reference gene signature represents a standard level of expression of each of the plurality of genes, and wherein a difference between the sample gene signature and the reference gene signature indicates that the subject is at risk of organ failure, and 
   b) if the subject is at risk of organ failure, administering to the subject an effective amount of one or more antibiotics.   
     
     
         35 . The method according to any one of  claims 29  to  34 , wherein the difference between the sample gene signature and the reference gene signature is defined by a difference in expression of at least two of the plurality of genes in an expression change direction. 
     
     
         36 . The method according to  claim 35 , wherein the difference between the sample gene signature and the reference gene signature is defined by a difference in expression of at least 5 of the plurality of genes in an expression change direction. 
     
     
         37 . The method according to  claim 35 , wherein the difference between the sample gene signature and the reference gene signature is defined by a difference in expression of at least 10 of the plurality of genes in an expression change direction. 
     
     
         38 . The method according to  claim 35 , wherein the difference between the sample gene signature and the reference gene signature is defined by a difference in expression of at least 15 of the plurality of genes in an expression change direction. 
     
     
         39 . The method according to  claim 35 , wherein the difference between the sample gene signature and the reference gene signature is defined by a difference in expression of at least 20 of the plurality of genes in an expression change direction. 
     
     
         40 . The method according to  claim 35 , wherein the difference between the sample gene signature and the reference gene signature is defined by a difference in expression of at least 25 of the plurality of genes in an expression change direction. 
     
     
         41 . The method according to  claim 35 , wherein the difference between the sample gene signature and the reference gene signature is defined by a difference in expression of at least 30 of the plurality of genes in an expression change direction. 
     
     
         42 . The method according to  claim 35 , wherein the difference between the sample gene signature and the reference gene signature is defined by a difference in expression of at least 31 of the plurality of genes in an expression change direction. 
     
     
         43 . The method according to any one of  claims 35  to  42 , wherein the expression change direction is upregulation if the gene is ADAMDEC1, ANKRD1, C19orf59, CA12, CCL1, CCL19, CCL22, CCL24, CCL7, CD14, CD300LF, CD93, CDK5RAP2, CYP1B1, CYP27B1, DDIT4, DPYSL3, EGR2, EMR1, EMR3, FBP1, FCER1G, FCER2, FPR1, FPR2, GK, GPR137B, HBEGF, HIST1H1C, HIST2H2AA3, HIST2H2AC, HK2, HK3, HPSE, HSD11B1, IL3RA, ITGB8, KIAA1199, LILRA3, LILRA5, MARCO, MGST1, MMP7, MT1F, MT1G, MT1H, MT1M, MT1X, MXD1, MYADM, NEFH, NRIP3, OLIG2, PANX2, PAPLN, PDLIM7, PLAUR, PPBP, PROCR, PTGES, PTGR1, RAB13, REIN, RHBDD2, S100A12, S100A8, S100A9, SERPINA1, SERPINB7, SLC16A10, SLC7A11, TGM2, TMEM158, TREM1, UPP1 or VCAN, and downregulation if the gene is ADAM15, ALCAM, ALDH1A1, CAMP, CPVL, CST3, CST6, CTSK, CXCL10, DHRS9, GPNMB, HTRA1, IL18BP, LIPA, LY86, NQO1, PLD3, PSTPIP2, RARRES1, RNASE1, S100A4, TLR7 or TSPAN4. 
     
     
         44 . The method according to any one of  claims 29  to  43 , wherein the plurality of genes are selected from C19orf59, CCL22, CD14, CD300LF, CYP1B1, DHRS9, FCER1G, FPR1, FPR2, GK, HISTH2H2AA3, HK2, HK3, HPSE, LILRA5, MGST1, PDLIM7, PLAUR, PSTPIP2, RAB13, RETN, RHBDD2, S100A4, S100A9, S100A12, SERPINA1, UPP1, CPVL, CST3, LY86 and PROCR. 
     
     
         45 . The method according to any one of  claims 29  to  43 , wherein the plurality of genes comprises C19orf59, CCL22, CD14, CD300LF, CYP1B1, DHRS9, FCER1G, FPR1, FPR2, GK, HISTH2H2AA3, HK2, HK3, HPSE, LILRA5, MGST1, PDLIM7, PLAUR, PSTPIP2, RAB13, RETN, RHBDD2, S100A4, S100A9, S100A12, SERPINA1, UPP1, CPVL, CST3, LY86 and PROCR. 
     
     
         46 . A method for decreasing the risk of a subject developing severe sepsis comprising administering an effective amount of an agent that counteracts endotoxin tolerance to a subject who has been diagnosed as being at risk of developing severe sepsis by the method according to  claim 3 . 
     
     
         47 . A method for decreasing the risk of organ failure in a subject comprising administering an effective amount of an agent that counteracts endotoxin tolerance to a subject who has been diagnosed as being at risk of organ failure by the method according to  claim 4 . 
     
     
         48 . A method for decreasing the risk of a subject developing severe sepsis or organ failure comprising administering to the subject an effective amount of an agent that counteracts endotoxin tolerance. 
     
     
         49 . The method according to  claim 48 , further comprising determining that the subject is at risk of developing severe sepsis or organ failure by:
 (a) determining in a biological sample obtained from the subject the level of expression of a plurality of genes selected from ADAM15, ADAMDEC1, ALCAM, ALDH1A1, ANKRD1, C19orf59, CA12, CAMP, CCL1, CCL19, CCL22, CCL24, CCL7, CD14, CD300LF, CD93, CDK5RAP2, CPVL, CST3, CST6, CTSK, CXCL10, CYP1B1, CYP27B1, DDIT4, DHRS9, DPYSL3, EGR2, EMR1, EMR3, FBP1, FCER1G, FCER2, FPR1, FPR2, GK, GPNMB, GPR137B, HBEGF, HIST1H1C, HIST2H2AA3, HIST2H2AC, HK2, HK3, HPSE, HSD11B1, HTRA1, IL18BP, IL3RA, ITGB8, KIAA1199, LILRA3, LILRA5, LIPA, LY86, MARCO, MGST1, MMP7, MT1F, MT1G, MT1H, MT1M, MT1X, MXD1, MYADM, NEFH, NQO1, NRIP3, OLIG2, PANX2, PAPLN, PDLIM7, PLAUR, PLD3, PPBP, PROCR, PSTPIP2, PTGES, PTGR1, RAB13, RARRES1, RETN, RHBDD2, RNASE1, S100A12, S100A4, S100A8, S100A9, SERPINA1, SERPINB7, SLC16A10, SLC7A11, TGM2, TLR7, TMEM158, TREM1, TSPAN4, UPP1 and VCAN to provide a sample gene signature, and   (b) comparing the sample gene signature with a reference gene signature, wherein the reference gene signature represents a standard level of expression of each of the plurality of genes,   wherein a difference between the sample gene signature and the reference gene signature indicates that the subject is at risk of developing severe sepsis or organ failure.   
     
     
         50 . The method according to any one of  claim 46 ,  47  or  49 , further comprising monitoring the expression of the plurality genes in samples obtained from the subject at one or more time points during treatment. 
     
     
         51 . The method according to any one of  claim 46 ,  47 ,  49  or  50 , wherein the difference between the sample gene signature and the reference gene signature is defined by a difference in expression of at least two of the plurality of genes in an expression change direction. 
     
     
         52 . The method according to  claim 51 , wherein the difference between the sample gene signature and the reference gene signature is defined by a difference in expression of at least 5 of the plurality of genes in an expression change direction. 
     
     
         53 . The method according to  claim 51 , wherein the difference between the sample gene signature and the reference gene signature is defined by a difference in expression of at least 10 of the plurality of genes in an expression change direction. 
     
     
         54 . The method according to  claim 51 , wherein the difference between the sample gene signature and the reference gene signature is defined by a difference in expression of at least 15 of the plurality of genes in an expression change direction. 
     
     
         55 . The method according to  claim 51 , wherein the difference between the sample gene signature and the reference gene signature is defined by a difference in expression of at least 20 of the plurality of genes in an expression change direction. 
     
     
         56 . The method according to  claim 51 , wherein the difference between the sample gene signature and the reference gene signature is defined by a difference in expression of at least 25 of the plurality of genes in an expression change direction. 
     
     
         57 . The method according to  claim 51 , wherein the difference between the sample gene signature and the reference gene signature is defined by a difference in expression of at least 30 of the plurality of genes in an expression change direction. 
     
     
         58 . The method according to  claim 51 , wherein the difference between the sample gene signature and the reference gene signature is defined by a difference in expression of at least 31 of the plurality of genes in an expression change direction. 
     
     
         59 . The method according to any one of  claims 51  to  58 , wherein the expression change direction is upregulation if the gene is ADAMDEC1, ANKRD1, C19orf59, CA12, CCL1, CCL19, CCL22, CCL24, CCL7, CD14, CD300LF, CD93, CDK5RAP2, CYP1B1, CYP27B1, DDIT4, DPYSL3, EGR2, EMR1, EMR3, FBP1, FCER1G, FCER2, FPR1, FPR2, GK, GPR137B, HBEGF, HIST1H1C, HIST2H2AA3, HIST2H2AC, HK2, HK3, HPSE, HSD11B1, IL3RA, ITGB8, KIAA1199, LILRA3, LILRA5, MARCO, MGST1, MMP7, MT1F, MT1G, MT1H, MT1M, MT1X, MXD1, MYADM, NEFH, NRIP3, OLIG2, PANX2, PAPLN, PDLIM7, PLAUR, PPBP, PROCR, PTGES, PTGR1, RAB13, RETN, RHBDD2, S100A12, S100A8, S100A9, SERPINA1, SERPINB7, SLC16A10, SLC7A11, TGM2, TMEM158, TREM1, UPP1 or VCAN, and downregulation if the gene is ADAM15, ALCAM, ALDH1A1, CAMP, CPVL, CST3, CST6, CTSK, CXCL10, DHRS9, GPNMB, HTRA1, IL18BP, LIPA, LY86, NQO1, PLD3, PSTPIP2, RARRES1, RNASE1, S100A4, TLR7 or TSPAN4. 
     
     
         60 . The method according to any one of  claims 46 ,  47  and  49  to  59 , wherein the plurality of genes are selected from C19orf59, CCL22, CD14, CD300LF, CYP1B1, DHRS9, FCER1G, FPR1, FPR2, GK, HISTH2H2AA3, HK2, HK3, HPSE, LILRA5, MGST1, PDLIM7, PLAUR, PSTPIP2, RAB13, REIN, RHBDD2, S100A4, S100A9, S100A12, SERPINA1, UPP1, CPVL, CST3, LY86 and PROCR. 
     
     
         61 . The method according to any one of  claims 46 ,  47  and  49  to  59 , wherein the plurality of genes comprises C19orf59, CCL22, CD14, CD300LF, CYP1B1, DHRS9, FCER1G, FPR1, FPR2, GK, HISTH2H2AA3, HK2, HK3, HPSE, LILRA5, MGST1, PDLIM7, PLAUR, PSTPIP2, RAB13, RETN, RHBDD2, S100A4, S100A9, S100A12, SERPINA1, UPP1, CPVL, CST3, LY86 and PROCR. 
     
     
         62 . The method according to any one of  claims 46  to  61 , wherein the agent that counteracts endotoxin tolerance is an immunotherapy. 
     
     
         63 . The method according to  claim 62 , wherein the agent comprises immune cells. 
     
     
         64 . The method according to any one of  claims 46  to  61 , wherein the agent is interferon gamma, a CpG-oligonucleotide (ODN), a combination of a CpG ODN with IL-10, an anti-CD40 antibody, an inhibitor of STAT3, an inhibitor of STAT6, an inhibitor of p50, an inhibitor of NFκB, an inhibitor of IKKβ, an imidazoquinolone or zoledronic acid. 
     
     
         65 . A method for identifying a candidate agent for the treatment of sepsis, the method comprising:
 a) contacting an endotoxin tolerant cell with a test agent,   b) determining the level of expression for each of a plurality of Endotoxin Tolerance Signature genes in the endotoxin tolerant cell to provide an expression signature,   c) comparing the expression signature with a reference expression signature, wherein the reference signature represents the levels of expression of the plurality of genes in a normal cell, and   d) selecting the test agent as a candidate agent for treatment of sepsis when the expression signature substantially corresponds with the reference signature.   
     
     
         66 . The method according to  claim 65 , wherein the plurality of genes is selected from ADAM15, ADAMDEC1, ALCAM, ALDH1A1, ANKRD1, C19orf59, CA12, CAMP, CCL1, CCL19, CCL22, CCL24, CCL7, CD14, CD300LF, CD93, CDK5RAP2, CPVL, CST3, CST6, CTSK, CXCL10, CYP1B1, CYP27B1, DDIT4, DHRS9, DPYSL3, EGR2, EMR1, EMR3, FBP1, FCER1G, FCER2, FPR1, FPR2, GK, GPNMB, GPR137B, HBEGF, HIST1H1C, HIST2H2AA3, HIST2H2AC, HK2, HK3, HPSE, HSD11B1, HTRA1, IL18BP, IL3RA, ITGB8, KIAA1199, LILRA3, LILRA5, LIPA, LY86, MARCO, MGST1, MMP7, MT1F, MT1G, MT1H, MT1M, MT1X, MXD1, MYADM, NEFH, NQO1, NRIP3, OLIG2, PANX2, PAPLN, PDLIM7, PLAUR, PLD3, PPBP, PROCR, PSTPIP2, PTGES, PTGR1, RAB13, RARRES1, RETN, RHBDD2, RNASE1, S100A12, S100A4, S100A8, S100A9, SERPINA1, SERPINB7, SLC16A10, SLC7A11, TGM2, TLR7, TMEM158, TREM1, TSPAN4, UPP1 and VCAN. 
     
     
         67 . The method according to  claim 65  or  66 , wherein the plurality of genes comprises at least 5 genes. 
     
     
         68 . The method according to  claim 65  or  66 , wherein the plurality of genes comprises at least 10 genes. 
     
     
         69 . The method according to  claim 65  or  66 , wherein the plurality of genes comprises at least 15 genes. 
     
     
         70 . The method according to  claim 65  or  66 , wherein the plurality of genes comprises at least 20 genes. 
     
     
         71 . The method according to  claim 65  or  66 , wherein the plurality of genes comprises at least 25 genes. 
     
     
         72 . The method according to  claim 65  or  66 , wherein the plurality of genes comprises at least 30 genes. 
     
     
         73 . The method according to  claim 65  or  66 , wherein the plurality of genes comprises at least 31 genes. 
     
     
         74 . The method according to any one of  claims 65  to  73 , wherein the plurality of genes are selected from C19orf59, CCL22, CD14, CD300LF, CYP1B1, DHRS9, FCER1G, FPR1, FPR2, GK, HISTH2H2AA3, HK2, HK3, HPSE, LILRA5, MGST1, PDLIM7, PLAUR, PSTPIP2, RAB13, RETN, RHBDD2, S100A4, S100A9, S100A12, SERPINA1, UPP1, CPVL, CST3, LY86 and PROCR. 
     
     
         75 . The method according to any one of  claims 65  to  73 , wherein the plurality of genes comprises C19orf59, CCL22, CD14, CD300LF, CYP1B1, DHRS9, FCER1G, FPR1, FPR2, GK, HISTH2H2AA3, HK2, HK3, HPSE, LILRA5, MGST1, PDLIM7, PLAUR, PSTPIP2, RAB13, RETN, RHBDD2, S100A4, S100A9, S100A12, SERPINA1, UPP1, CPVL, CST3, LY86 and PROCR. 
     
     
         76 . A kit for determining a level of expression for each of a plurality of genes selected from ADAM15, ADAMDEC1, ALCAM, ALDH1A1, ANKRD1, C19orf59, CA12, CAMP, CCL1, CCL19, CCL22, CCL24, CCL7, CD14, CD300LF, CD93, CDK5RAP2, CPVL, CST3, CST6, CTSK, CXCL10, CYP1B1, CYP27B1, DDIT4, DHRS9, DPYSL3, EGR2, EMR1, EMR3, FBP1, FCER1G, FCER2, FPR1, FPR2, GK, GPNMB, GPR137B, HBEGF, HIST1H1C, HIST2H2AA3, HIST2H2AC, HK2, HK3, HPSE, HSD11B1, HTRA1, IL18BP, IL3RA, ITGB8, KIAA1199, LILRA3, LILRA5, LIPA, LY86, MARCO, MGST1, MMP7, MT1F, MT1G, MT1H, MT1M, MT1X, MXD1, MYADM, NEFH, NQO1, NRIP3, OLIG2, PANX2, PAPLN, PDLIM7, PLAUR, PLD3, PPBP, PROCR, PSTPIP2, PTGES, PTGR1, RAB13, RARRES1, RETN, RHBDD2, RNASE1, S100A12, S100A4, S100A8, S100A9, SERPINA1, SERPINB7, SLC16A10, SLC7A11, TGM2, TLR7, TMEM158, TREM1, TSPAN4, UPP1 and VCAN in a sample, the kit comprising gene specific reagents, each of the gene specific reagents capable of detecting an expression product of a respective one of the plurality of genes or complement thereof, and instructions for use. 
     
     
         77 . The kit according to  claim 76 , wherein the plurality of genes comprises at least 5 genes. 
     
     
         78 . The kit according to  claim 76 , wherein the plurality of genes comprises at least 10 genes. 
     
     
         79 . The kit according to  claim 76 , wherein the plurality of genes comprises at least 15 genes. 
     
     
         80 . The kit according to  claim 76 , wherein the plurality of genes comprises at least 20 genes. 
     
     
         81 . The kit according to  claim 76 , wherein the plurality of genes comprises at least 25 genes. 
     
     
         82 . The kit according to  claim 76 , wherein the plurality of genes comprises at least 30 genes. 
     
     
         83 . The kit according to  claim 76 , wherein the plurality of genes comprises at least 31 genes. 
     
     
         84 . The kit according to any one of  claims 76  to  83 , wherein the plurality of genes are selected from C19orf59, CCL22, CD14, CD300LF, CYP1B1, DHRS9, FCER1G, FPR1, FPR2, GK, HISTH2H2AA3, HK2, HK3, HPSE, LILRA5, MGST1, PDLIM7, PLAUR, PSTPIP2, RAB13, RETN, RHBDD2, S100A4, S100A9, S100A12, SERPINA1, UPP1, CPVL, CST3, LY86 and PROCR. 
     
     
         85 . The kit according to any one of  claims 76  to  83 , wherein the plurality of genes comprises C19orf59, CCL22, CD14, CD300LF, CYP1B1, DHRS9, FCER1G, FPR1, FPR2, GK, HISTH2H2AA3, HK2, HK3, HPSE, LILRA5, MGST1, PDLIM7, PLAUR, PSTPIP2, RAB13, RETN, RHBDD2, S100A4, S100A9, S100A12, SERPINA1, UPP1, CPVL, CST3, LY86 and PROCR. 
     
     
         86 . The kit according to any one of  claims 76  to  85 , wherein the expression product or complement thereof is RNA, cDNA or a protein. 
     
     
         87 . The kit according to  claim 86 , wherein each expression product is a nucleic acid and each gene specific reagent comprises a polynucleotide probe capable of specifically binding to at least one of said nucleic acid expression products or the complement thereof. 
     
     
         88 . The kit according to  claim 87 , wherein the kit further comprises polynucleotide primers for amplification of at least a portion of the nucleic acid expression product. 
     
     
         89 . The kit according to  claim 87  or  88 , wherein the polynucleotide probes are provided as a microarray. 
     
     
         90 . The kit according to any one of  claims 76  to  89 , further comprising one or more controls. 
     
     
         91 . The kit according to any one of  claims 76  to  90 , wherein the kit is for use to diagnose sepsis in a subject, determine the risk of a subject developing severe sepsis or determine the risk of organ failure in a subject. 
     
     
         92 . A microarray for detecting expression of a plurality of Endotoxin Tolerance Signature genes in a sample, the microarray comprising a plurality of polynucleotide probes attached to a solid support, each of the polynucleotide probes capable of specifically hybridizing to an expression product of a respective one of the plurality of genes or the complement thereof. 
     
     
         93 . The microarray according to  claim 92 , wherein the plurality of genes are selected from ADAM15, ADAMDEC1, ALCAM, ALDH1A1, ANKRD1, C19orf59, CA12, CAMP, CCL1, CCL19, CCL22, CCL24, CCL7, CD14, CD300LF, CD93, CDK5RAP2, CPVL, CST3, CST6, CTSK, CXCL10, CYP1B1, CYP27B1, DDIT4, DHRS9, DPYSL3, EGR2, EMR1, EMR3, FBP1, FCER1G, FCER2, FPR1, FPR2, GK, GPNMB, GPR137B, HBEGF, HIST1H1C, HIST2H2AA3, HIST2H2AC, HK2, HK3, HPSE, HSD11B1, HTRA1, IL18BP, IL3RA, ITGB8, KIAA1199, LILRA3, LILRA5, LIPA, LY86, MARCO, MGST1, MMP7, MT1F, MT1G, MT1H, MT1M, MT1X, MXD1, MYADM, NEFH, NQO1, NRIP3, OLIG2, PANX2, PAPLN, PDLIM7, PLAUR, PLD3, PPBP, PROCR, PSTPIP2, PTGES, PTGR1, RAB13, RARRES1, REIN, RHBDD2, RNASE1, S100A12, S100A4, S100A8, S100A9, SERPINA1, SERPINB7, SLC16A10, SLC7A11, TGM2, TLR7, TMEM158, TREM1, TSPAN4, UPP1 and VCAN. 
     
     
         94 . The microarray according to  claim 92  or  93 , wherein the plurality of genes comprises at least 5 genes. 
     
     
         95 . The microarray according to  claim 92  or  93 , wherein the plurality of genes comprises at least 10 genes. 
     
     
         96 . The microarray according to  claim 92  or  93 , wherein the plurality of genes comprises at least 15 genes. 
     
     
         97 . The microarray according to  claim 92  or  93 , wherein the plurality of genes comprises at least 20 genes. 
     
     
         98 . The microarray according to  claim 92  or  93 , wherein the plurality of genes comprises at least 25 genes. 
     
     
         99 . The microarray according to  claim 92  or  93 , wherein the plurality of genes comprises at least 30 genes. 
     
     
         100 . The microarray according to  claim 92  or  93 , wherein the plurality of genes comprises at least 31 genes. 
     
     
         101 . The microarray according to any one of  claims 92  to  100 , wherein the plurality of genes are selected from C19orf59, CCL22, CD14, CD300LF, CYP1B1, DHRS9, FCER1G, FPR1, FPR2, GK, HISTH2H2AA3, HK2, HK3, HPSE, LILRA5, MGST1, PDLIM7, PLAUR, PSTPIP2, RAB13, RETN, RHBDD2, S100A4, S100A9, S100A12, SERPINA1, UPP1, CPVL, CST3, LY86 and PROCR. 
     
     
         102 . The microarray according to any one of  claims 92  to  100 , wherein the plurality of genes comprises C19orf59, CCL22, CD14, CD300LF, CYP1B1, DHRS9, FCER1G, FPR1, FPR2, GK, HISTH2H2AA3, HK2, HK3, HPSE, LILRA5, MGST1, PDLIM7, PLAUR, PSTPIP2, RAB13, RETN, RHBDD2, S100A4, S100A9, S100A12, SERPINA1, UPP1, CPVL, CST3, LY86 and PROCR. 
     
     
         103 . The microarray according to any one of  claims 92  to  102  further comprising one or more control polynucleotide probes. 
     
     
         104 . The microarray according to  claim 103 , wherein the microarray consists essentially of (i) the polynucleotide probes capable of specifically hybridizing to an expression product of a respective one of the plurality of genes or complement thereof, and (ii) the one or more control polynucleotide probes.