Methods for Diagnosis of Sepsis

Abstract

Methods for diagnosis of sepsis are disclosed. In particular, the invention relates to the use of bio -markers for aiding diagnosis, prognosis, and treatment of sepsis, and to a panel of biomarkers that can be used to distinguish sepsis from noninfectious sources of inflammation, such as caused by traumatic injury, surgery, autoimmune disease, thrombosis, or systemic inflammatory response syndrome (SIRS).

1 - 26 . (canceled) 
     
     
         27 . A method for treating sepsis, comprising:
 (a) measuring the expression levels of two or more biomarkers in a sample obtained from a subject;   (b) calculating a composite biomarker value using the expression levels;   (c) determining that the composite biomarker value exceeds a threshold value; and   (d) administering an antibiotic to the subject.   
     
     
         28 . The method of  claim 27 , wherein the two or more biomarkers comprise at least three biomarkers. 
     
     
         29 . The method of  claim 27 , wherein the two or more biomarkers are selected from ADAMTS3, ANKRD22, ANXA3, AP3B2, ARL8A, B3GNT8, BATF, BPI, BST1, C1orf162, C3AR1, C9orf103, C9orf95, CCR1, CD177, CD63, CD82, CEACAM1, CLEC5A, DHRS9, EMR1, FAM89A, FCER1G, FCGR1B, FES, FFAR3, FIG4, GNA15, GPR84, HK3, HP, IL10, IL18R1, KCNE1, LCN2, LIN7A, OSCAR, OSTalpha, P2RX1, PADI2, PECR, PLAC8, PLB1, PNPLA1, PPM1M, PSTPIP2, RETN, RGL4, S100A12, SEPHS2, SETD8, SGSH, SIGLEC9, SLC26A8, SPPL2A, SQRDL, TCN1, ZDHHC19, ZDHHC3, ARHGEF18, CACNA2D3, CNNM3, GLO1, GRAMD1C, HACL1, HLA-DPB1, KIAA1370, KLHDC2, METAP1, MRPS35, MTCH1, NOC3L, ODC1, PRKRIR, RPGRIP1, RPUSD4, SETD1B, TBC1D4, TGFBI, TOMM20, UBE2Q2, and WDR75. 
     
     
         30 . The method of  claim 27 , wherein the two or more biomarkers are selected from CEACAM1, ZDHHC19, C9orf95, GNA15, BATF, C3AR1, KIAA1370, TGFBI, MTCH1, RPGRIP1, and HLA-DPB1. 
     
     
         31 . The method of  claim 27 , wherein the measuring comprises measuring the mRNA expression levels of the two or more biomarkers selected from CEACAM1, ZDHHC19, C9orf95, GNA15, BATF, C3AR1, KIAA1370, TGFBI, MTCH1, RPGRIP1, and HLA-DPB1. 
     
     
         32 . The method of  claim 27 , wherein the measuring comprises measuring the protein expression levels of the two or more biomarkers selected from CEACAM1, ZDHHC19, C9orf95, GNA15, BATF, C3AR1, KIAA1370, TGFBI, MTCH1, RPGRIP1, and HLA-DPB1. 
     
     
         33 . The method of  claim 27 , wherein the expression levels of the two or more biomarkers are increased compared to reference value ranges for the two or more biomarkers, wherein the reference value ranges are derived from one or more patients that do not have inflammation caused by infection. 
     
     
         34 . The method of  claim 27 , wherein the expression levels of the two or more biomarkers are decreased compared to reference value ranges for the two or more biomarkers, wherein the reference value ranges are derived from one or more patients that do not have inflammation caused by infection. 
     
     
         35 . The method of  claim 27 , wherein the composite biomarker is determined by a computer comprising a processing unit using a formula based on the expression levels of the two or more biomarkers. 
     
     
         36 . The method of  claim 27 , wherein the composite biomarker has been validated in multiple cohorts, wherein the multiple cohorts comprise at least one discovery cohort from which the composite biomarker value was derived and at least one validation cohort fully independent from the at least one discovery cohort. 
     
     
         37 . The method of  claim 36 , wherein the at least one discovery cohort and the at least one validation cohort compare non-healthy, non-infected subjects to time-matched infected subjects. 
     
     
         38 . The method of  claim 36 , wherein the at least one validation cohort comprises at least three independent cohorts and has at least 200 samples in total. 
     
     
         39 . The method of  claim 36 , wherein the at least one validation cohort comprises at least five independent cohorts and has at least 500 samples in total. 
     
     
         40 . The method of  claim 36 , wherein the at least one validation cohort comprises time-matched samples of infected and non-infected patients. 
     
     
         41 . The method of  claim 40 , wherein the infected patients are sepsis patients. 
     
     
         42 . The method of  claim 41 , wherein the sepsis patients comprise patients within 48 hours of admission to a hospital for sepsis or within 24 hours from diagnosis of sepsis. 
     
     
         43 . The method of  claim 40 , wherein the non-infected patients have systemic inflammatory response syndrome (SIRS), an autoimmune disorder, a traumatic injury, or have undergone surgery. 
     
     
         44 . The method of  claim 27 , wherein the two or more biomarkers are differentially expressed between inflammation caused by infection and inflammation not caused by infection. 
     
     
         45 . The method of  claim 36 , wherein an area under the receiver operating characteristic (ROC) curve for the composite biomarker is at least 0.75 in the at least one validation cohort. 
     
     
         46 . The method of  claim 36 , wherein the average area under the receiver operating characteristic (ROC) curve for the composite biomarker across all available validation cohorts is at least 0.75. 
     
     
         47 . The method of  claim 36 , wherein an area under the receiver operating characteristic (ROC) curve for the composite biomarker is at least 0.85 in the at least one validation cohort. 
     
     
         48 . The method of  claim 36 , wherein the average area under the receiver operating characteristic (ROC) curve for the composite biomarker across all available validation cohorts is at least 0.83. 
     
     
         49 . The method of  claim 27 , further comprising obtaining a biological sample from the subject. 
     
     
         50 . The method of  claim 47 , the biological sample comprises a whole blood, a buffy coat, a plasma, a serum, a urine, a saliva, a tissue biopsy, a peripheral blood mononucleated cell (PBMC), a band cell, a neutrophil, a monocyte, a T cell, or a combination thereof. 
     
     
         51 . The method of  claim 27 , wherein the measuring comprises microarray analysis, polymerase chain reaction (PCR), quantitative PCR (qPCR), reverse transcriptase polymerase chain reaction (RT_PCR), isothermal amplification, Northern blot, or serial analysis of gene expression (SAGE). 
     
     
         52 . The method of  claim 27 , further comprising admitting the subject to a hospital.