Diagnostic for Sepsis

a sepsis and sepsis technology, applied in the field of diagnosis, can solve the problems of poorly characterized relations, achieve the effect of decreasing reducing the risk of organ failure, and reducing the risk of a subj

Inactive Publication Date: 2017-03-16
HANCOCK ROBERT E W
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  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0029]In another aspect, the invention relates to 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 described above.
[0030]In another aspect, the invention relates to 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 described above.
[0031]In another aspect, the invention relates to 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. In certain embodiments, the method may further comprise 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.

Problems solved by technology

However, this relationship remains poorly characterized, in part due to the limitations of the ex vivo cytokine assays employed to date.

Method used

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  • Diagnostic for Sepsis
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Examples

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example 1

Definition and Characterization of the Signature

[0231]Confirmed Sepsis Patients Express an “Endotoxin Tolerance Signature.”

[0232]To characterize the development of the immunosuppressive stage in sepsis and to conclusively determine its links with endotoxin tolerance, a robust bioinformatics approach was taken. To define an endotoxin tolerance gene signature, microarray analyses of human peripheral blood mononuclear cells (PBMC) treated either once with LPS to model inflammatory signalling, or twice to model endotoxin tolerance was used. An “Endotoxin Tolerance Signature” (Table A below), comprising 99 genes was identified based on genes uniquely differentially expressed in endotoxin-tolerant PBMCs, but not inflammatory PBMCs, as compared to controls. For comparison, we defined an “Inflammatory Signature” from previous PBMC microarray data (Pena et al., 2011) and an in vivo experimental endotoxemia dataset (Calvano et al., 2005) (FIG. 1, Table 4). Having defined a genetic signature f...

example 2

New Therapies Based on the Endotoxin Tolerance Signature

[0252]Network analysis of the Endotoxin Tolerance genes revealed that most of the genes formed a very tight subnetwork strongly suggesting that the signature reflects critical mechanisms likely related to immune dysfunction in sepsis patients (FIG. 8).

[0253]One implication of knowing that a patient is going to soon suffer from sepsis is that one can apply an appropriate antibiotic therapy comprising a cocktail of the most potent drugs. Current clinical guidelines indicate that while waiting for culture results, a patient should be started on intravenous ceftriaxone and azithromycin. The purpose of this regimen is to try to avoid major resistance issues since only a portion of the patients who are thought to have the potential to acquire sepsis actually do so (see e.g. Table 3). Knowing that a patient has sepsis very early in the course of disease would enable physicians to prescribe the most aggressive therapies to try to reduc...

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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.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims priority to U.S. provisional patent application No. 61 / 953,458 filed on Mar. 14, 2014. The entire contents of U.S. provisional patent application No. 61 / 953,458 are incorporated by reference herein.FIELD OF THE INVENTION[0002]The present invention relates to the field of diagnostics and, in particular, to a unique set of DNA sequences that in combination enable the early diagnosis of sepsis, and the prediction of severe sepsis and / or organ failure.BACKGROUND OF THE INVENTION[0003]Sepsis continues to be the major infection-related cause of death globally, leading to an estimated 8.5% of deaths (5 million) annually [Angus D, et al. Critical Care Medicine 2001; 29(7): 1303-10; Kumar G, Kumar N, Taneja A, et al. Chest 2011; 140:1223-31]. Despite advances in modern medicine including new antibiotics and vaccines, early recognition and best practice treatments, and efficient well-equipped intensive care units [Angus D et ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12Q1/68A61K35/15C12N15/10
CPCC12Q1/689C12N15/1068C12Q2600/172C12Q2600/158C12Q2600/136A61K35/15C12Q1/6883C12Q2600/118C12Q2600/16A61P31/04
Inventor HANCOCK, ROBERT E. W.PENA SERRATO, OLGA M.HANCOCK, DAVID G.BOYD, JOHN
Owner HANCOCK ROBERT E W
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