# US 11,299,785 B2 · Septic shock endotyping strategy and mortality risk for clinical application

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- Number: US 11,299,785 B2
- Document ID: US11299785B2
- Status: Granted
- Kind: B2
- Application number: 16/539,128
- Filed: 2019-08-13
- Published: 2020-05-07
- Granted: 2022-04-12
- Earliest claimed: 2016-05-13
- Assignees: Children's Hospital Medical Center; University of Cincinnati
- Applicants: Children's Hospital Medical Center; University of Cincinnati
- Inventors: Hector R. Wong; Christopher John Lindsell
- Web page: https://patentgrep.com/patent/US11299785B2

## CPC

- C12Q 1/6883: for diseases caused by alterations of genetic material
- G16B 5/00: ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
- G16B 40/20: Supervised data analysis
- C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
- C12Q 2600/112: Disease subtyping, staging or classification
- C12Q 2600/118: Prognosis of disease development
- C12Q 2600/158: Expression markers
- G16B 25/10: Gene or protein expression profiling; Expression-ratio estimation or normalisation
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- G16B: BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY

## Abstract

Methods and compositions disclosed herein generally relate to methods of identifying, validating, and measuring clinically relevant, quantifiable biomarkers of diagnostic and therapeutic responses for blood, vascular, cardiac, and respiratory tract dysfunction, particularly as those responses relate to septic shock in pediatric patients. In particular, the invention relates to identifying two or more biomarkers associated with septic shock in pediatric patients, obtaining a sample from a pediatric patient having at least one indication of septic shock, then quantifying from the sample an amount of two or more of said biomarkers, wherein the level of said biomarker correlates with a predicted outcome.

## Claims

### Claim 1

A method of treating a pediatric patient having septic shock, the method comprising:
obtaining a blood sample from a pediatric patient having septic shock at a first time point;
analyzing the sample to determine mRNA expression levels of JAK2, LYN, PRKCB, and SOS2 biomarkers;
determining whether the mRNA expression levels of each of the biomarkers are greater than a respective cut-off mRNA expression level;
classifying the patient as endotype A/high risk of adverse outcome or other than endotype A/high risk of adverse outcome, based on the determination of whether the mRNA expression levels of each of the biomarkers are greater than the respective cut-off mRNA expression level, wherein a classification of endotype A/high risk of adverse outcome comprises:
a) a non-elevated level of JAK2 and a non-elevated level of PRKCB; or
b) a non-elevated level of JAK2, an elevated level of PRKCB, and a non-elevated level of LYN;
and wherein a classification other than endotype A/high risk of adverse outcome comprises:
c) a non-elevated level of JAK2, an elevated level of PRKCB, and an elevated level of LYN; or
d) an elevated level of JAK2, a non-elevated level of SOS2, and a highly elevated level of LYN; or
e) elevated levels of JAK2 and SOS2; or
f) an elevated level of JAK2, a non-elevated level of SOS2, and a non-highly elevated level of LYN;
administering a treatment comprising one or more corticosteroid to a patient that is not endotype A/high risk of adverse outcome, or administering a treatment comprising one or more therapy comprising one or more high risk therapies comprising at least one selected from the group consisting of immune enhancing therapy, extracorporeal membrane oxygenation/life support, plasmapheresis, pulmonary artery catheterization, and/or high volume continuous hemofiltration to a patient that is classified as endotype A/high risk of adverse outcome;
obtaining a second blood sample from the patient at a second time point;
analyzing the second sample to determine the mRNA expression levels of JAK2, LYN, PRKCB, and SOS2 biomarkers, and determining whether the expression levels of each of the biomarkers are non-elevated above a cut-off level, thereby determining a change to the patient's endotype classification; and
maintaining the treatment being administered if the patient's endotype classification has not changed, or changing the treatment being administered if the patient's endotype classification has changed.

### Claim 2 (depends on 1)

The method of claim 1, wherein the biomarker mRNA expression levels are determined by mRNA quantification, by normalized mRNA counts, and/or by cycle threshold (CT) values.

### Claim 3 (depends on 1)

The method of claim 1, wherein the biomarker mRNA levels are determined by normalized mRNA counts, and wherein:
a) an elevated level of JAK2 corresponds to a JAK2 mRNA count greater than 1780;
b) an elevated level of PRKCB corresponds to a PRKCB mRNA count greater than 990;
c) an elevated level of SOS2 corresponds to a SOS2 mRNA count greater than 480;
d) an elevated level of LYN corresponds to a LYN mRNA count greater than 870; and
e) a highly elevated level of LYN corresponds to a LYN mRNA count greater than 940.

### Claim 4 (depends on 1)

The method of claim 1, wherein the biomarker mRNA levels are determined by normalized mRNA counts, and wherein:
a) an elevated level of JAK2 corresponds to a JAK2 mRNA count greater than 1784;
b) an elevated level of PRKCB corresponds to a PRKCB mRNA count greater than 986;
c) an elevated level of SOS2 corresponds to a SOS2 mRNA count greater than 480;
d) an elevated level of LYN corresponds to a LYN mRNA count greater than 873; and
e) a highly elevated level of LYN corresponds to a LYN mRNA count greater than 938.

### Claim 5 (depends on 1)

The method of claim 1, wherein the determination of whether the mRNA levels of the biomarkers are non-elevated above a cut-off level comprises applying the biomarker expression level data to a decision tree comprising the JAK2, LYN PRKCB, and SOS2 biomarkers.

### Claim 6 (depends on 1)

The method of claim 1, wherein a classification other than endotype A/high risk of adverse outcome comprises a classification of endotype B/low risk of adverse outcome or endotype C/moderate risk of adverse outcome.

### Claim 7 (depends on 1)

The method of claim 1, wherein the determination of whether the mRNA levels of the biomarkers are non-elevated is combined with one or more patient demographic data and/or clinical characteristics and/or results from other tests or indicia of septic shock.

### Claim 8 (depends on 7)

The method of claim 7, wherein the patient demographic data and/or clinical characteristics and/or results from other tests or indicia of septic shock comprise at least one selected from the group consisting of the septic shock causative organism, the presence or absence or chronic disease, and/or the age, gender, race, and/or co-morbidities of the patient.

### Claim 9 (depends on 1)

The method of claim 1, wherein the determination of whether the mRNA levels of the biomarkers are non-elevated above a cut-off level is combined with one or more additional population-based risk scores.

### Claim 10 (depends on 9)

The method of claim 9, wherein the one or more population-based risk scores comprises at least one selected from the group consisting of Pediatric Sepsis Biomarker Risk Model (PERSEVERE), Pediatric Risk of Mortality (PRISM), Pediatric Index of Mortality (PIM), and/or Pediatric Logistic Organ Dysfunction (PELOD).

### Claim 11 (depends on 1)

The method of claim 1, wherein the first time point is within the first hour or within the first 48 hours of presentation with septic shock.

### Claim 12 (depends on 1)

The method of claim 1, wherein the immune enhancing therapy comprises administration of GMCSF, interleukin-7, and/or anti-PD-1.

### Claim 13 (depends on 1)

The method of claim 1, wherein the second time point is at least 18 hours after the first time point.

### Claim 14 (depends on 13)

The method of claim 13, wherein the second time point is in the range of 24 to 96 hours, or longer, after the first time point.

### Claim 15 (depends on 14)

The method of claim 14, wherein the second time point is about 1 day, 2 days, 3 days, or longer, after the first time point.

### Claim 16 (depends on 15)

The method of claim 15, wherein the first time point is at day 1, wherein day 1 is within 24 hours of a septic shock diagnosis, and the second time point is at day 3.

### Claim 17 (depends on 13)

The method of claim 13, wherein the patient is classified as endotype A/high risk of adverse outcome after the second time point, and wherein the patient is administered one or more high risk therapy after the second time point; or wherein a patient not classified as endotype A/high risk of adverse outcome after the second time point, and wherein the patient is administered a treatment comprising one or more corticosteroid after the second time point, wherein the one or more high risk therapy comprises at least one selected from the group consisting of immune enhancing therapy, extracorporeal membrane oxygenation/life support, plasmapheresis, pulmonary artery catheterization, and/or high volume continuous hemofiltration.

### Claim 18 (depends on 17)

The method of claim 17, wherein the patient classified as endotype A and administered one or more high risk therapy after the first time point is not classified as endotype A/high risk of adverse outcome after the second time point.