Septic shock endotyping strategy and mortality risk for clinical application
View Patent ↗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.
1. A method of treating a pediatric patient having septic shock, the method comprising:
analyzing a blood sample from a pediatric patient having septic shock 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; and
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;
wherein the method further comprises administering a treatment comprising one or more corticosteroids to the patient if classified as other than endotype A/high risk of adverse outcome, or administering a treatment 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 the patient if classified as endotype A/high risk of adverse outcome, to provide a method of treating a pediatric patient having septic shock.
2. 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.
3. 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.
4. 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.
5. 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 biomarkers.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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).
11. The method of claim 1 , wherein the sample is obtained within the first hour of presentation with septic shock.
12. The method of claim 1 , wherein the sample is obtained within the first 48 hours of presentation with septic shock.
13. The method of claim 1 , further comprising:
obtaining an additional blood sample from the patient at a later time point, analyzing the subsequent sample to determine subsequent expression levels of each of the JAK2, LYN, PRKCB, and SOS2 biomarkers, and determining whether the subsequent expression levels of the biomarkers are greater than the respective cut-off mRNA levels, thereby determining if the patient's endotype classification has changed; 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.