Multi-biomarker-based outcome risk stratification model for pediatric septic shock

1. A method of classifying a pediatric patient with septic shock as high risk or low risk, the method comprising:

identifying a pediatric patient with septic shock;

obtaining a sample from the patient;

analyzing the sample to determine the level(s) of one or more biomarkers selected from the group consisting of the biomarkers listed in Table 1, wherein the one or more biomarkers comprise all of C-C chemokine ligand 3 (CCL3), heat shock protein 70 kDa 1B (HSPA1B), interleukin-8 (IL8), lipocalin 2 (LCN2), and elastase 2 (ELA2) ;

determining whether the level(s) of the one or more biomarkers are elevated above a cut-off level, wherein the presence of an elevated level of one or more biomarkers associated with septic shock in pediatric patients indicates that the patient has an elevated likelihood of being classified as high risk and the absence of an elevated level of one or more biomarkers associated with septic shock in pediatric patients indicates that the patient has a reduced likelihood of being classified as high risk,

wherein a classification of high risk comprises:

a) an elevated level of CCL3, or

b) a non-elevated level of CCL3 and an elevated level of HSPA1B, or

c) non-elevated levels of CCL3, HSPA1B , and ELA2, and elevated levels of IL8 and LCN2;

and wherein a classification of low risk comprises:

d) non-elevated levels of CCL3, HSPA1B, and IL8, or

e) non-elevated levels of CCL3 and HSPA1B, and elevated levels of IL8 and ELA1, or

f) non-elevated levels of CCL3, HSPA1B , ELA2, and LCN2, and an elevated level of IL8.

2. The method of claim 1 , wherein

a) an elevated level of CCL3 corresponds to a serum CCL3 concentration greater than 358 pg/ml,

b) an elevated level of HSPA1B corresponds to a serum HSPA1B concentration greater than 3.3 μg/ml,

c) an elevated level of IL8 corresponds to a serum IL8 concentration greater than 356 pg/ml,

d) an elevated level of ELA2 corresponds to a serum ELA2 concentration greater than 345 ng/ml, and

e) an elevated level of LCN2 corresponds to a serum LCN2 concentration greater than 8.7 ng/ml.

3. A method of classifying a pediatric patient with septic shock as high risk or low risk, the method comprising:

identifying a pediatric patient with septic shock;

obtaining a sample from the patient; analyzing the sample to determine the level(s) of one or more biomarkers selected from the group consisting of the biomarkers listed in Table 1, wherein the one or more biomarkers comprise all of C-C chemokine ligand 3 (CCL3),heat shock protein 70 kDa 1B (HSPA1B), interleukin-8 (IL8), granzyme B (GZMB), and matrix metalloproteinase-8 (MMP8),

determining whether the level(s) of the one or more biomarkers are elevated above a cut-off level, wherein the presence of an elevated level of one or more biomarkers associated with septic shock in pediatric patients indicates that the patient has an elevated likelihood of being classified as high risk and the absence of an elevated level of one or more biomarkers associated with septic shock in pediatric patients indicates that the patient has a reduced likelihood of being classified as high risk,

wherein a classification of high risk comprises

a) elevated levels of CCL3, IL8, and GZMB, or

b) a non-elevated level of IL8 and elevated levels of CCL3 and MMP8, or

c) a non-elevated level of GZMB, elevated levels of CCL3 and IL8, and a patient age of 0.5 years or younger, or

d) a non-elevated level of CCL3 and an elevated level of HSPA1B, or

e) non-elevated levels of CCL3 and HSPA1B, and a highly elevated level of IL8, and wherein a classification of low risk comprises:

f) non-elevated levels of CCL3 and HSPA1B, and a non-highly elevated level of IL8 or

g) non-elevated levels of IL8 and MMP8 and an elevated level of CCL3, or

h) a non-elevated level of GZMB, elevated levels of CCL3 and IL8, and a patient age of older than 0.5 years.

4. The method of claim 3 , wherein

a) an elevated level of CCL3 corresponds to a serum CCL3 concentration greater than 160 pg/ml,

b) an elevated level of HSPA1B corresponds to a serum HSPA1B concentration greater than 3.3 μg/ml,

c) an elevated level of IL8 corresponds to a serum IL8 concentration greater than 507 pg/ml,

d) a highly elevated level of IL8 corresponds to a serum IL8 concentration greater than 829 pg/ml,

e) an elevated level of GZMB corresponds to a serum GZMB concentration greater than 55 pg/ml, and

f) an elevated level of MMP8 corresponds to a serum LCN2 concentration greater than 47.5 ng/ml.

5. The method of claim 1 , wherein the determination of whether the level(s) of the one or more biomarkers are elevated is combined with one or more additional population-based risk scores.

6. The method of claim 5 , wherein the one or more population-based risk scores comprises Acute Physiology and Chronic Health Evaluation II (APACHE) Pediatric Risk of Mortality (PRISM), Pediatric Index of Mortality (PIM), and/or PEdiatric Logistic Organ Dysfunction (PELOD).

7. The method of claim 1 , wherein the sample is obtained within the first hour of presentation with septic shock.

8. The method of claim 1 , wherein the sample is obtained within the first 48 hours of presentation with septic shock.