Septic shock continues to be a major public health problem in both adults and children. An important and unmet clinical gap in the field is the lack of robust stratification and diagnostic tools specific for septic shock. This proposal seeks to directly address this gap. We have leveraged our extensive, multi-center gene expression databank of children with septic shock to identify gene signatures that provide a strong foundation for the development of novel stratification and diagnostic tools for clinical septic shock. The major innovation of this proposal is the ability to directly leverage transcriptomic dat as a basis for clinical advancements, an often stated, but seldom achieved goal of transcriptomics. We are proposing three independent, but highly complementary Specific Aims, all of which directly address the aforementioned, unmet clinical gap.
In Specific Aim 1, we will test the hypothesis that the mRNA expression of 84 genes can enhance the accuracy of an existing, validated model to stratify more reliably the risk of death or survival in children with septic shock. We have identified 84 candidate stratification genes having predictive capacity of mortality/survival. Using a digital mRNA measurement platform, we will incorporate the mRNA expression data from these 84 genes to enhance the predictive capacity of a recently developed, serum protein biomarker-based model. The enhanced model will be derived in an existing cohort of 300 patients, and subsequently validated in a prospectively enrolled cohort of 200 patients.
In Specific Aim 2, we will test the hypothesis that interleukin-27 can serve as a diagnostic biomarker for bacterial infection. We have identified IL-27 as a candidate diagnostic biomarker for bacterial infection. In a cohort of critically ill children, we have demonstrated tha IL-27 serum protein concentrations can predict bacterial infection with a specificity and positive predictive value of >90%. We will further test the ability of serum IL-27 protein concentration to serve as a diagnostic biomarker in two separate cohorts of patients recruited from the Emergency Department and the Intensive Care Unit.
In Specific Aim 3, we will test the hypothesis that there exists a group of patients with septic shock characterized by decreased expression of the glucocorticoid receptor (GCR). Our gene expression data have identified a group of patients with septic shock who are characterized by widespread repression of genes corresponding to the GCR signaling pathway, and this particular group of patients has higher illness severity and mortality, compare to two other groups without repression of GCR signaling pathway genes. This suggests the existence of an identifiable group of patients with septic shock who are relatively less responsive to adjunctive glucocorticoids. If this holds true, it woul represent a major confounder for studying the role of adjunctive corticosteroids for septic shock, which is currently a major controversy in the field. We have developed a flow cytometry-based protocol to directly measure GCR expression in the blood compartment of patients with septic shock. We will systematically measure GCR expression and correlate GCR expression with clinical phenotypes. Collectively, these three Aims have the potential to substantially advance the stratification and diagnostic armamentarium for clinical septic shock.

Public Health Relevance

The deliverable of this program will be a set of novel tools for stratification and diagnosis of pediatric septic shock. Child health will be positively impacted by developing the capability to more effectively stratify and diagnose children with septic shock.

National Institute of Health (NIH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Dunsmore, Sarah
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Atkinson, Sarah J; Nolan, Meghan; Klingbeil, Lindsey et al. (2016) Intestine-Derived Matrix Metalloproteinase-8 Is a Critical Mediator of Polymicrobial Peritonitis. Crit Care Med 44:e200-6
Wong, Hector R; Atkinson, Sarah J; Cvijanovich, Natalie Z et al. (2016) Combining Prognostic and Predictive Enrichment Strategies to Identify Children With Septic Shock Responsive to Corticosteroids. Crit Care Med 44:e1000-3
Wheeler, Derek S; Wong, Hector R (2016) Sepsis in Pediatric Cardiac Intensive Care. Pediatr Crit Care Med 17:S266-71
Wong, Hector R (2016) Estimating Mortality Risk of Pediatric Critical Illness: A Worthy Obsession. Pediatr Crit Care Med 17:887-8
Wong, Hector R; Cvijanovich, Natalie Z; Anas, Nick et al. (2016) Pediatric Sepsis Biomarker Risk Model-II: Redefining the Pediatric Sepsis Biomarker Risk Model With Septic Shock Phenotype. Crit Care Med 44:2010-2017
Sweeney, Timothy E; Wong, Hector R (2016) Risk Stratification and Prognosis in Sepsis: What Have We Learned from Microarrays? Clin Chest Med 37:209-18
Wynn, James Lawrence; Wilson, Chris S; Hawiger, Jacek et al. (2016) Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18. Proc Natl Acad Sci U S A 113:E2627-35
Jacobs, Lauren; Wong, Hector R (2016) Emerging infection and sepsis biomarkers: will they change current therapies? Expert Rev Anti Infect Ther 14:929-41
Wong, Hector R; Lindsell, Christopher J (2016) An Enrichment Strategy For Sepsis Clinical Trials. Shock 46:632-634
Eckerle, Michelle; Lahni, Patrick; Wong, Hector (2016) Estimating the probability of bacterial infection using a novel biomarker among pediatric patients in the emergency department. Biomarkers 21:404-8

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