Septic shock is a major public health problem in both adults and children. Septic shock is a heterogeneous syndrome having highly variable expression in a given patient cohort. A key challenge in the field is to reduce and manage this heterogeneity by more effectively stratifying patients for the purposes of more rational and effective clinical research and individualized clinical management. Over the last 7 years we have developed a genomic expression data base of children with septic shock. We are now proposing to leverage this richly annotated database to develop novel septic shock stratification tools via 3 Specific Aims focused on gene expression-based septic shock subclasses, biomarkers for early detection of septic shock associated renal failure, and genotyping of a novel candidate gene in sepsis biology.
In Specific Aim 1 we will derive a classification strategy that groups septic shock patients into distinct subclasses based on a 100 gene expression signature. The classification strategy will be derived in an existing cohort of 180 patients and gene expression measurements will be conducted using the NanoString nCounter platform. Based on our recently published data, we expect that the expression-based subclasses will have clinically important phenotypic differences. The subclass-defining expression signatures will be converted to visually intuitive """"""""mosaics"""""""" using the Gene Expression Dynamic Inspector (GEDI) platform. After generating the subclass- defining mosaics, we will prospectively validate the ability of these mosaics to identify clinically relevant, gene expression-based septic shock subclasses using a separate cohort of 200 patients.
In Specific Aim 2 we will derive a risk model for the prediction and early detection of septic shock associated renal failure (SSARF). We have objectively derived a panel of 7, serum-based, candidate protein biomarkers for the early detection of SSARF. We will measure these candidate biomarkers in a derivation cohort of 180 patients and develop a multi-biomarker based risk model. The model will be subsequently validated in a prospectively enrolled cohort of 200 patients.
In Specific Aim 3 we will sequence the entire matrix metallopeptidase-8 (MMP-8) gene region and measure associations between sequence variations and illness severity. We will also test associations between MMP-8 sequence variations and expression levels of MMP-8 (mRNA, protein, and activity). The expected deliverables of this application are novel tools for clinically useful stratification of sptic shock.

Public Health Relevance

The deliverable of this program will be a set of novel tools to more effectively stratify patients with septic shock. Child health will be positively impacted by developing the capability to more effectively stratify patients for interventional clinical trials nd for the application of high risk therapies in children with septic shock.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM099773-02
Application #
8525406
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
2012-08-07
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$335,797
Indirect Cost
$116,322
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Wong, Hector R (2018) Embracing Enrichment and Unknown Unknowns. Crit Care Med 46:156-158
Wong, Hector R; Cvijanovich, Natalie Z; Anas, Nick et al. (2018) Endotype Transitions During the Acute Phase of Pediatric Septic Shock Reflect Changing Risk and Treatment Response. Crit Care Med 46:e242-e249
Yehya, Nadir; Wong, Hector R (2018) Adaptation of a Biomarker-Based Sepsis Mortality Risk Stratification Tool for Pediatric Acute Respiratory Distress Syndrome. Crit Care Med 46:e9-e16
Stenson, Erin K; Cvijanovich, Natalie Z; Anas, Nick et al. (2018) Hyperchloremia Is Associated With Complicated Course and Mortality in Pediatric Patients With Septic Shock. Pediatr Crit Care Med 19:155-160
Wong, Hector R; Sweeney, Timothy E; Hart, Kimberly W et al. (2017) Pediatric Sepsis Endotypes Among Adults With Sepsis. Crit Care Med 45:e1289-e1291
Alder, Matthew N; Opoka, Amy M; Lahni, Patrick et al. (2017) Olfactomedin-4 Is a Candidate Marker for a Pathogenic Neutrophil Subset in Septic Shock. Crit Care Med 45:e426-e432
Wong, Hector R; Cvijanovich, Natalie Z; Anas, Nick et al. (2017) Improved Risk Stratification in Pediatric Septic Shock Using Both Protein and mRNA Biomarkers. PERSEVERE-XP. Am J Respir Crit Care Med 196:494-501
Flores, Saul; FitzGerald, Michael R; Iliopoulos, Ilias et al. (2017) An International Survey of Corticosteroid Use for the Management of Low Cardiac Output Syndrome. Pediatr Crit Care Med 18:630-637
Typpo, Katri V; Wong, Hector R; Finley, Stacey D et al. (2017) Monitoring Severity of Multiple Organ Dysfunction Syndrome: New Technologies. Pediatr Crit Care Med 18:S24-S31
Wong, Hector R (2017) Searching for a Pediatric Severe Sepsis Phenotype: We Might Indeed Be There. Pediatr Crit Care Med 18:502-503

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