Pediatric Sepsis Biorepository and Clinical Database

PROJECT SUMMARY
Sepsis is broadly defined as life-threatening organ dysfunction caused by infection. However, the experience of
sepsis varies widely between individuals and within individuals. Such inter- and intra-individual heterogeneity
reflects complex, evolving pathobiology induced by host-pathogen interactions and modified by pre-existing
patient characteristics and ongoing medical treatments. It is highly unlikely that a single—or even a small
panel—of biomarkers will characterize an individual’s pathobiology with enough accuracy to unlock precision
medicine approaches in sepsis. The challenge, therefore, is to identify and accurately characterize relevant
phenotypes of sepsis and develop enrichment strategies to design and test novel targeted therapies. For this
project, we propose testing the feasibility of novel approaches to collect, process, and analyze biologic data
representing the immuno-inflammatory-metabolic response to infection early in the sepsis course and link this
information to relevant organ dysfunction-based phenotype data from the electronic health record (EHR).
We have assembled a multi-disciplinary team composed of experts in translational immunology, pediatric
emergency medicine, critical care, and data science. We will test the feasibility of collecting and processing
blood samples of different volumes for deep phenotyping at the pre-resuscitation phase, which is a critical
timepoint, as well as 48 hours later to capture dynamic changes post-resuscitation. We will use these samples
to characterize the functional immuno-inflammatory-metabolic biology using high dimensional flow cytometry to
track surface and intracellular markers of lymphocyte proliferation, apoptosis, exhaustion, and cytokine
production. In addition, we will extend flow cytometric techniques to perform bioenergetic evaluation, and will
perform proteomic evaluation of the plasma immuno-inflammatory-metabolomic response using O-link.
This project will take advantage of extensive clinical research infrastructure at the three study sites. In
addition, the investigators will have access to innovative biologic assays at CHOP which will allow our
collaborative team to glean key biologic phenotypes from critically ill and complex patients. In the R21 phase,
we will complete a single-center pilot study to test the feasibility of collecting, processing, and analyzing the
optimal blood specimens for deep phenotyping in the early phase of sepsis, linking them to the EHR registry
data, and developing and testing a data pipeline to characterize the patients’ organ dysfunction-based clinical
phenotypes. In the R33 phase, we will expand the sample collection to three sites and perform a proof-of-
concept analysis to determine if there are differences in the immuno-inflammatory-metabolomic patterns of the
children who develop either of the high-risk organ dysfunction-based sepsis phenotypes. Identifying relevant
biological patterns in the R33 phase can then lead to future hypothesis-driven mechanistic studies and the
development of targeted therapies.

Grant Number: 5R33GM146159-04
NIH Institute/Center: NIH
Principal Investigator: Frances Balamuth