# Inflammation Phenotypes in Pediatric Sepsis Induced Multiple Organ Failure Renewal

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $524,648

## Abstract

Project Abstract
Every year over 1 million American adults and children develop overwhelming infection leading to a rotting of
their body we call ‘sepsis’, and death in up to 1 of 4 afflicted. We and others have asked the question “why do
patients continue to die of organ shutdown?” In the previous funding period we used clinical information and
samples already obtained in our R01 funded audit of 401 children with sepsis and took advantage of the
wonderful advances made this millenia in computer technology, big data, bioinformatics, and the study of
human and virus genetics to understand how too much inflammation and too little immune response lead to
organ shutdown. First, we used ‘Watson’ like machine learning at 24 hours to identify a sub-group of children
we named PedSep-D who subsequently go on to death with organ shutdown caused by too much inflammation
and clotting that we can now reverse with anti-inflammatory and anti-thrombotic therapies. Second, we used
an ‘Ancestry.com’-like or ‘23 and me’-like next generation sequencing approach to identify genes in individual
children that were related to too much inflammation and too little ability to kill infection which we can now treat
on an individual basis using ‘precision medicine’ therapies. Third, we used molecular biology testing
approaches to identify Latent Epstein Barr Virus infection as an asymptomatic preexisting high- risk condition
that is associated with death when children develop sepsis.
Disordered inflammation and immunity are closely related to altered metabolism. We previously linked all
three to organ shutdown and death in pediatric sepsis. In the next funding period we will investigate toxic
‘metabolism’ as a cause of organ shutdown by measuring plasma metabolomics in these same 401 child
samples. In Specific Aim 1 we test the hypothesis that PedSep D patients have a shift to aerobic glycolysis
that drives toxic macrophage activation that can potentially be reversed with glucose restriction and / or
Metformin treatment. In Specific Aim 2 we test the hypothesis that gene variants related to Inborn Errors of
Metabolism contribute to organ shutdown that can be reversed using established Precision Medicine metabolic
therapies. In Specific Aim 3 we test the hypothesis that Epstein Barr Virus latent infection is causally
associated with organ shutdown because it induces Immuno-Metabolic reprogramming of the host response in
sepsis towards aerobic glycolysis that is potentially reversed with repurposed drugs such as Metformin. We
also examine methylation epigenetics in these children to begin to understand the molecular basis for this host
pathogen response. Our long-term objective is to plan ‘precision’ medicine and ‘individualized’ medicine
clinical trials testing therapies that address Inflammation-Immune-Metabolism dysregulation on an individual
patient basis in order to further reduce death from sepsis induced organ shutdown in children.

## Key facts

- **NIH application ID:** 10799035
- **Project number:** 2R01GM108618-09
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** JOSEPH A CARCILLO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $524,648
- **Award type:** 2
- **Project period:** 2014-03-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10799035

## Citation

> US National Institutes of Health, RePORTER application 10799035, Inflammation Phenotypes in Pediatric Sepsis Induced Multiple Organ Failure Renewal (2R01GM108618-09). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10799035. Licensed CC0.

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