# Ancillary to ABC PICU to study MOD in critically ill children

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $620,571

## Abstract

PROJECT SUMMARY/ABSTRACT
Multiple Organ Dysfunction Syndrome (MODS) occurs frequently in the setting of critical illnesses and is
associated with a nearly 10-fold higher mortality risk. It is a “syndrome” rather than a specific pathological entity
that is characterized by a severe, systemic, and uncontrolled inflammatory process. Several clinical studies
have reported that alterations in inflammation and coagulation are common in critically ill patients and may be
worsened by transfusion of RBCs. Our published and yet to be published data suggest that higher plasma
levels of IL-6, IL-8, PAI-1, Thrombomodulin (TM), and Angiopoietin -2 (Ang-2), and genetic variants in PAI-1
and TM are associated with increased organ dysfunction and mortality in critically ill children and adults.
Neutrophil Extracellular Traps (NETs), produced by activated neutrophils, have been reported to play a role in
organ injury, and extracellular heme released from transfused RBCs is known to trigger the production of
NETs. Our preliminary studies suggest that NETs tend to be increased in non-survivor children with MODS.
Finally, blood from healthy subjects contains a host of bacterial genomic material (microbiome) and this
circulating microbiome has the potential to lead to non-infectious inflammation, thereby contributing to MODS.
However, markers of altered inflammation and thrombosis, and the role of NETs and circulating microbiome
have not yet been studied rigorously in a sufficient number of critically ill children with MODS. We propose to
leverage the infrastructure of the ABC PICU study, an ongoing multi-center clinical trial to enroll critically ill
children undergoing RBC transfusions and collect biological samples pre- and post-transfusion (day 1, 3 and 5)
to characterize inflammation and coagulation related biomarkers and examine their relationship to the
development of NPMODS and mortality. In Aim1, we will assay plasma levels and expression profile of
selected markers (IL-6, IL-8, PAI-1,TM and Ang-2) and association of post-transfusion slope of change in the
measured biomarkers with NPMODS and mortality will be tested using mixed effect models. In Aim 2. we will
genotype tag SNPs and sequence target regions to detect genetic variants and assess their effect on
biomarker trajectories and development of NPMODS and mortality. In Aim 3, unbiased next generation
sequencing followed by alignment of non-human sequences will be used to identify and characterize the
circulating microbiome and we will test for association of microbial diversity and burden with circulating
biomarkers and NPMODS. This study will characterize prognostic and predictive biomarkers and provide
mechanistic insights that establish a link between these markers and the development of NPMODS. The
knowledge acquired and molecular phenotypes thus defined may identify novel therapeutic targets, and will
inform future clinical trials and lead to development of precision medicine strategies targeting th...

## Key facts

- **NIH application ID:** 9905545
- **Project number:** 5R01HD092471-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** ANIL SAPRU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $620,571
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9905545

## Citation

> US National Institutes of Health, RePORTER application 9905545, Ancillary to ABC PICU to study MOD in critically ill children (5R01HD092471-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9905545. Licensed CC0.

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