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 therapeutic agents to patients with specific molecular phenotypes or biomarker patterns.

Public Health Relevance

Multiple Organ Dysfunction (MODS) occurs frequently among critically ill children and carries a high mortality risk. Our study will define the relationship between specific markers of inflammation, coagulation, neutrophil extracellular traps (NETs) and circulating microbiome and the development of New or Progressive MODS and mortality. The results of the study will improve the management of children with NPMODS and may lead to identification of development of novel treatments.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Maholmes, Valerie
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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