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Phenotype prediction and therapeutic targets in high-risk pediatric sepsis-associated MODS

Award Number: R01HD113695
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Phenotype prediction and therapeutic targets in high-risk pediatric sepsis-associated MODS - ABSTRACT Sepsis-associated multiple organ dysfunction syndrome (MODS) affects approximately 1 in every 6 children admitted to a pediatric intensive care unit (PICU) in the U.S. and is associated with about 1 in every 3 PICU deaths. Despite this, the current management approach for pediatric sepsis and sepsis-associated MODS and the use of adjuvant therapies remains highly variable in the PICU. This is in part due to the heterogeneity of sepsis and the high variability in which it presents and evolves in children. This heterogeneity can delay the recognition of sepsis and the early identification of patients at high risk of poor outcomes, and has limited the development of targeted interventions. Unraveling this heterogeneity and identifying high-risk sepsis phenotypes with prognostic and therapeutic relevance is considered a major research priority in the path towards precision medicine in sepsis. However, for precision medicine strategies to be most clinically impactful for children with sepsis, it is critical that they are implementable in real-time, generalizable to more settings, and cost-effective. This would enable timely enrollment in enriched randomized controlled trials and initiation of targeted interventions with potential for higher public health impact. We previously identified and characterized the persistent hypoxemia and shock phenotype in critically ill children with sepsis-associated MODS using a data-driven approach. This phenotype was present in almost a third of children with sepsis-associated MODS, had features of systemic inflammation and endothelial activation, was highly reproducible, and was independently associated with mortality, accounting for more than two-thirds of all deaths in this population. Furthermore, in a causal inference analyses, patients with persistent hypoxemia and shock were associated with a higher likelihood to benefit from intravenous hydrocortisone and albumin when compared to other patients. Importantly, phenotypes with similar characteristics in terms of hypoxemia, shock, inflammation, and endothelial activation has been identified in prior studies of sepsis and acute respiratory distress syndrome in children and adults. However, the persistent hypoxemia and shock phenotype currently requires longitudinal data for up to 72 hours to be classified, so there is a need to determine whether it can be predicted early in the course using routinely collected clinical data. Furthermore, amongst patients who achieve a high probability of having the phenotype, there is a need to determine which common adjuvant therapies are associated with heterogeneity of treatment effect (HTE) in order to inform future clinical trials. In this study we aim to: (1) Derive and externally validate a prediction model of persistent hypoxemia and shock in children admitted to the PICU with confirmed or suspected infection; (2) Determine which common adjuvant therapies and therapeutic goals are associated with HTE amongst children with high probability of having persistent hypoxemia and shock; and (3) Implement and prospectively evaluate the performance of the prediction model of persistent hypoxemia and shock in the EHRs of three institutions.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $411,710 )
2026	2026	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Child Health and Human Development Extramural Research	000	3	1/7/2026	NON-COMPETING CONTINUATION	$411,710
														Subtotal = $411,710

Issue Date FY: 2025 ( Subtotal = $365,676 )
2025	2025	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Child Health and Human Development Extramural Research	000	2	11/22/2024	NON-COMPETING CONTINUATION	$329,109
2025	2025	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Child Health and Human Development Extramural Research	001	2	4/18/2025	NON-COMPETING CONTINUATION	$36,567
														Subtotal = $365,676

Issue Date FY: 2024 ( Subtotal = $390,046 )
2024	2024	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Child Health and Human Development Extramural Research	000	1	12/15/2023	NEW	$390,046
														Subtotal = $390,046

Grand Total All Awards = $1,167,432

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Phenotype prediction and therapeutic targets in high-risk pediatric sepsis-associated MODS

Award Number: R01HD113695

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/15/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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