Refining Immune Heterogeneity in Pediatric Sepsis Multiple Organ Dysfunction Syndrome - ABSTRACT Pediatric sepsis induced multiple organ dysfunction syndrome (siMODS) affects ~60% of critically ill children, with sepsis and has a very high mortality. These patients may develop persistent impaired host protective immunity leading to potentially chronic critical illness marked by a failure to completely eradicate the initial invading pathogens, recurrent secondary nosocomial infections, increased hospital length of stay, and late mortality. Key gaps in knowledge exist in understanding why some children develop these persistent defects in host protective immunity. New translational approaches have been hindered by a lack of useful timely technology deployed from bedside to bench and back for precisely delivered therapies. Key challenges hindering the development and deployment of immunomodulatory therapies in restoring immune function and improving long-term outcomes in siMODS include: (1) defining specific functional immune endotypes, refining the heterogeneity over time in immunosuppressive or hyperinflammatory phenotypes and the unique biological and physiological mechanisms that define these groups; and (2) identifying immunomodulatory molecules that effectively restore normal immunity against these endotypes. This proposal aims to close these critical knowledge gaps, increase collection of data on both innate and adaptive markers of immune alteration in MODS, and pave the way while improving the design of targeted clinical trials of immune stimulation or suppression. Our group has studied over the last 10 years and determined real-time immune function in adults with sepsis by stimulating their whole blood (WB) and measuring ex vivo production of IFNγ and TNFα using enzyme-linked immunospot (ELISpot). The results remarkably correlated with key clinical metrics that reflect the patient’s immune competence. Here, we plan to test these interesting results in children. Our scientific premise is that immune profiling of pediatric siMODS patients using temporal functional immune analyses combined with transcriptomic analyses will: (1) identify functional immune endotypes that reflect protective immune status in siMODS children; (2) uncover the mechanistic pathways to help design targeted therapies to restore protective immune status; (3) identify heterogeneity in ex vivo response to immune therapies among afflicted endotypes; and (4) separate the endotypes with the highest risk and poor clinical outcomes, which may require personalized therapies. To achieve these goals, we build upon existing collaborations across four children’s hospitals via a prospective, observational trial of 382 siMODS and critically ill nonseptic MODS patients This study fills a critical gap in knowledge by assessing and clarifying the heterogeneity and dynamic functional immune state in siMODS and establishing endotypes to predict relevant outcomes. The assessment of ex vivo response to mechanistically derived candidate immunoadjuvant therapies will allow for immediate and precisely designed clinical trials to evaluate potentially life-saving therapies to accurately endotyped patients along with the elucidation of their molecular drivers that will illuminate a new landscape for effectively positioning existing and new therapies.
