PROJECT SUMMARY/ABSTRACT – Children’s Hospital of Philadelphia The Collaborative Pediatric Critical Care Research Network (CPCCRN) is essential to advancing the science and practice of pediatric critical care medicine. The overall aim of this site proposal is for Children’s Hospital of Philadelphia (CHOP), under the continued leadership of Athena Zuppa and Robert Berg, to continue as a clinical site in the new and expanded CPCCRN. Drs. Zuppa and Berg, site-PIs for the past 11 years, are pediatric intensivists with a wealth of clinical and translational research experience, who have successfully mentored many junior investigators and produced numerous scientific publications for the CPCCRN. CHOP is a free-standing, tertiary care, academic children’s hospital located in Philadelphia that serves children and families with diverse racial, ethnic, and socioeconomic backgrounds. CHOP, one of the largest children’s hospitals in the country, is a 559-bed children’s hospital with 49 pediatric medical and surgical subspecialties, a staff of over 14,585, a faculty of 860, and an annual operating budget of $3.2 billion. CHOP is home to one of the largest pediatric research programs in the country with more than $147 million in total federal awards and an annual budget of more than $404 million (FY19). The “Personalized Immunomodulation in Sepsis-Induced Multiple Organ Dysfunction Syndrome (MODS)” trial proposed in this application is a large RCT of personalized, targeted management of immune function in children with sepsis-induced MODS. The trial addresses the hypothesis that immunosuppressed children will benefit from granulocyte macrophage-colony stimulating factor (GM-CSF), and children with hyperinflammation will benefit from targeted anti-inflammatory therapy with anakinra (recombinant IL-1 receptor antagonist) or tocilizumab (IL-6 receptor blocking antibody). Benefit will be evaluated in terms of short- and long-term health-related quality of life. This study builds on CPCCRN studies that have demonstrated the existence of specific immune phenotypes among children with sepsis-induced MODS, and successful reversal of immune suppression by administration of the GM-CSF. It also complements the ongoing NICHD R01-funded study investigating the risk factors for immunoparalysis in pediatric MODS, of which Dr. Zuppa is a co-PI. This study proposes a transformative approach to personalized immune-targeted care of the septic child. Drs. Zuppa and Berg and their research team are thoroughly familiar with the CPCCRN studies on which this trial is based including methods of sample collection and processing for immunophenotyping, dosing and administration of GM-CSF, and collection of short- and long-term sepsis- related outcomes. Drs. Zuppa and Berg, and the ancillary site PI Dr. Neal Thomas have the full support of their respective institutions to participate in the CPCCRN, and are strongly committed to collaboration with other CPCCRN sites and the Data Coordinati...