PROJECT SUMMARY: Sepsis, defined as life-threatening organ dysfunction resulting from a dysregulated immune response of the patient to infection, is a major cause of pediatric morbidity and mortality. Annually, sepsis accounts for ~100,000 emergency department (ED) and ~25-50% of children with sepsis will die due to complications that include shock and multiple organ dysfunction. These unacceptably high bad outcomes are mostly because of our limited understanding of the fundamental underlying immune response processes at the cellular level that are involved in pediatric sepsis. There is an urgent need for generating high quality evidence using multidisciplinary teams to rapidly and accurately diagnoses sepsis so that appropriate therapies can be initiated in the ED to reduce morbidity and mortality in children. We believe that the patient has a unique “sepsis” signature when they first present to the ED and we can define this signature by studying the changes in the vital signs (such as temperature, heart rate) and initial laboratory tests, i.e. physiologic profile along with tests that measure the immune response i.e. the immunologic profile and their changes in the ribosomal nucleic acids (RNA) at the cellular level i.e. transcriptomic profile. We will also be able to better identify the cause of sepsis i.e. bacteria or non-bacteria (for e.g. viruses) using a more sensitive and faster turnaround test called nanorod PCR, which will help the ED provider in initiating appropriate treatments. We also believe that the changes in the sepsis signature over time will allow us to reliably predict which child is more at risk for developing complications and death very early in the disease course to help reduce sepsis related mortality. In order to achieve our aims, we will conduct a prospective, observational study in children (3 months ≤ 18 years of age) with suspected sepsis in the ED at a tertiary care Children’s Hospital and monitor patients through their inpatient stay (ICU, general unit). We have assembled a team of experienced investigators and have the necessary resources and expertise to achieve the goals of our project that are directly aligned with the NOSI to Advance Understanding and Management of MODS in Children. Our project is the first step towards precision medicine to improve diagnosis, guide appropriate therapies, and reliably prognosticate patient outcomes in children with sepsis.