Hyperinflammation is the term often used to describe a type of life-threatening systemic inflammation that can occur due to genetic defects, infections, rheumatic diseases, cancers, etc. Understanding the factors driving hyperinflammation is critical for treating it properly, but these are difficult to appreciate in any given patient. Previously, levels of the inflammatory proteins “CXCL9” (a biomarker of Interferon-gamma, IFNg, activity) and “IL-18” to distinguish between different causes of hyperinflammation. In this proposal, we will develop a collaborative of five CARRA sites active in hyperinflammation research to collect the earliest samples and test how diagnostically useful IL-18 and CXCL9 are in a more “real-world” scenario. This project will build this collaborative and collect and store a diverse set of samples and clinical data. Long-term, we hope to establish processes that could be rolled out CARRA-wide and build the scientific and logistical foundations for treatment studies that target IL-18 and IFNg.