This study, Neonatal Enterovirus and Human Parechovirus Viral Sepsis: Natural History and Predictors of Morbidity and Mortality, is scientifically led by Mark Abzug, MD. Neonatal viral sepsis is a clinical syndrome characterized by a constellation of organ involvement that includes hepatitis, coagulopathy (thrombocytopenia with or without derangement of clotting times), and/or myocarditis, sometimes occurring in concert with meningoencephalitis or pneumonitis. Although a number of viruses can cause neonatal viral sepsis, including herpes simplex virus (HSV), cytomegalovirus (CMV), and adenovirus, two of the most frequent causes are enteroviruses (EVs) and human parechoviruses (HPeVs). Antiviral treatment for neonatal EV or HPeV sepsis is needed, but not yet commercially available. The design of future antiviral trials for neonatal viral sepsis would greatly benefit from a better understanding of the natural history of this serious, but rare, condition. More precise definition of rates of long-term morbidity and mortality associated with neonatal EV and HPeV sepsis, and better delineation of clinical and laboratory parameters that are predictive of adverse outcomes, are important to inform the optimal design of therapeutic trials, including issues such as appropriate endpoints, sample size, and inclusion criteria. The potential utility of quantitative PCR (qPCR) or other laboratory biomarkers to predict severity of illness, long-term sequelae, or mortality in these illnesses is currently unknown. If qPCR was shown to be a useful predictor of or surrogate for clinical outcomes, this could greatly facilitate the performance of therapeutic trials. Finally, studies to date suggest that a portion of children presenting clinically with neonatal viral sepsis do not have EVs, HPeVs, or other known viruses. It is important to better understand the full spectrum of etiologic agents using state-of-the-art tools for pathogen discovery. The proposed study is designed to fill in these gaps in our knowledge about neonatal viral sepsis to advance trial readiness for the anticipated development of antiviral treatment therapy for this condition. This will be accomplished by evaluating the following specific aims: 1) to estimate the morbidity and mortality rates of neonatal EV sepsis and neonatal HPeV sepsis; 2) to identify clinical and laboratory parameters, including quantitative polymerase chain reaction (qPCR), predictive of morbidity and mortality from neonatal EV and neonatal HPeV sepsis; and 3) to determine the etiologies of neonatal viral sepsis not due to EV, HPeV, HSV, CMV, and adenovirus using next-gen sequencing for pathogen discovery. The systematic prospective multicenter assessment of neonatal viral sepsis, including EV and HPeV sepsis, will produce data that can be used in the design of future Phase I, II, and III treatment studies with antiviral drugs currently in development by pharmaceutical companies, such as KYORIN Pharmaceutical Co., Ltd., and Vaxart, Inc.