Sepsis has its greatest impact in the prematurely born (preterm) population. Neonatal sepsis (sepsis within the first month of life) causes over one million deaths worldwide annually, and is one of the most common, difficult and costly problems to diagnose, treat and prevent. The preterm infant can suffer rates of sepsis up to 1000-fold higher than the full-term infant, and bears the brunt of the associated mortality and lifelong sepsis-survivor morbidity. Substantial clinical questions in the management of the potentially infected neonate remain unanswered: 1) Is the infant infected?, 2) Which infants have the greatest risk for a complicated clinical course with infection?, and 3) Why are preterm infants (especially very low birth weight infants) at such high risk of developing infections? The paucity of investigations in the preterm infant can be attributed in large part to very limited blood volume for study (80-100 milliliter total blood volume in a typical 28 week, 1000 gram infant), and prior assumptions that the neonatal host immune response is similar to that seen in older children and adults. We propose that deficiencies in innate immune function of neutrophils (PMN) in neonates are one underlying cause of this decrease in host protective immunity, and their function can be used to predict the development of sepsis and protracted clinical course. We intend to deliver accurate methods to diagnose sepsis, identify prognostic and critical illness stratification markers, and uncover immunological differences with the potential for translational interventions that may improve neonatal infection-related outcomes, all based on a novel microfluidics platform. Specifically, we propose a prospective, observational study of 300 preterm (<30 weeks gestational age) and 60 full-term (>36 weeks) infants in whom we will identify specific deficiencies in PMN function, develop prediction models for sepsis, and ultimately, clinical outcome, based on microfluidics measurements of PMN function and transcriptomics, and classical clinical measures. The project is enabled by several novel, validated, microfluidic technologies that are robust and easy to use with little training. These technologies provide comprehensive measures of the functionality of blood PMN population; a critical cellular component of innate immunity. We will also extract high-quality nucleic acids from microfluidic-sorted PMNs for transcriptomic analyses, and deliver a complete blood count with 5-part differential integrated with clinical chemistry and inflammatory biomarkers. Collectively, these techniques require a total of ~100 microliters (?L) of blood, which makes them particularly useful for preterm infants where sample volume is limited, and facilitates serial assessments with unprecedented temporal resolution of key functions of PMNs. These studies, integrated with bioinformatics approaches, will generate new tools for diagnosing sepsis in the newborn and predicting clinical outcomes. Such approaches have the capability to dramatically change the clinical management of the preterm infant, and potentially improve long-term outcomes while reducing hospital costs.
Premature newborns have a very high risk of death or life-long complications due to systemic infections or sepsis (also known as ?blood poisoning?), despite being treated with antimicrobial drugs. Understanding and diagnosing sepsis is currently difficult because the extremely small blood volume in the premature newborn limits both our diagnostic and research approaches. Using innovative microfluidic technologies focused on innate immune function and the most commonly used clinical diagnostics, we propose a paradigm-changing approach to identifying sepsis and its underlying causes in premature newborns at risk of sepsis.
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