Human studies

Our sepsis-targeted observational human neonatal studies have been performed in parallel with our mechanistic murine studies. We have three active, large-scale, human neonatal sepsis research projects:

Salivary Profiling in Infants Treated for Suspected Sepsis (SPITSS)

This NIH/NICHD-funded multi-center project (R01HD097081) combines the latest technological advances for biomarker quantification (Single Molecule Arrays or SiMoA) with noninvasive salivary diagnostics to integrate the first comprehensive, ultra-sensitive multiplexed salivary infection-screening platform into neonatal care. The salivary protein expression levels of six inflammatory biomarkers will be assessed in 2,250 newborns undergoing a rule out sepsis evaluation at Tufts Medical Center (Boston, MA) and Women and Infants’ Hospital (Providence, RI) NICUs, and validated on an independent cohort of newborns (n=1,750) from the University of Florida, Gainesville. Data will be used to develop and validate a predictive model of neonatal infection, establish normative reference ranges of each inflammatory biomarker across varying gestational ages, sex, and weights, and assess the potential of these biomarkers to predict other neonatal morbidities associated with an inflammatory response.

Neonatal Sequential Organ Failure Assessment (nSOFA)

In contrast to sepsis definitions in adults and children, definitions of sepsis commonly used in neonatology are variable and heavily predicated on the isolation of pathogens from blood and/or the associated length of prescribed antimicrobial treatment. Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. The presence of life-threatening organ dysfunction is demonstrated using a sequential organ failure assessment (SOFA) to determine risk of ICU admission or mortality. To define sepsis in neonates therefore requires an operational definition of organ dysfunction applicable specifically to this population (neonatal SOFA; nSOFA) that predicts mortality in the setting of presumed infection. We recently showed the progression of organ failure in neonates with lethal LOS in a large retrospective cohort (2016). Guided by those data, we developed and tested an objective, electronic health record (EHR)-automated, nSOFA scoring system to predict mortality from LOS in premature, very low birth weight infants (2019).

Neonatal Cellular Function and Transcriptomics

We are fortunate to have received funding from the NIH (NICHD R01HD089939) to use microfluidic measurements of preterm PMN function and transcriptomics to develop prediction models for sepsis, and ultimately, clinical outcome, using several novel, validated, microfluidic technologies that are robust and easy to use with little training. The low volume 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 by bioinformatics approaches, will generate new tools for diagnosing sepsis in the newborn and predicting clinical outcomes.