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: The SPITSS Study: 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 cellar function and transcriptomics: We used peripheral blood genome-wide expression profiling (GWEP) to demonstrate that among older age groups of children with septic shock, neonates exhibited a unique host response (2011). In particular, neonates exhibited predominantly down-regulation of genes, comprising pathways of critical innate immune importance, whereas older pediatric patients showed predominantly up-regulated expression of these pathways. In a similar study of infants in the NICU, we showed that timing of sepsis after birth is a critical determinant of the host response to sepsis in preterm neonates (2015). We are continuing our studies focused on the changes in peripheral blood and cell-specific GWEPs associated with sepsis in preterm infants. We showed the transcriptomic response to sepsis is age-dependent, and diagnostic and therapeutic efforts to identify and treat sepsis will have to consider age as an important variable (2017). 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.
We developed and validated the gold standard of murine neonatal sepsis modeling: the cecal slurry model of generalized peritonitis (2007). This model permits in-depth mechanistic investigation of the neonatal-specific host immune response to sepsis through the application of pharmacologic and genetic (knock-in, knock-out, and humanized) approaches. We showed the neonate exhibits fundamental differences compared to the adult in the inflammatory response to sepsis; specifically a Th2-skewed plasma cytokine profile with 20-55 times less IL-1β, IFN-γ, and TNF-α. In subsequent publications using our model we showed the neonate, in stark contrast to the adult, does not depend on adaptive immunity or type I interferon signaling for a successful host response (2008). In that report, we also demonstrated that innate immune priming (trained immunity) using selected toll-like receptor agonists dramatically reduced subsequent sepsis mortality by up to 40 percent and was associated with enhanced innate immune cellular function. We showed the neonate has a strong dependence on TRIF-signaling, CXCR3, and CXCL10 for sepsis survival whereas the adult depends more heavily on MyD88 signaling. Recently, we showed murine neonatal CD71+ erythroid cells, although immunomodulatory ex vivo, had no impact on murine neonatal sepsis survival (2015). We showed the deleterious role of IL-18 in neonatal sepsis and is published in the Proceedings of the National Academy of Sciences (2016) and the subject of our NIGMS-funded R01 entitled Modifiable Determinants of Mortality in Neonatal Sepsis (R01HD089939). We showed IL-1α and not IL-1β drives IL-1R1-dependent neonatal murine sepsis lethality, highlighting a potential mechanism behind the inability of anakinra to reduce sepsis mortality (2018) We are actively investigating other beneficial mechanisms of innate immune stimulation and detrimental mechanisms of sepsis.
We are very fortunate to have spectacular collaborators that make the work we do possible.
We are grateful to the agencies below that have provided support for our research program.