Immune Dysregulation During Sepsis: A Natural History Cohort

Study Description:

This is a natural history study intended to allow the characterization of neutrophil biology and other contributors to the pathogenesis along with short-term outcomes of patients hospitalized with sepsis. Patients admitted to INOVA Fairfax Hospital with sepsis will be enrolled, undergo clinical evaluation, clinical data capture, and will have blood drawn that will be processed and analyzed at the NIH.

Objectives:

The aim of this natural history/observational study is to develop a cohort of patients admitted to the hospital with sepsis who can be followed longitudinally to achieve the following:

Primary objectives:

To investigate the contribution of neutrophils and neutrophil subsets including low density neutrophils to the dysregulated immune response that occurs during the acute phase of sepsis.

Secondary objective:

-To characterize spleen tyrosine kinase expression across immune cells and correlate with soluble biomarkers, cellular phenotypes and gene expression to determine mechanistic pathways that may be amenable to host-direct therapies.

Exploratory:

-To identify novel cellular and soluble phenotypes using multiomic and functional datasets and correlate them with clinical sepsis phenotypes, mortality, and cardiac dysfunction to inform sepsis clinical trajectory and novel therapeutic targets.

Endpoints:

Primary Endpoint:

Changes in the frequency, activation and functional status of neutrophils and neutrophil subsets including low density neutrophils during the acute phase of sepsis and their association with in hospital mortality.

Secondary Endpoints:

-Changes in spleen tyrosine kinase expression across immune cells and its correlation with soluble biomarkers, cellular phenotypes and gene expression and their association with in hospital mortality.

Exploratory:

-Identification of novel cellular and soluble immunological signatures of immune dysregulation during sepsis and their association with cardiac dysfunction, disease severity, and in hospital mortality.

• INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

• Age >= 18 years old
• Admitted to INOVA Fairfax Hospital
• Meets sepsis-3 definition of sepsis in the last 48 hours

• Suspected infection
• Evidence of organ dysfunction (SOFA score >= 2)
• Ability of subject or LAR to understand and the willingness to sign a written informed consent document

Exclusion criteria

Any individual who meets any of the following criteria will be excluded from participation in this study:

• Hemoglobin < 7 microgram/dL at the time of enrollment
• Hemoglobin <10 microgram/dL in patients with known coronary artery disease or active EKG changes consistent with acute ischemia
• Currently receiving infusion of epinephrine; or dopamine at an infusion rate of > 2.5

microgram/kg/min, norepinephrine of > 20 mircogram/min, or vasopressin > 0.04 units/min

• Neutropenia (absolute neutrophil count less than 1000 cells/microliter)
• Baseline cognitive impairment
• Pregnancy