(1633) Host RNA Biomarkers Detect Neutrophil Activation in Early Sepsis: Trajectory Matters

Introduction: Early stage sepsis diagnosis can be challenging. The survival chances are improved by early diagnosis and treatment. In the prospective SENSOR study, we sought to identify biomarkers indicating increased risk of sepsis in patients meeting systemic inflammatory response syndrome (SIRS) criteria. We hypothesized that progression to septic shock exhibits higher neutrophil activation RNA markers compared against no progression to septic shock.

Methods: Adult patients in the ED meeting SIRS criteria were consented. Subjects (n=73) were grouped by physician-adjudicated infection and/or sepsis status. Severe sepsis was judged by heart rate, blood pressure, respiratory rate, and organ failure. A blood sample was drawn in RNA preservative (Tempus) for blood RNA biomarkers of infection analysis. Whole blood RNA was analyzed by a droplet digital PCR test for RNA transcripts related to neutrophil response to infection by bacterial (alpha-defensin, DEFA1), viral (IFI27, RSAD2), and biofilm (ALPL, IL8RB/CXCR2) pathogens.

Results: Subjects with a diagnosed infection showed 4-fold increase in DEFA1 mRNA vs those without infection (p < 0.05). No significant difference observed in RNA levels in severe sepsis vs infection without sepsis. However, in patients with both 0hr and 3hr blood samples (n=28), a change in RNA levels was strongly associated with sepsis progression (80% PPV, 82% NPV, OR =18.7). RNA levels detected host immune activation in 86% of diagnosed sepsis, and in ~53% of infected but not septic patients or diagnosed as uninfected. RNA biomarkers identified activation by bacterial (42%), biofilm (31%) and viral (9.7%) pathogens, altering infection diagnosis in 38% of cases.

Conclusions: Patients progressing to sepsis did not have higher levels of neutrophil activation RNA biomarkers than patients with infections not becoming sepsis. Consistent with active translation, a rapid change in those markers, is a strong sign of the transition from infection to severe sepsis/septic shock. Digital PCR is time consuming in the acute setting, but rapid evolution of point-of-care RNA quantitation could allow real-time tracking of the host immune system’s response to infection.