D. Holden1, T. Murphy1, T. O. Baslanti1, Z. Wang1, G. Ghita1, S. Brakenridge1, A. Bihorac1, P. Efron1, F. Moore1, L. L. Moldawer1 1University Of Florida,College Of Medicine,Gainesville, FL, USA
Introduction: Nuclear DNA (ncDNA) and mitochondrial DNA (mtDNA) are damage associated molecular patterns (DAMPs) that are known to stimulate a pro-inflammatory response through pattern recognition receptors such as Toll-like receptors. The association of circulating ncDNA and mtDNA with the persistence of organ dysfunction and the development of chronic critical illness (CCI) after sepsis are poorly understood.
Methods: In this prospective observational cohort of critically ill surgical patients that developed sepsis, we measured circulating ncDNA and mtDNA levels on 0.5, 1, 4, 7, 14, and 21 days after sepsis by ddPCR. DAMP levels were then compared based on clinical outcomes, including the development of CCI (≥14 days ICU LOS with ongoing organ dysfunction) in comparison to those with rapid recovery (RAP), as well as by 1-year mortality.
Results: We found that ncDNA and mtDNA were significantly higher in sepsis patients than in healthy controls. Additionally, ncDNA levels were significantly higher at 0.5, 1, 4 and 7 days after sepsis in patients that subsequently developed CCI as compared to RAP (Figure; p<0.05). ncDNA was correlated with serum lactate (Pearson: 0.85) and aspartate aminotransferase (Pearson: 0.97) consistent with shock severity and end organ tissue damage. ncDNA levels peaked at 4 days after sepsis in both groups. There were no significant differences in mtDNA levels between CCI and RAP at all time points. Elevated mtDNA levels at days 14 and 21 in hospitalized patients were significantly associated with 1 year survival (Figure 1).
Conclusion: Elevated nuDNA levels early after sepsis are associated with persistent organ dysfunction and the development of CCI. In the population of patients who experience prolonged hospital stays, the patients who have higher levels of circulating mtDNA do better, and more of these patients are alive at one year. Since these same patients who have higher circulating mtDNA levels, do not have elevated circulating ncDNA levels, this means that the circulating mtDNA is not resulting from tissue death and cell necrosis. Therefore for the patients who following sepsis, both experience prolonged hospital stays AND go on to survive greater than 1 year, there is something actively occurring in their bodies that is contributing to the release of circulating mtDNA. This active release may be part of neutrophil NETosis, and it may be that patients with prolonged hospital stay who are capable of efficiently producing NETs and the associated circulating mtDNA have greater 1 year survival.
