Circulating mitochondrial DNA is an early indicator of severe illness and mortality from COVID-19

Background: Mitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether circulating cell-free MT-DNA quantitation could be used to predict the risk of poor COVID-19 outcomes remains undetermined. Methods: We measured circulating MT-DNA levels in prospectively collected, cell-free plasma samples from 97 subjects with COVID-19 at hospital presentation. Our primary outcome was mortality. ICU admission, intubation, vasopressor and renal replacement therapy requirements were secondary outcomes. Multivariate regression analysis determined whether MT-DNA levels were independent of other reported COVID-19 risk factors. Receiver operating characteristics and area under-the-curve assessment were used to compare MT-DNA levels to established and emerging inflammatory markers of COVID-19. Results: Circulating MT-DNA levels were highly elevated in patients who eventually died, required ICU admission, intubation, vasopressor use or renal replacement therapy. Multivariate regression revealed that high circulating MT-DNA is an independent risk factor for these outcomes after adjusting for age, sex, and comorbidities. We also found that circulating MT-DNA levels have a similar or superior area-under-the curve when compared against clinically-established measures of inflammation and emerging markers currently of interest as investigational targets for COVID-19 therapy. Conclusions: These results show that high circulating MT-DNA levels are a potential early indicator for poor COVID-19 outcomes. Funding: This project was supported by Washington University Institute of Clinical Translational Sciences COVID-19 Research Program. Sample procurement and patient outcome data collection was supported by the Washington University ICTS NIH grant UL1TR002345.