Plasma Mitochondrial DNA Levels are Associated with Acute Respiratory Distress Syndrome in Trauma and Sepsis Patients

ABSTRACT BACKGROUND Critically ill patients who develop the acute respiratory distress syndrome (ARDS) have substantial associated morbidity and mortality. Circulating mitochondrial DNA (mtDNA) released during critical illness causes endothelial dysfunction and lung injury in experimental models. We hypothesized that elevated plasma mtDNA is associated with ARDS in critically ill trauma and sepsis patients. METHODS We measured plasma mtDNA concentrations at emergency department presentation and approximately 48 hours later in separate prospective cohorts of critically ill trauma and sepsis patients. ARDS was classified according to the Berlin definition. We tested the association of mtDNA with ARDS using multivariable logistic regression, adjusted for covariates previously demonstrated to contribute to ARDS risk in each population. RESULTS ARDS developed in 41 of 224 (18%) trauma patients and in 45 of 120 (38%) sepsis patients. Forty-eight-hour mtDNA levels were significantly associated with ARDS (trauma: OR 1.58/ log copies/uL, 95% CI 1.14-2.19, p=0.006; sepsis: OR 1.52/log copies/uL, 95% CI 1.12-2.06, p=0.007). Plasma mtDNA on presentation was not significantly associated with ARDS in either cohort. In sepsis patients, 48-hour mtDNA was more strongly associated with ARDS among those with non-pulmonary infectious source (OR 2.20/log copies/uL, 95% CI 1.36-3.55, p=0.001, n=69) than those with pulmonary source (OR 1.04/log copies/uL, 95% CI 0.68-1.59, p=0.84; n=51; p=0.014 for interaction). CONCLUSIONS Plasma mtDNA levels were associated with incident ARDS in two critical illness populations. Given supportive preclinical data, our findings may suggest a potential link between circulating mtDNA and lung injury and merit further investigation as a potentially targetable mediator of ARDS.