Plasma Mitochondrial DNA Levels Are Associated With ARDS in Trauma and Sepsis Patients

Abstract

Background: Critically ill patients who develop ARDS have substantial associated morbidity and mortality. Circulating mitochondrial DNA (mtDNA) released during critical illness causes endothelial dysfunction and lung injury in experimental models. This study hypothesized that elevated plasma mtDNA is associated with ARDS in critically ill patients with trauma and sepsis.

Methods: Plasma mtDNA concentrations were measured at ED presentation and approximately 48 h later in separate prospective cohorts of critically ill patients with trauma and sepsis. ARDS was classified according to the Berlin definition. The association of mtDNA with ARDS was tested by using multivariable logistic regression, adjusted for covariates previously shown to contribute to ARDS risk in each population.

Results: ARDS developed in 41 of 224 (18%) trauma patients and in 45 of 120 (38%) patients with sepsis. Forty-eight-hour mtDNA levels were significantly associated with ARDS (trauma: OR, 1.58/log copies/μL; 95% CI, 1.14-2.19 [P = .006]; sepsis: OR, 1.52/log copies/μL; 95% CI, 1.12-2.06 [P = .007]). Plasma mtDNA on presentation was not significantly associated with ARDS in either cohort. In patients with sepsis, 48-h mtDNA was more strongly associated with ARDS among those with a nonpulmonary infectious source (OR, 2.20/log copies/μL; 95% CI, 1.36-3.55 [P = .001], n = 69) than those with a pulmonary source (OR, 1.04/log copies/μL; 95% CI, 0.68-1.59 [P = .84], n = 51; P = .014 for interaction).

Conclusions: Plasma mtDNA levels were associated with incident ARDS in two critical illness populations. Given supportive preclinical data, our findings suggest a potential link between circulating mtDNA and lung injury and merit further investigation as a potentially targetable mediator of ARDS.

Keywords: ARDS; biomarkers; sepsis; trauma.

Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Association of mtDNA and ARDS in the first 6 days of hospitalization. Adjusted risk of ARDS as a function of presentation and 48-h plasma mtDNA is presented for the PETROS (A = Presentation, B = 48-h) and MESSI (C = Presentation, D = 48-h) cohorts. Forty-eight-hour plasma mtDNA was associated with ARDS in the PETROS and MESSI cohorts. mtDNA is presented in log copies per microliter of plasma. MESSI = Molecular Epidemiology of SepsiS in the ICU; mtDNA = mitochondrial DNA; PETROS = Penn TRauma Organ Dysfunction Study.

Figure 2

Association of 48-h mtDNA and ARDS stratified according to infection source in the MESSI cohort. Adjusted risk of ARDS as a function of 48-h plasma mtDNA in patients with a nonpulmonary infection source compared with patients with pneumonia. Forty-eight-hour mtDNA was strongly associated with ARDS in patients with nonpulmonary infectious sources but not in patients with pneumonia. mtDNA is presented in log copies per microliter of plasma. See Figure 1 legend for expansion of abbreviations.

Figure 3

Association of mtDNA and mortality. Plasma mtDNA at presentation (A) was associated with mortality in the PETROS cohort. B = adjusted risk of mortality as a function of mtDNA at 48-h. C = adjusted risk of mortality as a function of presentation (C) and 48-h (D) in the MESSI cohort. mtDNA is presented in log copies per microliter of plasma. See Figure 1 legend for expansion of abbreviations.