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

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Abstract

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. Intensive care unit (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 characteristic and area under the curve assessments were used to compare MT-DNA levels with established and emerging inflammatory markers of COVID-19.

Results

Circulating MT-DNA levels were highly elevated in patients who eventually died or required ICU admission, intubation, vasopressor use, or renal replacement therapy. Multivariate regression revealed that high circulating MT-DNA was an independent risk factor for these outcomes after adjusting for age, sex, and comorbidities. We also found that circulating MT-DNA levels had 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.

Conclusion

These results show that high circulating MT-DNA levels are a potential early indicator for poor COVID-19 outcomes.

Funding

Washington University Institute of Clinical Translational Sciences COVID-19 Research Program and Washington University Institute of Clinical Translational Sciences (ICTS) NIH grant UL1TR002345.

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Most cited references 74

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OpenSAFELY: factors associated with COVID-19 death in 17 million patients

Elizabeth J Williamson, Alex J Walker, Krishnan Bhaskaran … (2020)

COVID-19 has rapidly impacted on mortality worldwide. 1 There is unprecedented urgency to understand who is most at risk of severe outcomes, requiring new approaches for timely analysis of large datasets. Working on behalf of NHS England we created OpenSAFELY: a secure health analytics platform covering 40% of all patients in England, holding patient data within the existing data centre of a major primary care electronic health records vendor. Primary care records of 17,278,392 adults were pseudonymously linked to 10,926 COVID-19 related deaths. COVID-19 related death was associated with: being male (hazard ratio 1.59, 95%CI 1.53-1.65); older age and deprivation (both with a strong gradient); diabetes; severe asthma; and various other medical conditions. Compared to people with white ethnicity, black and South Asian people were at higher risk even after adjustment for other factors (HR 1.48, 1.29-1.69 and 1.45, 1.32-1.58 respectively). We have quantified a range of clinical risk factors for COVID-19 related death in the largest cohort study conducted by any country to date. OpenSAFELY is rapidly adding further patients’ records; we will update and extend results regularly.

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Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study

Christopher Petrilli, Simon A. Jones, Jie Yang … (2020)

Abstract Objective To describe outcomes of people admitted to hospital with coronavirus disease 2019 (covid-19) in the United States, and the clinical and laboratory characteristics associated with severity of illness. Design Prospective cohort study. Setting Single academic medical center in New York City and Long Island. Participants 5279 patients with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection between 1 March 2020 and 8 April 2020. The final date of follow up was 5 May 2020. Main outcome measures Outcomes were admission to hospital, critical illness (intensive care, mechanical ventilation, discharge to hospice care, or death), and discharge to hospice care or death. Predictors included patient characteristics, medical history, vital signs, and laboratory results. Multivariable logistic regression was conducted to identify risk factors for adverse outcomes, and competing risk survival analysis for mortality. Results Of 11 544 people tested for SARS-Cov-2, 5566 (48.2%) were positive. After exclusions, 5279 were included. 2741 of these 5279 (51.9%) were admitted to hospital, of whom 1904 (69.5%) were discharged alive without hospice care and 665 (24.3%) were discharged to hospice care or died. Of 647 (23.6%) patients requiring mechanical ventilation, 391 (60.4%) died and 170 (26.2%) were extubated or discharged. The strongest risk for hospital admission was associated with age, with an odds ratio of >2 for all age groups older than 44 years and 37.9 (95% confidence interval 26.1 to 56.0) for ages 75 years and older. Other risks were heart failure (4.4, 2.6 to 8.0), male sex (2.8, 2.4 to 3.2), chronic kidney disease (2.6, 1.9 to 3.6), and any increase in body mass index (BMI) (eg, for BMI >40: 2.5, 1.8 to 3.4). The strongest risks for critical illness besides age were associated with heart failure (1.9, 1.4 to 2.5), BMI >40 (1.5, 1.0 to 2.2), and male sex (1.5, 1.3 to 1.8). Admission oxygen saturation of 1 (4.8, 2.1 to 10.9), C reactive protein level >200 (5.1, 2.8 to 9.2), and D-dimer level >2500 (3.9, 2.6 to 6.0) were, however, more strongly associated with critical illness than age or comorbidities. Risk of critical illness decreased significantly over the study period. Similar associations were found for mortality alone. Conclusions Age and comorbidities were found to be strong predictors of hospital admission and to a lesser extent of critical illness and mortality in people with covid-19; however, impairment of oxygen on admission and markers of inflammation were most strongly associated with critical illness and mortality. Outcomes seem to be improving over time, potentially suggesting improvements in care.

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Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases

Cynthia M Magro, J. Mulvey, David Berlin … (2020)

Acute respiratory failure and a systemic coagulopathy are critical aspects of the morbidity and mortality characterizing infection with severe acute respiratory distress syndrome-associated coronavirus-2 (SARS-CoV-2), the etiologic agent of Coronavirus disease 2019 (COVID-19). We examined skin and lung tissues from 5 patients with severe COVID-19 characterized by respiratory failure (n=5) and purpuric skin rash (n=3). The pattern of COVID-19 pneumonitis was predominantly a pauci-inflammatory septal capillary injury with significant septal capillary mural and luminal fibrin deposition and permeation of the inter-alveolar septa by neutrophils. No viral cytopathic changes were observed and the diffuse alveolar damage (DAD) with hyaline membranes, inflammation, and type II pneumocyte hyperplasia, hallmarks of classic ARDS, were not prominent. These pulmonary findings were accompanied by significant deposits of terminal complement components C5b-9 (membrane attack complex), C4d, and mannose binding lectin (MBL)-associated serine protease (MASP)2, in the microvasculature, consistent with sustained, systemic activation of the alternative and lectin-based complement pathways. The purpuric skin lesions similarly showed a pauci-inflammatory thrombogenic vasculopathy, with deposition of C5b-9 and C4d in both grossly involved and normally-appearing skin. In addition, there was co-localization of COVID-19 spike glycoproteins with C4d and C5b-9 in the inter-alveolar septa and the cutaneous microvasculature of two cases examined. In conclusion, at least a subset of sustained, severe COVID-19 may define a type of catastrophic microvascular injury syndrome mediated by activation of complement pathways and an associated procoagulant state. It provides a foundation for further exploration of the pathophysiologic importance of complement in COVID-19, and could suggest targets for specific intervention.

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Author and article information

Contributors

Davide Scozzi

Marlene Cano:

ORCID: http://orcid.org/0000-0002-2368-9256

Lina Ma

Dequan Zhou

Ji Hong Zhu

Jane A. O’Halloran

Adriana M. Rauseo:

ORCID: http://orcid.org/0000-0001-9555-2550

Zhiyi Liu

Valentina Peritore

Monica Rocco:

ORCID: http://orcid.org/0000-0001-8380-3607

Alberto Ricci:

ORCID: http://orcid.org/0000-0002-1718-1587

Rachele Amodeo

Laura Aimati

Mohsen Ibrahim:

ORCID: http://orcid.org/0000-0002-9288-2359

Daniel Kreisel

Philip A. Mudd:

ORCID: http://orcid.org/0000-0002-3860-5473

Hrishikesh S. Kulkarni:

ORCID: http://orcid.org/0000-0003-4830-5084

Andrew E. Gelman:

ORCID: http://orcid.org/0000-0002-0711-6343

Journal

Journal ID (nlm-ta): JCI Insight

Journal ID (iso-abbrev): JCI Insight

Journal ID (publisher-id): JCI Insight

Title: JCI Insight

Publisher: American Society for Clinical Investigation

ISSN (Electronic): 2379-3708

Publication date (Electronic, pub): 22 February 2021

Publication date (Electronic, collection): 22 February 2021

Publication date PMC-release: 22 February 2021

Volume: 6

Issue: 4

Electronic Location Identifier: e143299

Affiliations

[1 ]Division of Cardiothoracic Surgery, Department of Surgery;

[2 ]Division of Pulmonary and Critical Care Medicine, Department of Medicine;

[3 ]Division of Infectious Diseases, Department of Medicine; and

[4 ]Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, USA.

[5 ]Division of Thoracic Surgery and

[6 ]Division of Anesthesiology, Department of Medical-Surgical Science and Translational Medicine, Sapienza University of Rome, Rome, Italy.

[7 ]Division of Pulmonology, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy.

[8 ]Laboratory Analysis-Flow Cytometry Section, Sapienza University of Rome, Rome, Italy.

[9 ]Division of Emergency Medicine,

[10 ]Department of Molecular Microbiology, and

[11 ]Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

Author notes

Address correspondence to: Andrew E. Gelman or Hrishikesh S. Kulkarni, Washington University School of Medicine, Campus Box 8234 (AEG) or Campus Box 8052 (HSK), 660 South Euclid Avenue, St. Louis, Missouri 63110, USA. Phone: 314.362.8382; Email: gelmana@ 123456wudosis.wustl.edu (AEG). Phone: 314.362.8391; Email: hkulkarn@ 123456wustl.edu (HSK).

Authorship note: DS and MC contributed equally to this work. DS and MC are co–first authors. HSK and AEG are co–corresponding authors.

Author information

Marlene Cano http://orcid.org/0000-0002-2368-9256

Adriana M. Rauseo http://orcid.org/0000-0001-9555-2550

Monica Rocco http://orcid.org/0000-0001-8380-3607

Alberto Ricci http://orcid.org/0000-0002-1718-1587

Mohsen Ibrahim http://orcid.org/0000-0002-9288-2359

Philip A. Mudd http://orcid.org/0000-0002-3860-5473

Hrishikesh S. Kulkarni http://orcid.org/0000-0003-4830-5084

Andrew E. Gelman http://orcid.org/0000-0002-0711-6343

Article

Publisher ID: 143299

DOI: 10.1172/jci.insight.143299

PMC ID: 7934921

PubMed ID: 33444289

SO-VID: ae649300-ae11-46f4-9b1b-b8c83734bf10

License:

This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 13 August 2020

Date accepted : 6 January 2021

Funding

Funded by: Washington University Institute of Clinical Translational Sciences

Award ID: UL1TR002345

Sample procurement and patient outcome data collection was supported by the Washington University ICTS NIH grant

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

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Abstract

Background

Methods

Results

Conclusion

Funding

Related collections

Novel Coronavirus Disease COVID-19

Most cited references 74

OpenSAFELY: factors associated with COVID-19 death in 17 million patients

Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study

Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases

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