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Circulating microbial cell-free DNA is associated with inflammatory host-responses in severe pneumonia
  1. Haopu Yang1,2,3,4,
  2. Ghady Haidar5,
  3. Nameer S Al-Yousif6,
  4. Haris Zia7,
  5. Daniel Kotok8,
  6. Asim A Ahmed9,
  7. Lily Blair9,
  8. Sudeb Dalai9,
  9. Sivan Bercovici9,
  10. Carine Ho9,
  11. Bryan J McVerry3,4,10,
  12. Alison Morris3,4,10,11,
  13. Georgios D Kitsios3,4,10
  1. 1 School of Medicine, Tsinghua University, Beijing, People's Republic of China
  2. 2 Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  3. 3 Division of Pulmonary Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
  4. 4 Center for Medicine and the Microbiome, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  5. 5 Division of Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
  6. 6 Internal Medicine Residency Program, Mercy, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
  7. 7 Internal Medicine Residency Program, McKeesport, University of Pittsburgh Medical Center, McKeesport, Pennsylvania, USA
  8. 8 Weston Hospital, Cleveland Clinic Florida, Weston, Florida, USA
  9. 9 Karius Inc, Redwood City, California, USA
  10. 10 Acute Lung Injury Center for Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  11. 11 Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
  1. Correspondence to Dr Georgios D Kitsios, Pulmonary Allergy and Critical Care Medicine, University of Pittsburgh Medical Center Health System, Pittsburgh, PA 15213, USA; kitsiosg{at}upmc.edu

Abstract

Host inflammatory responses predict worse outcome in severe pneumonia, yet little is known about what drives dysregulated inflammation. We performed metagenomic sequencing of microbial cell-free DNA (mcfDNA) in 83 mechanically ventilated patients (26 culture-positive, 41 culture-negative pneumonia, 16 uninfected controls). Culture-positive patients had higher levels of mcfDNA than those with culture-negative pneumonia and uninfected controls (p<0.005). Plasma levels of inflammatory biomarkers (fractalkine, procalcitonin, pentraxin-3 and suppression of tumorigenicity-2) were independently associated with mcfDNA levels (adjusted p<0.05) among all patients with pneumonia. Such host–microbe interactions in the systemic circulation of patients with severe pneumonia warrant further large-scale clinical and mechanistic investigations.

  • pneumonia

Data availability statement

To ensure transparency and reproducibility of our study, our de-identified dataset and code for analyses have been made publicly available at https://github.com/MicrobiomeALIR

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Data availability statement

To ensure transparency and reproducibility of our study, our de-identified dataset and code for analyses have been made publicly available at https://github.com/MicrobiomeALIR

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Footnotes

  • Twitter @KitsiosMd

  • Contributors Conception and design: GK, BJM, AM, HY, AA. Acquisition, analyses and interpretation of data: HY, GH, NSAY, HZ, DK, AA, LB, SD, SB, CH, BJM, AM, GK. Clinical cohort phenotyping: NSAY, HZ, DK, GK, BJM, AM. Drafting of work and/or revising for important intellectual content: HY, GH, NSAY, HZ, DK, AA, LB, SD, SB, CH, BJM, AM, GK. Final approval of version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: HY, GH, NSAY, HZ, DK, AA, LB, SD, SB, CH, BJM, AM, GK.

  • Funding National Institute of Health [K23-KL139987-03 (GK), P01-HL114453-07 (BJM)]

  • Competing interests GK has received research funding from Karius Inc.; GH received research funding from Karius Inc. AA, LB, SD and SB are employed by Karius Inc.; BJM receives research funding from Bayer Pharmaceuticals Inc.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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