Enhanced Performance of Next-Generation Sequencing Diagnostics Compared With Standard of Care Microbiological Diagnostics in Patients Suffering From Septic Shock.pdf
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1、Downloaded from http:/ by BhDMf5ePHKbH4TTImqenVJKnHXMTrNzpDxfgK8xMyFr3+7Ndz+AKjjLr3rLkpi50pll5g3tDpCQ= on 02/07/2019Downloaded from http:/ by BhDMf5ePHKbH4TTImqenVJKnHXMTrNzpDxfgK8xMyFr3+7Ndz+AKjjLr3rLkpi50pll5g3tDpCQ= on 02/07/2019Critical Care Medicine www.ccmjournal.org 1Objectives: Culture-based
2、 diagnostics represent the standard of care in septic patients, but are highly insensitive and in many cases unspecific. We recently demonstrated the general fea-sibility of next-generation sequencing-based diagnostics using free circulating nucleic acids (cell-free DNA) in plasma samples of septic
3、patients. Within the presented investigation, higher per-formance of next-generation sequencing-based diagnostics was validated by comparison to matched blood cultures.Design: A secondary analysis of a prospective, observational, single-center study.Setting: Surgical ICU of a university hospital and
4、 research labo-ratory.Patients: Fifty patients with septic shock, 20 uninfected patients with elective surgery as control cohort.Interventions: None.Measurements and Main Results: From 256 plasma samples of 48 septic patients at up to seven consecutive time points within the 28-day observation perio
5、d, cell-free DNA was isolated and analyzed by next-generation sequencing and relevance scoring. In parallel, results from culture-based diagnostics (e.g., blood culture) were obtained. Plausibility of blood culture and next-generation sequencing results as well as adequacy of antibiotic therapy was
6、evaluated by an independent expert panel. In con-trast to blood culture with a positivity rate of 33% at sepsis onset, the positivity rate for next-generation sequencing-based pathogen identification was 72%. Over the whole study period, blood cul-ture positivity was 11%, and next-generation sequenc
7、ing positivity was 71%. Ninety-six percent of positive next-generation sequenc-ing results for acute sepsis time points were plausible and would have led to a change to a more adequate therapy in 53% of cases as assessed by the expert evaluation.Conclusions: Our results show that next-generation seq
8、uencing-based analyses of bloodstream infections provide a valuable DOI: 10.1097/CCM.00000000000036581Fraunhofer IGB, Stuttgart, Germany.2Noscendo GmbH, Duisburg, Germany.3Department of Anesthesiology, Heidelberg University Hospital, Heidel-berg, Germany.4Westpfalz-Klinikum GmbH, 1, Hellmut-Hartert-
9、Strae, Kaiserslautern, Germany.Drs. Brenner and Sohn share senior authorship.Drs. S. Grumaz, Decker, Hofer, Brenner, and Sohn conceived of, designed, and supervised the study. Drs. Decker, Hofer, and Brenner col-lected clinical samples and clinical data. Drs. S. Grumaz, C. Grumaz, and Glanz performe
10、d all sample processing and next-generation sequencing experiments. Drs. Vainshtein and Stevens performed bioinformatic data processing and statistical analyses. Drs. S. Grumaz, C. Grumaz, Stevens, and Sohn analyzed the data. Drs. Hofer, Weigand, Brenner, and Sohn provided materials. Drs. S. Grumaz
11、and C. Grumaz prepared the tables and figures. Drs. S. Grumaz and Sohn wrote the article with contributions from all other authors. All authors read, critically revised, and approved the final article.A data visualization tool associated with this article can be viewed here: https:/lippincott.shinya
12、pps.io/Sohn/.Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journals website (http:/ in part, by the Fraunhofer IGB (Stuttgart, Germany), Fraun-hofer Future Foundation, D
13、epartment of Anesthesiology (University of Heidelberg, Germany), Heidelberg Foundation of Surgery (University of Heidelberg, Germany). Our study sponsors were not involved in study design, collection, analysis, or interpretation of data.Drs. Decker and Brenner received project funding from Heidelber
14、g Foun-dation of Surgery. Drs. S. Grumaz, Stevens, and Sohn disclosed that they are co-founders of the company Noscendo active in molecular diagnostics for infectious diseases. The remaining authors have disclosed that they do not have any potential conflicts of interest.For information regarding th
15、is article, E-mail: kai.sohnigb.fraunhofer.deCopyright 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY),
16、 which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Enhanced Performance of Next-Generation Sequencing Diagnostics Compared With Standard of Care Microbiological Diagnostics in Patients Suffering From Septic ShockSilke Grumaz, P
17、hD1; Christian Grumaz, PhD1; Yevhen Vainshtein, PhD1; Philip Stevens, PhD2; Karolina Glanz1; Sebastian O. Decker, MD3; Stefan Hofer, MD4; Markus A. Weigand, MD3; Thorsten Brenner, MD3; Kai Sohn, PhD1S. Grumaz et al2 www.ccmjournal.org XXX 2019 Volume XX Number XXX diagnostic platform for the identif
18、ication of clinically relevant pathogens with higher sensitivity and specificity than blood cul-ture, indicating that patients might benefit from a more appropriate therapy based on next-generation sequencing-based diagnosis. (Crit Care Med 2019; XX:0000)Key Words: blood culture; cell-free nucleic a
19、cids; deep sequencing; molecular diagnostic techniques; sepsis; septic shockSepsis is a major health concern with increasing fre-quency and an estimated global mortality rate of 5.3 million deaths per year (1). Time is crucial in the man-agement of septic patients and early treatment, including an-t
20、ibiotic administration and source control are the decisive first steps that influence patients outcome dramatically (24). Current guidelines recommend the initiation of antimicrobial therapy as early as possible and preferably within 1 hour (5). However, most of early treatments are empirical, and 4
21、6% of empirical antibiotic treatments were shown to be inappro-priate and associated with 35% mortality (6). About 50% was either unnecessary or too broad spectrum, increasing the risk for resistance and toxicity. Early recognition of the infecting microorganism is therefore crucial for a targeted a
22、ntimicrobial therapy, reducing side effects for the patient and improving patients outcome. The current standard of care blood culture (BC) however is limited by long time to positivity, low sensi-tivity, and low specificity.We recently published a proof of concept study, in which the general applic
23、ability of microbial circulating cell-free DNA (cfDNA) to diagnose causative pathogens in sepsis using a sig-nificance scoring system and to identify single-gene resistances via next-generation sequencing (NGS) was demonstrated (7).The aim of the presented study was to evaluate the perfor-mance of t
24、he NGS-based diagnostic approach with a larger cohort of patients and benchmark it by direct comparison to the current standard of care BC. Due to the limitations of BC, our findings were reviewed by an independent expert jury for plausibility, and the antimicrobial treatment regimen was reas-sessed
25、 for putative changes.METHODSStudy DesignData result from a secondary analysis of septic patients (n = 50) participating in a previously published, prospective ob-servational clinical study of our workgroup, which was con-ducted in the surgical ICU of Heidelberg University Hospital, Germany between
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