Next-Generation Sequencing Diagnostics of Bacteremia in Sepsis

NCT03356249 | Completed

• 1 other identifier: S-084/2017
• Study Type: observational
• Target: 500
• Locations: 1 country
• Sites: 21

Brief Summary

Sepsis remains a major challenge, even in modern intensive care medicine. The identification of the causative pathogen is crucial for an early optimization of the antimicrobial treatment regime in patients with sepsis. In this context, culture-based diagnostic procedures (e.g. blood cultures) represent the standard of care, although they are associated with relevant limitations. Therefore, culture independent methods (e.g. Next-Generation Sequencing (NGS)) seem to be an attractive alternative. By the identification of circulating cell-free DNA in the blood and the use of the quantitative sepsis indicating quantifier (SIQ) score, causing pathogens can be identified and potential contaminations can be excluded. The goal of the presented study is therefore, to assess the diagnostic performance of a NGS-based approach for the detection of relevant infecting organisms in a big cohort of septic patients (n=500). Moreover, the plausibility of this NGS-based approach will be estimated by a panel of independent clinical specialists, retrospectively identifying potential changes in patients´ management based on NGS results.

Conditions

Sepsis; Septic Shock

Keywords

Sepsis; Septic shock; Next-Generation Sequencing; Bacteremia

Outcome Measures

Primary Outcomes (5)

• Sensitivity [%] (of the NGS-based SIQ-score in comparison to blood culture diagnostics, as the goldstandard for the identification of the causative pathogen in sepsis)

  Proportion of positives that are correctly identified as such.

  2 years

• Specificity [%] (of the NGS-based SIQ-score in comparison to blood culture diagnostics, as the goldstandard for the identification of the causative pathogen in sepsis)

  Proportion of negatives that are correctly identified as such.

  2 years

• Positive predictive value [%] (of the NGS-based SIQ-score in comparison to blood culture diagnostics, as the goldstandard for the identification of the causative pathogen in sepsis)

  Proportion of positives that are true positive.

  2 years

• Negative predictive value [%] (of the NGS-based SIQ-score in comparison to blood culture diagnostics, as the goldstandard for the identification of the causative pathogen in sepsis)

  Proportion of negatives that are true negative.

  2 years

• Cohen's kappa coefficient [no measuring unit; 0</=k</=1] (of the NGS-based SIQ-score in comparison to blood culture diagnostics, as the goldstandard for the identification of the causative pathogen in sepsis)

  Measurement of the interobserver agreement between both items.

  2 years

Secondary Outcomes (2)

• Plausibility [%] (of the NGS-based SIQ-score)

  2,5 years

• Changes in therapy [%] (that may have occurred if the NGS-based SIQ-score had been available for clinical use)

  2,5 years

Study Arms (1)

Sepsis Group

Patients (n=500) with suspected or proven sepsis or septic shock (according to the Sepsis-3 definitions).

Diagnostic Test: Next-Generation Sequencing

Interventions

Next-Generation Sequencing DIAGNOSTIC_TEST

In 500 patients with suspected or proven sepsis or septic shock (according to the Sepsis-3 definitions), patients´ characteristics and routine blood parameters will be determined at sepsis onset as well as 72 hours afterwards. At the same time points, 2 sets of blood cultures and one blood tube for Next-Generation Sequencing (NGS)-diagnostics will be collected. An evaluation of outcome will be performed at 28 days after sepsis onset.

Sepsis Group

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients with sepsis or septic shock according to the new sepsis definitions (Sepsis-3) with an onset \<24h are eligible for study inclusion.

You may qualify if:

• Age ≥18yr
• Informed consent
• Sepsis (with an onset ≤24h): Patients with a life-threatening organ dysfunction caused by a dysregulated host response to a suspected or proven infection. Organ dysfunction can be identified as an acute change in total SOFA score ≥2 points consequent to the infection. Patients can also be promptly identified at the bedside with qSOFA, ie, alteration in mental status, systolic blood pressure ≤100mmHg, or respiratory rate ≥22/min.
• or Septic shock (with an onset ≤24h): Patients with septic shock can be identified with a clinical construct of sepsis with persisting hypotension requiring vasopressors to maintain mean arterial pressure (MAP) ≥65mmHg and having a serum lactate level \>2mmol/L (18mg/dL) despite adequate volume resuscitation.

You may not qualify if:

• Age ≤18yr
• Refusal to give consent
• Palliative treatment intent
• Clinician is not committed to aggressive treatment
• Death is deemed imminent and inevitable
• Patients who had previously been included, but are readmitted to the ICU during the same hospitalization, will not be included a second time.

Sponsors & Collaborators

• University Hospital Heidelberg: lead
• Fraunhofer Institute for Interfacial Engineering and Biotechnology: collaborator
• Dietmar Hopp Stiftung GmbH: collaborator

Study Sites (21)

RWTH Aachen University

Aachen, 52074, Germany

Location

Klinikum Mittelbaden Baden-Baden Balg

Baden-Baden, 76532, Germany

Location

Charité - Universitätsmedizin Berlin

Berlin, Germany

Location

Evangelisches Krankenhaus Bethel gGmbH

Bielefeld, 33617, Germany

Location

University Hospital Bonn

Bonn, Germany

Location

Klinikum Bremerhaven Reinkenheide gGmbH

Bremerhaven, 27574, Germany

Location

University Hospital Köln

Cologne, Germany

Location

Duesseldorf University Hospital

Düsseldorf, 40225, Germany

Location

University Hospital Essen

Essen, 45147, Germany

Location

University Hospital Frankfurt

Frankfurt, 60590, Germany

Location

University Medical Center Göttingen

Göttingen, 37077, Germany

Location

Medical School Hannover

Hanover, 30625, Germany

Location

University Hospital Heidelberg

Heidelberg, 69120, Germany

Location

Kliniken Landkreis Heidenheim gGmbH

Heidenheim, Germany

Location

University Hospital Leipzig

Leipzig, Germany

Location

Evangelisches Krankenhaus Luckau gGmbH

Luckau, 15926, Germany

Location

University Hospital rechts der Isar

Munich, 81675, Germany

Location

University Hospital of Regensburg

Regensburg, 93053, Germany

Location

University of Rostock

Rostock, 18057, Germany

Location

University Hospital Tübingen

Tübingen, 72076, Germany

Location

Ulm University Medical Center

Ulm, 89081, Germany

Location

Related Publications (3)

• Decker SO, Sigl A, Grumaz C, Stevens P, Vainshtein Y, Zimmermann S, Weigand MA, Hofer S, Sohn K, Brenner T. Immune-Response Patterns and Next Generation Sequencing Diagnostics for the Detection of Mycoses in Patients with Septic Shock-Results of a Combined Clinical and Experimental Investigation. Int J Mol Sci. 2017 Aug 18;18(8):1796. doi: 10.3390/ijms18081796.

  PMID: 28820494 BACKGROUND

• Grumaz S, Stevens P, Grumaz C, Decker SO, Weigand MA, Hofer S, Brenner T, von Haeseler A, Sohn K. Next-generation sequencing diagnostics of bacteremia in septic patients. Genome Med. 2016 Jul 1;8(1):73. doi: 10.1186/s13073-016-0326-8.

  PMID: 27368373 BACKGROUND

• Brenner T, Decker SO, Grumaz S, Stevens P, Bruckner T, Schmoch T, Pletz MW, Bracht H, Hofer S, Marx G, Weigand MA, Sohn K; TIFOnet Critical Care Trials Group. Next-generation sequencing diagnostics of bacteremia in sepsis (Next GeneSiS-Trial): Study protocol of a prospective, observational, noninterventional, multicenter, clinical trial. Medicine (Baltimore). 2018 Feb;97(6):e9868. doi: 10.1097/MD.0000000000009868.

  PMID: 29419698 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

Plasma samples with circulating cell-free DNA (cfDNA)

MeSH Terms

Conditions

Sepsis; Shock, Septic; Bacteremia

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock; Bacterial Infections; Bacterial Infections and Mycoses

Study Officials

• Thorsten Brenner, MD

  University Hospital, Essen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. med. Thorsten Brenner, MHBA

Study Record Dates

• First Submitted: November 19, 2017
• First Posted: November 29, 2017
• Study Start: March 1, 2019
• Primary Completion: August 31, 2021
• Study Completion: September 30, 2021
• Last Updated: May 18, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will not share

Locations

DE (21)