Next-Generation Sequencing Diagnostics of Bacteremia in Sepsis
Condition: Sepsis; Septic Shock
MeSH terms: Sepsis; Toxemia; Shock, Septic; Bacteremia
Study type: Observational

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.
    

Detailed description: 
      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. Accordingly, culture-independent molecular diagnostic procedures might be of
      help for the identification of the causative pathogen in infected patients. Especially the
      concept of an unbiased sequence analysis of circulating cell-free DNA (cfDNA) from plasma
      samples of septic patients by next-generation sequencing (NGS) has recently been identified
      to be a promising diagnostic platform for critically ill patients suffering from bloodstream
      infections. Although this new approach might be more sensitive and specific than
      culture-based state-of-the-art technologies, additional clinical trials are needed to exactly
      define the performance as well as clinical value of a NGS-based approach.

      Next GeneSiS is a prospective, observational, non-interventional, multicenter study to assess
      the diagnostic performance of a NGS-based approach for the detection of relevant infecting
      organisms in patients with suspected or proven sepsis (according to recent sepsis definitions
      [sepsis-3]) by the use of the quantitative sepsis indicating quantifier (SIQ) score in
      comparison to standard (culture-based) microbiological testings. Moreover, the clinical value
      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.
      Further subgroup analyses will focus on the clinical value especially for patients suffering
      from a failure of empiric treatment within the first three days after onset (as assessed by
      (1.) death of the patient or lack of improvement of the patient´s clinical condition (in
      terms of an inadequate decrease of SOFA-score) or (2.) persistent high procalcitonin levels).

      This prospective, observational, non-interventional, multicenter study trial for the first
      time investigates the performance as well as the clinical value of a NGS based approach for
      the detection of bacteremia in patients with sepsis and may therefore be a pivotal step
      toward the clinical use of NGS in this indication.

      Two sets of blood cultures (2x aerobic / 2x anaerobic) will be collected at study inclusion
      (=Onset) as well as 72 hours afterwards (=72h). In parallel, plasma samples for NGS-based
      measurements need to be obtained as described previously. Further blood samples for NGS-based
      measurements can be collected whenever physicians order blood cultures (2x aerobic / 2x
      anaerobic) because of the clinical suspicion of a bloodstream infection (BSI) within the
      first 3 days after study inclusion. Results of microbiological routine diagnostics in
      specimens different from blood (e.g. body fluid, tissue, bronchoalveolar lavage, endotracheal
      aspirate) will be used for further analyses when they are obtained within a timeframe of ≤72
      hours prior or after the timepoints for NGS-based measurements. Clinical data collection and
      (if possible) PCT measurements will be performed at Onset as well as at 72h after study
      inclusion. The final outcome evaluation of patients will be performed at 28 days.
    

Intervention name(s): Next-Generation Sequencing
Intervention type(s): Diagnostic Test
Intervention description(s): 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.
Observational model: Cohort
Time perspective: Prospective
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.
      
Biospecimen description: 
      Plasma samples with circulating cell-free DNA (cfDNA)
    
Keywords: Sepsis; Septic shock; Next-Generation Sequencing; Bacteremia