Optimization of Sepsis Therapy Based on Patient-specific Digital Precision Diagnostics
Optimization of Sepsis Therapy Based on Patient-specific Digital Precision Diagnostics
Sepsis is triggered by an infection and represents one of the greatest challenges of modern
 intensive care medicine. With regard to a targeted antimicrobial treatment strategy, the
 earliest possible pathogen detection is of crucial importance. Until now, culture-based
 detection methods represent the diagnostic gold standard, although they are characterized by
 numerous limitations. Culture-independent molecular diagnostic procedures may represent a
 promising alternative. In particular, the concept of plasmatic detection of circulating, free
 DNA employing next-generation sequencing (NGS) has shown to be suitable for the detection of
 disease-causing pathogens in patients with bloodstream infections.

 The DigiSep-Trial is a randomized, controlled, interventional, multicenter trial to
 characterize the effect of the combination of NGS-based digital precision diagnostics,
 standard-of-care microbiological analyses and optional expert exchanges compared to solely
 standard-of-care microbiological analyses in the clinical picture of sepsis / septic shock.
 The study examines in 410 patients (n = 205 per arm) with sepsis / septic shock whether the
 so-called DOOR-RADAR (Desirability of Outcome Ranking / Response Adjusted for Duration of
 Antibiotic Risk) score (representing a combined endpoint including the criteria (1) inpatient
 admission time, (2) consumption of antibiotics, (3) mortality and (4) acute renal failure
 (ARF)) can be significantly improved, by application of an additional NGS-based diagnostic
 concept. We also aim to investigate whether the new diagnostic procedure is cost-effective.
 It is postulated that the inpatient admission time, mortality rate, incidence of ARF, the
 duration of antimicrobial therapy as well as the costs of complications and outpatient
 aftercare can be reduced. Moreover, a significant improvement in the quality of life (QoL) of
 the affected patients can be expected.

 Extensive preparatory work suggests that NGS-based diagnostics have higher specificity and
 sensitivity compared to standard-of-care microbiological analyses for detecting bloodstream
 infections. This preliminary work for the DigiSep-Trial with the help of an interventional
 study design provides the optimal basis to establish this new concept as part of the national
 standard based on the best possible evidence.
Sepsis is a disease which is triggered by an infection and represents one of the greatest
 challenges of modern intensive care medicine. With regard to targeted anti-microbial therapy,
 the earliest possible pathogen detection is of crucial importance. Until now, culture-based
 detection methods represent the gold standard for diagnosis, although numerous limitations
 characterize these. In this context, culture-independent molecular biological processes are
 an alternative. In particular, the concept of serum detection of circulating, free DNA
 employing next-generation sequencing (NGS) seems to represent a promising diagnostic
 procedure in patients with bloodstream infections. The applicant's extensive preparatory work
 suggests that NGS-based diagnostics using the SIQ score have higher specificity and
 sensitivity compared to traditional culture-based methods for detecting bloodstream
 infections. This preliminary work for the DigiSep trial with the help of interventional study
 design provides the optimal basis to establish this new concept as part of the national
 standard based on the best possible evidence. The DigiSep trial is intended to characterize
 the effect of the combination of digital precision diagnostics, expert exchange and
 culture-based standard diagnostics compared to a purely culture-based conventional diagnosis
 in the clinical picture of sepsis / septic shock. The study examines in 410 patients (n = 205
 per arm) with sepsis / septic shock whether the so-called DOOR-RADAR score (Desirability of
 Outcome Ranking / Response Adjusted for Duration of Antibiotic Risk Score) can be
 significantly improved, by application of the NGS. We also aim to also study whether the new
 procedure is cost-effective. It is postulated that the inpatient admission time, mortality
 rate, incidence of acute renal failure (ARF), the duration of anti-microbial therapy as well
 as the costs of complications and outpatient aftercare can be reduced. Also, a significant
 improvement in the quality of life of the affected patients can be expected.

 As part of the study, the essential data is collected once at the time of sepsis (= onset).
 The culture-based diagnostics include the guideline-oriented collection of 2 blood culture
 sets (2 x aerobic / 2 x anaerobic) to the onset and three days later. At the same time, serum
 samples are obtained for NGS-based pathogen diagnostics. Additional sampling for NGS-based
 diagnostics can be made up to day 14 after onset or whenever the attending physician
 establishes a clinical indication for the collection of further blood cultures. The
 aforementioned cultures vs NGS-based pathogen diagnostics are also accompanied by extended
 immunological monitoring from blood plasma samples as well as an NGS-based transcriptome
 analysis. The associated sampling takes place at the time of onset, 3, 7 and 14 days after
 the beginning of sepsis. Routine microbiological findings from other biological samples (e.g.
 surgical swabs, drainage secretions, tracheal secretions, tissue samples) are included in the
 evaluation if these were collected three days before or after the extraction of serum samples
 for NGS-based diagnostics. The clinical data collection is also carried out at the time of
 sepsis (= onset), 3, 7 and 14 days later, analogous to the above-mentioned sample collection.
 The final outcome evaluation takes place 28 days (= 28 d) after the onset of sepsis. The
 study-related burden on the individual study patient includes a total of 17 ml of whole blood
 for NGS-based diagnostics, the four samples of 7.5 ml of whole blood for immunological
 monitoring and the four samples of 2.7 ml of whole blood for transcriptome analysis. The
 minimum total volume, therefore, amounts to the collection of approximately 75 ml of whole
 blood within the first 14 days after the onset of sepsis. The sampling takes place with the
 collection of the blood cultures or within the framework of the daily routine blood samples
 so that no further venous punctures are required here. Infection parameters such as
 procalcitonin (PCT) are carried out within the framework of daily regular blood collection
 and therefore, do not require any additional vascular punctures. The same principle applies
 to the collection of blood cultures which are routinely obtained as part of standard
 diagnostics in patients with suspected or proven sepsis. The required blood samples of two 40
 ml of whole blood (each two sets of 2 x aerobic / 2 x anaerobic = 4 x 10 ml = 40 ml)
 therefore do not represent any additional burden due to the study. A further additional
 burden for the patient concerning invasive procedures or examinations is not expected in the
 study.
Inclusion Criteria:

 -  All patients who develop sepsis or septic shock within < 24 h in accordance with the
 new sepsis definition (Sepsis-3) in the above-mentioned participating centers and
 consent to participation in the study will be included.

 General inclusion criteria:

 -  Written consent by the study participant or a legally appointed representative

 -  Age >18 years

 Sepsis:

 -  Life-threatening organ dysfunction due to a dysregulated immune response on the basis
 of a suspected or proven infection

 -  Detection of organ dysfunction indicated by SOFA score of ≥ 2 points Alternative:

 Change of the quick (q) SOFA score of 2 points as an indication of a sepsis

 Or septic shock:

 -  Persistent hypotension despite adequate volume substitution, which necessitates the
 use of vasopressors, to maintain an arterial medium pressure of > 65 mmHg

 -  Serum lactate > 2 mmol/l (18 mg/dl)

 Exclusion Criteria:

 -  Age < 18 years

 -  Refusal to participate in the study

 -  Probable discharge of the patient from the intensive care unit within the first 72 h
 of initial study inclusion

 -  Palliative therapy approach

 -  Death of the patient is already foreseeable or inevitable at trial inclusion

 -  Patients who have already been included in the study but require re-admission to the
 intensive care unit cannot be included a second