Top

Published in:

Open Access 01-12-2021 | Septicemia | Study protocol

Optimization of sepsis therapy based on patient-specific digital precision diagnostics using next generation sequencing (DigiSep-Trial)—study protocol for a randomized, controlled, interventional, open-label, multicenter trial

Authors: Thorsten Brenner, Annabell Skarabis, Philip Stevens, Jennifer Axnick, Peter Haug, Silke Grumaz, Thomas Bruckner, Steffen Luntz, Oliver Witzke, Mathias W. Pletz, Thomas M. Ruprecht, Ursula Marschall, Sibel Altin, Wolfgang Greiner, Marc Moritz Berger, for the TIFOnet Critical Care Trials Group

Published in: Trials | Issue 1/2021

Abstract

Background

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 represent a promising alternative. In particular, the plasmatic detection of circulating, cell-free DNA by next-generation sequencing (NGS) has shown to be suitable for identifying disease-causing pathogens in patients with bloodstream infections.

Methods

The DigiSep-Trial is a randomized, controlled, interventional, open-label, multicenter trial characterizing the effect of the combination of NGS-based digital precision diagnostics with standard-of-care microbiological analyses compared to solely standard-of-care microbiological analyses in the clinical picture of sepsis/septic shock. Additional anti-infective expert consultations are provided for both study groups. In 410 patients (n = 205 per arm) with sepsis/septic shock, the study examines 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) intensive/intermediate care unit length of stay, (2) consumption of antibiotics, (3) mortality, and (4) acute kidney injury (AKI)) can be improved by an additional NGS-based diagnostic concept. We also aim to investigate the cost-effectiveness of this new diagnostic procedure. It is postulated that intensive/intermediate care unit length of stay, mortality rate, incidence of AKI, the duration of antimicrobial therapy as well as the costs caused by complications and outpatient aftercare can be reduced. Moreover, a significant improvement in patient’s quality of life is expected.

Discussion

The authors´ previous work suggests that NGS-based diagnostics have a higher specificity and sensitivity compared to standard-of-care microbiological analyses for detecting bloodstream infections. In combination with the here presented DigiSep-Trial, this work provides the optimal basis to establish a new NGS-driven concept as part of the national standard based on the best possible evidence.

Trial registrations

DRKS-ID DRKS00022782. Registered on August 25, 2020

ClinicalTrials.govNCT04571801. Registered October 1, 2020

Available only for authorised users

Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet. 2020;395(10219):200–11. https://doi.org/10.1016/S0140-6736(19)32989-7.CrossRefPubMedPubMedCentral

Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 2016;315(8):801–10. https://doi.org/10.1001/jama.2016.0287.CrossRefPubMedPubMedCentral

Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017;45(3):486–552. https://doi.org/10.1097/CCM.0000000000002255.CrossRefPubMed

Brunkhorst FM, Weigand MA, Pletz M, Gastmeier P, Lemmen SW, Meier-Hellmann A, et al. Bucher M et al: [S3 Guideline Sepsis-prevention, diagnosis, therapy, and aftercare : Long version]. Med Klin Intensivmed Notfmed. 2020;115(Suppl 2):37–109. https://doi.org/10.1007/s00063-020-00685-0.CrossRefPubMed

Mayr FB, Yende S, Angus DC. Epidemiology of severe sepsis. Virulence. 2014;5(1):4–11. https://doi.org/10.4161/viru.27372.CrossRefPubMed

Walkey AJ, Wiener RS, Lindenauer PK. Utilization patterns and outcomes associated with central venous catheter in septic shock: a population-based study. Crit Care Med. 2013;41(6):1450–7. https://doi.org/10.1097/CCM.0b013e31827caa89.CrossRefPubMedPubMedCentral

Vincent JL, Brealey D, Libert N, Abidi NE, O'Dwyer M, Zacharowski K, et al. Rapid diagnosis of infection in the critically ill, a multicenter study of molecular detection in bloodstream infections, pneumonia, and sterile site infections. Crit Care Med. 2015;43(11):2283–91. https://doi.org/10.1097/CCM.0000000000001249.CrossRefPubMedPubMedCentral

Tiru B, DiNino EK, Orenstein A, Mailloux PT, Pesaturo A, Gupta A, et al. The economic and humanistic burden of severe sepsis. Pharmacoeconomics. 2015;33(9):925–37. https://doi.org/10.1007/s40273-015-0282-y.CrossRefPubMed

Decker SO, Sigl A, Grumaz C, Stevens P, Vainshtein Y, Zimmermann S, et al. 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;18(8). https://doi.org/10.3390/ijms18081796.

10.

Grumaz S, Grumaz C, Vainshtein Y, Stevens P, Glanz K, Decker SO, et al. Enhanced performance of next-generation sequencing diagnostics compared with standard of care microbiological diagnostics in patients suffering from septic shock. Crit Care Med. 2019;47(5):e394–402. https://doi.org/10.1097/CCM.0000000000003658.CrossRefPubMedPubMedCentral

11.

Grumaz S, Stevens P, Grumaz C, Decker SO, Weigand MA, Hofer S, et al. Next-generation sequencing diagnostics of bacteremia in septic patients. Genome Med. 2016;8(1):73. https://doi.org/10.1186/s13073-016-0326-8.CrossRefPubMedPubMedCentral

12.

De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008;46(12):1813–21. https://doi.org/10.1086/588660.CrossRefPubMed

13.

Kazis LE, Miller DR, Skinner KM. Lee A, Ren XS, Clark JA, Rogers WH, Spiro A, 3rd, Selim A, Linzer M et al: Patient-reported measures of health: The Veterans Health Study. J Ambul Care Manage. 2004;27(1):70–83. https://doi.org/10.1097/00004479-200401000-00012.CrossRefPubMed

14.

Evans SR, Rubin D, Follmann D, Pennello G, Huskins WC, Powers JH, et al. Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR). Clin Infect Dis. 2015;61(5):800–6. https://doi.org/10.1093/cid/civ495.CrossRefPubMedPubMedCentral

15.

Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358(2):125–39. https://doi.org/10.1056/NEJMoa070716.CrossRefPubMed

16.

Brunkhorst FM, Oppert M, Marx G, Bloos F, Ludewig K, Putensen C, et al. Effect of empirical treatment with moxifloxacin and meropenem vs meropenem on sepsis-related organ dysfunction in patients with severe sepsis: a randomized trial. JAMA. 2012;307(22):2390–9. https://doi.org/10.1001/jama.2012.5833.CrossRefPubMed

17.

Keh D, Trips E, Marx G, Wirtz SP, Abduljawwad E, Bercker S, et al. Effect of hydrocortisone on development of shock among patients with severe sepsis: the HYPRESS randomized clinical trial. JAMA. 2016;316(17):1775–85. https://doi.org/10.1001/jama.2016.14799.CrossRefPubMed

18.

Bloos F, Trips E, Nierhaus A, Briegel J, Heyland DK, Jaschinski U, et al. Effect of sodium selenite administration and procalcitonin-guided therapy on mortality in patients with severe sepsis or septic shock: a randomized clinical trial. JAMA Intern Med. 2016;176(9):1266–76. https://doi.org/10.1001/jamainternmed.2016.2514.CrossRefPubMed

19.

Federal Ministry of Health and Social Security in agreement with the Federal Ministry of Economics and Labour. Ordinance on the implementation of Good Clinical Practice in the conduct of clinical trials on medicinal products for use in humans (GCP Ordinance - GCP-V)*. Federal Law Gazette. 2004;1(14):2081.

20.

van Buuren S. Multiple imputation of discrete and continuous data by fully conditional specification. Stat Methods Med Res. 2007;16(3):219–42. https://doi.org/10.1177/0962280206074463.CrossRefPubMed

21.

ICH Expert Working Group. ICH harmonised tripartite guideline, Guideline for Good Clinical Practice E6(R1). 1996. p. 1-59.

22.

World Medical A. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. Jama. 2013;310(20):2191–4. https://doi.org/10.1001/jama.2013.281053.CrossRef

23.

Federal Data Protection Act (Bundesdatenschutzgesetz, BDSG) 1990.

24.

Engel C, Brunkhorst FM, Bone HG, Brunkhorst R, Gerlach H, Grond S, et al. Epidemiology of sepsis in Germany: results from a national prospective multicenter study. Intensive Care Med. 2007;33(4):606–18. https://doi.org/10.1007/s00134-006-0517-7.CrossRefPubMed

25.

Schmitz RP, Keller PM, Baier M, Hagel S, Pletz MW, Brunkhorst FM. Quality of blood culture testing - a survey in intensive care units and microbiological laboratories across four European countries. Crit Care. 2013;17(5):R248. https://doi.org/10.1186/cc13074.CrossRefPubMedPubMedCentral

26.

Kirn TJ, Weinstein MP. Update on blood cultures: how to obtain, process, report, and interpret. Clin Microbiol Infect. 2013;19(6):513–20. https://doi.org/10.1111/1469-0691.12180.CrossRefPubMed

27.

Bacconi A, Richmond GS, Baroldi MA, Laffler TG, Blyn LB, Carolan HE, et al. Improved sensitivity for molecular detection of bacterial and Candida infections in blood. J Clin Microbiol. 2014;52(9):3164–74. https://doi.org/10.1128/JCM.00801-14.CrossRefPubMedPubMedCentral

28.

Ecker DJ, Sampath R, Li H, Massire C, Matthews HE, Toleno D, et al. New technology for rapid molecular diagnosis of bloodstream infections. Expert Rev Mol Diagn. 2010;10(4):399–415. https://doi.org/10.1586/erm.10.24.CrossRefPubMed

29.

Eshoo MW, Crowder CD, Li H, Matthews HE, Meng S, Sefers SE, et al. Detection and identification of Ehrlichia species in blood by use of PCR and electrospray ionization mass spectrometry. J Clin Microbiol. 2010;48(2):472–8. https://doi.org/10.1128/JCM.01669-09.CrossRefPubMed

30.

Kaleta EJ, Clark AE, Cherkaoui A, Wysocki VH, Ingram EL, Schrenzel J, et al. Comparative analysis of PCR-electrospray ionization/mass spectrometry (MS) and MALDI-TOF/MS for the identification of bacteria and yeast from positive blood culture bottles. Clin Chem. 2011;57(7):1057–67. https://doi.org/10.1373/clinchem.2011.161968.CrossRefPubMedPubMedCentral

31.

Kaleta EJ, Clark AE, Johnson DR, Gamage DC, Wysocki VH, Cherkaoui A, et al. Use of PCR coupled with electrospray ionization mass spectrometry for rapid identification of bacterial and yeast bloodstream pathogens from blood culture bottles. J Clin Microbiol. 2011;49(1):345–53. https://doi.org/10.1128/JCM.00936-10.CrossRefPubMed

Title: Optimization of sepsis therapy based on patient-specific digital precision diagnostics using next generation sequencing (DigiSep-Trial)—study protocol for a randomized, controlled, interventional, open-label, multicenter trial
Authors: Thorsten Brenner
Annabell Skarabis
Philip Stevens
Jennifer Axnick
Peter Haug
Silke Grumaz
Thomas Bruckner
Steffen Luntz
Oliver Witzke
Mathias W. Pletz
Thomas M. Ruprecht
Ursula Marschall
Sibel Altin
Wolfgang Greiner
Marc Moritz Berger
for the TIFOnet Critical Care Trials Group
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Septicemia
Septicemia
Antibiotic
Published in: Trials / Issue 1/2021
Electronic ISSN: 1745-6215
DOI: https://doi.org/10.1186/s13063-021-05667-x

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Optimization of sepsis therapy based on patient-specific digital precision diagnostics using next generation sequencing (DigiSep-Trial)—study protocol for a randomized, controlled, interventional, open-label, multicenter trial

Abstract

Background

Methods

Discussion

Trial registrations

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Discussion

Trial registrations

Please log in to get access to this content

Other articles of this Issue 1/2021

Acupuncture for persistent atrial fibrillation after catheter ablation: study protocol for a pilot randomized controlled trial

A fixed nitrous oxide/oxygen mixture as an analgesic for patients with postherpetic neuralgia: study protocol for a randomized controlled trial

The UPTAKE study: implications for the future of COVID-19 vaccination trial recruitment in UK and beyond

Correction to: IMMPACT-recommended outcome measures and tools of assessment in burning mouth syndrome RCTs: an international Delphi survey protocol

Lithium and preventing chemotherapy-induced peripheral neuropathy in breast cancer patients: a placebo-controlled randomized clinical trial