Effects of a clinical metagenomics intervention on clinical outcomes, healthcare costs, and health-related quality of life in patients with sepsis or septic shock: results of the randomized-controlled DigiSep trial

PURPOSE: Early pathogen detection is crucial in sepsis. We hypothesized that detection of microbial circulating cell-free DNA by metagenomic next-generation sequencing (mNGS) improves clinical outcomes and health-related quality of life without increasing healthcare costs. METHODS: This randomized, controlled, interventional, open-label, multicenter trial was conducted in 24 intensive care units across Germany. The intervention group (n = 200) received mNGS diagnostics in addition to standard-of-care microbiology, compared with standard-of-care microbiology alone (control group; n = 189). The primary endpoint was the Desirability of Outcome Ranking/Response Adjusted for Duration of Antibiotic Risk (DOOR/RADAR) score. RESULTS: The DOOR/RADAR score was not significantly improved at 28 days after sepsis onset (intervention group: 3.21 ± 1.54; control group: 3.49 ± 1.51; 95% CI - 0.58 to 0.03). However, other secondary endpoints were improved, including a reduced duration of mechanical ventilation (intervention group: 6.6 ± 9.4 days; control group: 9.3 ± 10.6 days; 95% CI - 5.03 to - 0.34) and faster shock resolution (intervention group: 6.9 ± 7.4 days; control group: 8.8 ± 8.5 days; 95% CI - 3.75 to - 0.04). Health-related quality of life at 90 days (EQ-5D-5L) was improved in the intervention group (0.312 ± 0.386) compared with the control group (0.208 ± 0.373; p = 0.047). In the subgroup with available claims data (33.2% of participating patients), healthcare costs over 180 days did not differ. CONCLUSION: The DOOR/RADAR score as primary endpoint was not significantly improved by mNGS. Exploratory secondary analyses revealed improvements in secondary endpoints. (Funding: German Innovation Fund; ClinicalTrials.gov number, NCT04571801, registration: 25.8.2020).