Highlight
- Adding metagenomic next-generation sequencing (mNGS) to standard microbiology did not significantly improve the primary DOOR/RADAR score at 28 days after sepsis onset.
- Secondary endpoints showed meaningful benefits with mNGS, including shorter mechanical ventilation duration and faster resolution of shock.
- Patients receiving mNGS-guided diagnostics experienced improved health-related quality of life at 90 days post-sepsis.
- Healthcare costs over 180 days did not increase with the addition of mNGS diagnostics.
Study Background
Sepsis and septic shock remain major causes of critical illness worldwide, characterized by dysregulated host response to infection leading to life-threatening organ dysfunction. Early and accurate identification of causative pathogens is pivotal to guiding targeted antimicrobial therapy, improving outcomes, and minimizing antibiotic overuse. Standard microbiological cultures, while central to diagnosis, often suffer from delayed results and limited sensitivity, particularly in culture-negative sepsis scenarios. Clinical metagenomics using next-generation sequencing (mNGS) enables pathogen detection through sequencing cell-free microbial DNA directly from blood samples, potentially revealing a broader range of pathogens more rapidly than conventional methods. However, evidence on whether mNGS translates into improved clinical outcomes and cost-effectiveness remains limited. The DigiSep trial addressed this gap by evaluating whether adjunctive mNGS diagnostics influence clinical outcomes, healthcare costs, and health-related quality of life in critically ill septic patients.
Study Design
The DigiSep trial was a randomized, controlled, open-label, interventional multicenter study conducted across 24 intensive care units in Germany. Participants included 389 adult patients diagnosed with sepsis or septic shock. Patients were randomized into two groups: 200 patients received mNGS diagnostics in addition to standard-of-care microbiological testing (intervention group), and 189 patients received standard-of-care microbiology alone (control group). The primary endpoint was the Desirability of Outcome Ranking/Response Adjusted for Duration of Antibiotic Risk (DOOR/RADAR) score assessed 28 days after sepsis onset. Secondary endpoints included duration of mechanical ventilation, time to shock resolution, health-related quality of life measured by EQ-5D-5L at 90 days, and healthcare costs over 180 days (in a subset of patients with available claims data).
Key Findings
Primary Endpoint
The study found no statistically significant improvement with mNGS in the primary DOOR/RADAR score at 28 days post-sepsis onset: the intervention group had a mean score of 3.21 ± 1.54 versus 3.49 ± 1.51 in the control group (95% CI for difference: −0.58 to 0.03). This indicates that, according to this composite endpoint that integrates clinical outcome and antibiotic exposure duration, mNGS-based diagnostics did not significantly alter overall short-term clinical outcomes.
Secondary Endpoints
Nevertheless, several important secondary outcomes favored the mNGS group. Duration of mechanical ventilation was significantly reduced, averaging 6.6 ± 9.4 days in the intervention group versus 9.3 ± 10.6 days in controls (95% CI for difference: −5.03 to −0.34). Similarly, shock resolution occurred faster in patients receiving mNGS diagnostics (6.9 ± 7.4 days) compared with controls (8.8 ± 8.5 days; 95% CI: −3.75 to −0.04). Both outcomes are clinically meaningful indicators of ICU recovery.
At 90 days, health-related quality of life measured by the EQ-5D-5L instrument was significantly higher in the intervention group (mean 0.312 ± 0.386) compared to the control group (0.208 ± 0.373; p = 0.047), suggesting a sustained benefit in patient-centered outcomes.
Healthcare Costs
In a prespecified subgroup with available healthcare claims data (approximately one-third of participants), total healthcare costs over 180 days did not differ significantly between groups, indicating that mNGS diagnostics did not increase healthcare expenditures despite additional testing.
Expert Commentary
The DigiSep trial represents one of the largest randomized investigations into the clinical utility of mNGS in sepsis management. The lack of statistically significant improvement in the composite primary endpoint highlights the complexity of demonstrating benefit in a heterogeneous patient population and the challenges of integrating novel diagnostics into established clinical pathways. The improvements in secondary endpoints such as mechanical ventilation duration and shock resolution indicate potential physiological benefits of more rapid or precise pathogen detection enabled by mNGS.
Faster identification of causative pathogens may facilitate earlier optimization of antimicrobial therapy, reduction of broad-spectrum antibiotic use, and consequently improved organ function and recovery. Enhanced health-related quality of life at three months further supports this interpretation, though definitive causal pathways remain to be elucidated.
Limitations of the study include its open-label design and incomplete cost data for all participants. Additionally, the timing and clinical integration of mNGS results into treatment decisions were not extensively detailed, which may impact efficacy. Further research is warranted to delineate optimized workflows, cost-effectiveness across healthcare settings, and patient subgroups most likely to benefit.
Conclusion
The DigiSep randomized controlled trial demonstrates that while adjunctive mNGS diagnostics for sepsis did not significantly improve the composite DOOR/RADAR score at 28 days, it was associated with shorter mechanical ventilation, faster shock resolution, and improved quality of life at 90 days without increasing healthcare costs. These exploratory findings support the potential clinical utility of mNGS in complex sepsis care and justify further investigation and refinement of metagenomic diagnostic integration in critical care settings.
Funding and Registration
The study was funded by the German Innovation Fund. Clinical trial registry: ClinicalTrials.gov identifier NCT04571801, registered on August 25, 2020.
References
1. Brenner T, Skarabis A, Schaller SJ, et al. 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. Intensive Care Med. 2026 Jun 30. PMID: 42377463.
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