Beneficial effects of a clinical metagenomics intervention on clinical outcomes, healthcare economics, and health related quality of life in patients with sepsis/septic shock – Results of the randomized controlled DigiSep trial

Background: The aim of this randomized, controlled, interventional, multicenter trial was to assess the effect of a clinical metagenomics intervention using cell-free DNA from blood plasma and next-generation sequencing (NGS) in addition to standard-of-care (SOC) microbiology on clinical outcomes, health-related quality of life (HRQoL), and healthcare costs in patients with sepsis/septic shock. Materials: A total of 409 patients were enrolled from March 2022 to August 2023 across 24 German hospitals, of which 389 patients could be included in the final analysis. The interventional group (IG; n=200) included the clinical metagenomics approach (DISQVER® test, Noscendo GmbH, Germany) in addition to SOC microbiology, compared to SOC microbiology alone in the control group (CG; n=189). Samples were acquired at sepsis onset as well as 72 hours later. The primary endpoint was the Desirability of Outcome Ranking/Response Adjusted for Duration of Antibiotic Risk (DOOR/RADAR) score. Additionally, several clinical secondary endpoints, healthcare costs, and HRQoL were evaluated. Results: While there was no significant improvement in the DOOR/RADAR score at 28 days after sepsis onset, significant effects of the intervention were observed for other clinically relevant outcomes (e.g., reduction of duration of mechanical ventilation by 2.7 days and time to shock resolution by 1.9 days). Moreover, long-term survival at 180 days was improved in the IG group by 8%. Although total healthcare costs did not differ significantly between the two groups, the deterministic cost-effectiveness analysis indicates clear benefits in terms of long-term mortality. Furthermore, HRQoL was significantly improved at 90 days in the IG. Unfortunately, an NGS-based therapy adjustment by clinicians at bedside was documented in only 12% of IG patients, indicating that the full potential of the new diagnostic approach has not been realized. Accordingly, a retrospective expert evaluation revealed that the NGS-based approach provided four times more therapy-relevant results than blood culture, resulting in a recommendation for an NGS-based therapy change in 32% of patients. Conclusions: Although the primary endpoint was not reached, the DigiSep trial revealed significant benefits in terms of diagnostic depth and important secondary outcomes in the IG.