Reliable pathogen identification in patients with sepsis or septic shock applying a metagenomic diagnostic approach – Results of the multicentric Next GeneSiS-Trial

Sepsis remains a major health threat with early optimization of the antimicrobial treatment regimen as a prerequisite for treatment success. Despite limited sensitivity and specificity, blood cultures still represent the gold standard of diagnostic care. We aimed to overcome current diagnostic limitations by unbiased next-generation sequencing (NGS) of circulating microbial cell-free DNA (mcfDNA) in plasma samples of septic patients. We performed a prospective, observational, non-interventional, multicenter study to compare positivity rates for NGS-based identification of causative pathogens with standard of care blood cultures in patients suffering from sepsis or septic shock. The plausibility of NGS-based findings as well as the potential for antiinfective treatment adaptations based on NGS results were retrospectively evaluated by an independent expert panel. The positivity rate of NGS-based diagnostics (SIQ+) for plasma samples from 491 septic patients was 70.5% in contrast to blood cultures (BC+) with 19.4% combining the first three days after sepsis onset. SIQ+ results were evaluated plausible in 98.6% of cases by an independent expert panel. Based on the experts´ recommendations, additional knowledge of NGS-based pathogen findings would have resulted in antiinfective treatment adaptations in 32.6% of all patients. Inadequately treated SIQ+/BC- patients showed worse outcomes, including extended length of intensive care unit stay, mechanical ventilation and kidney replacement therapy. The integration of NGS-based pathogen diagnostics in sepsis or septic shock has the potential to improve patients´ clinical outcomes as compared to a treatment strategy based on standard of care microbiological diagnostics alone.