Enhanced performance of next-generation sequencing diagnostics compared to standard of care microbiological diagnostics in patients suffering from septic shock

Objective: Culture-based diagnostics represent the standard of care in septic patients, but are highly insensitive and in many cases unspecific. We recently demonstrated the general feasibility of next-generation sequencing (NGS)-based diagnostics using free circulating nucleic acids (cfDNA) in plasma samples of septic patients. Within the presented investigation, higher performance of NGS-based diagnostics was validated by comparison to matched blood cultures (BC). Design: A secondary analysis of a prospective, observational, single-center study Setting: Surgical intensive care unit of a university hospital and research laboratoryPatients: 50 patients with septic shock, 20 uninfected patients with elective surgery as control cohortInterventions: NoneMeasurements and Main Results: From 256 plasma samples of 48 septic patients at up to seven consecutive time points within the 28-day observation period, cfDNA was isolated and analyzed by NGS and relevance scoring. In parallel, results from culture-based diagnostics (e.g. BC) were obtained. Plausibility of BC and NGS results as well as adequacy of antibiotic therapy was evaluated by an independent expert panel. In contrast to BC with a positivity rate of 33% at sepsis onset, the positivity rate for NGS-based pathogen identification was 72%. Over the whole study period, BC positivity was 11% and NGS positivity was 71%. 96% of positive NGS results for acute sepsis time points were plausible and would have led to a change to a more adequate therapy in 53% of cases as assessed by the expert evaluation. Conclusions: Our results show that NGS-based analyses of bloodstream infections provide a valuable diagnostic platform for the identification of clinically relevant pathogens with higher sensitivity and specificity than BC, indicating that patients might benefit from a more appropriate therapy based on NGS-based diagnosis.