8 - Metagenomic next-generation sequencing is a useful diagnostic tool in culture-negative sepsis

Sepsis is associated with high morbidity and mortality in critically ill children, and more effective identification of causative pathogens through novel diagnostic tests may improve outcomes. The current gold standard for identifying an infectious pathogen is through cell culture, which is limited by long growth times and low yield for some organisms. Metagenomic next-generation sequencing (mNGS) provides an unbiased diagnostic method for detecting pathogens by analyzing plasma microbial cell-free DNA (mcfDNA). mNGS has increased pathogen identification in many diseases, but its diagnostic role in pediatric culture-negative sepsis is unknown.

Objective:

Determine the utility of mNGS of plasma mcfDNA in the diagnostic evaluation of pediatric patients with culture-negative sepsis.

Design/Methods:

This is a prospective pilot study in a pediatric intensive care unit (PICU) at an urban, tertiary care children’s hospital, approved by the local IRB. Subjects are enrolled into Stage 1 if they are < 18 years old and the PICU team is concerned for sepsis, obtains a blood culture, and initiates antimicrobials. Extra blood is obtained at this time and stored. The subject is accrued into Stage 2 if, after 48 hours, all cultures show no pathogen growth and the clinical team continues antimicrobial treatment due to a concern for culture-negative sepsis. The stored blood is sent to Karius, a commercial laboratory specializing in mNGS. Results are provided to the treatment team.

Results:

Eleven subjects have been recruited into Stage 1, and three subjects have been accrued into Stage 2. All three subjects met sepsis criteria, had negative cultures, and continued antimicrobial treatment for >48 hours. The subjects received a 7-day treatment course of antimicrobials, with piperacillin-tazobactam as the most common agent. mNGS identified 1-2 potential causative organisms in all three subjects. In one case, the results led to a de-escalation of antimicrobial therapy.

Conclusion(s):

mNGS can identify potential causative pathogens and refine treatment in patients with culture-negative sepsis. An identified pathogen can lead to optimal antimicrobial stewardship with de-escalation of therapy and prevention of prolonged courses of broad-spectrum antimicrobials, which can lead to toxicity and promote resistance. Recruitment is ongoing, with future investigations focused on qualitative interviews with clinical teams.