1756. Prediction of Bloodstream Infection Prior to Onset of Symptoms by Plasma Metagenomic Sequencing in Pediatric Patients With Relapsed or Refractory Malignancy (PREDSEQ)

Abstract

BackgroundPatients undergoing treatment for relapsed or refractory malignancies are at high risk of life-threatening bloodstream infection (BSI). A predictive screening test for BSI might allow pre-emptive therapy, but no validated test is currently available. We tested the hypothesis that plasma metagenomic next generation pathogen sequencing (NGS) would predict BSI before the onset of attributable symptoms.MethodsWe enrolled 31 pediatric patients receiving for treatment relapsed or refractory malignancy in an IRB-approved prospective cohort study (PREDSEQ) of predictive sequencing. Episodes of febrile neutropenia or documented infection were collected prospectively from the medical record. BSI was defined according to NHSN criteria. Control Samples were defined as samples collected ≥7 clear days before or after any fever or documented infection. Residual clinical samples were stored for NGS; after filtering human sequences, reads were aligned to a curated pathogen database, and organisms above a predefined threshold were reported (Karius Inc., Redwood City, CA). Only bacteria and fungi were included in this analysis.ResultsA total of 11 BSI episodes occurred in 9 participants (Table 1) during the study period. Predictive sensitivity of NGS in the 2 days before onset of infection (n = 9) was 78% (95% CI 45–94%), and diagnostic sensitivity on the day of infection (n = 11) was 82% (95% CI 52–95%). Specificity of NGS for development of fever or infection within 7 days (n = 16) was 81% (95% CI 57–93%). NGS was positive up to 6 days prior to onset of BSI. In samples collected before or during documented infections, NGS also identified additional bacteria and fungi that were not detected by standard clinical testing.ExpectedNGS PredictionNGS DiagnosisAdditional OrganismsBSI√√No1 S. epidermidis √√No2 E. coli √√Yes3 E. faecium √√Yes4 E. faecium √√Yes5 R. mucilaginosa √√Yes6 S. epidermidis √√Yes7 E. coli/R. mucilaginosa √√Yes8 E. coli XXYes9 C. kruzei XXYes10 S. epidermidis N/A√No11 C. jeikeium N/A√YesControl1N/AN/AN/A V. parvula 2N/AN/AN/A F. magna 3N/AN/AN/A H. pylori and L. fermentum4–10N/AN/AN/ANoConclusionPlasma NGS shows promise for the detection of BSI prior to onset of symptoms in high-risk patients.Disclosures K. Goggin, Karius Inc.: Investigator, Research support. K. L. Chan, Karius Inc.: Employee, Salary. D. Hollemon, Karius Inc.: Employee, Salary. A. Ahmed, Karius, Inc.: Employee, Salary. D. Hong, Karius, Inc.: Employee, Salary. R. Hayden, Roche Molecular: Scientific Advisor, Consulting fee. Abbott Molecular: Scientific Advisor, Consulting fee. Quidel: Scientific Advisor, Consulting fee. C. Gawad, Karius Inc.: Investigator, Research support. J. Wolf, Karius Inc.: Investigator, Research support.

Pathogen Detection by Metagenomic Next-Generation Sequencing During Neutropenic Fever in Patients With Hematological Malignancies

“…The advantage of mNGS in comparison to BC is the ability to identify viral and fungal as well as polymicrobial infections particularly from the gastrointestinal tract during the neutropenic phase after chemotherapy [ 16 ]. In one publication, mNGS was able to reliably predict and diagnose the onset of bloodstream infection before onset of symptoms in cancer patients [ 27 ]. However, in another report of 167 asymptomatic patients undergoing measurement of microbial cfDNA sequencing, mNGS detected low-level (mostly apathogenic human commensals) organisms in 23%, whereas true infections displayed high-level concentrations pointing to putative difficulties in interpreting mNGS results in some test systems and underscores the importance of ID specialists [ 28 ].…”