Background: Fever is a common complication in hematopoietic stem-cell transplant recipients, yet an etiology is often not found. Plasma microbial cell-free DNA sequencing may improve diagnosis and management of fever in this population. Methods: This prospective study (ClinicalTrials.gov; NCT02804464) enrolled 70 patients undergoing allogeneic HCT and followed them for one year. Plasma microbial cell-free DNA sequencing was collected within 24 hours of fever and for infection surveillance weekly after HCT through day 63 post-HCT followed by monthly until study end. Plasma mcfDNA sequencing results were compared with all standard microbiological testing results collected within 48 hours of fever onset. Results: Among 53 fevers eligible for analysis, clinical adjudication determined that a probable cause of fever was detected by blood culture in in 7 (13%), by all microbiology in 9 (17%), and by plasma microbial cell-free DNA sequencing in 12 (23%), including 5 in which microbiology was negative, increasing the diagnostic yield by 56%. The positive percent agreement with microbiology was 78% (7/9) and the negative percent agreement was 89% (39/44). Adjudication determined that plasma microbial cell-free DNA sequencing results would have led to a change in antimicrobial management in 55% (7/12) of fevers with detections. Weekly surveillance with plasma microbial cell-free DNA sequencing detected 8 of 15 causative pathogens prior to fever by a mean of 4.8 days (range 1-8 days). Conclusions: Plasma microbial cell-free DNA sequencing shows promise in the surveillance, diagnosis and management of fever in hematopoietic stem cell transplant recipients.

Potential conflicts of interest: M.F.: the work associated with this study was funded by Karius, Inc. N.D.: Employed at Karius, Inc. during the conduct of this study. S.S.: Employed at Karius, Inc. during the conduct of this study. H.C.: the work associated with this study was funded by Karius, Inc. J.T.: the work associated with this study was funded by Karius, Inc. S.P.: the work associated with this study was funded by Karius, Inc. D.S.: the work associated with this study was funded by Karius, Inc. T.B.: Employed at Karius, Inc. during the conduct of this study. P.C.: the work associated with this study was funded by Karius, Inc.

This study was funded by Karius Inc

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