Plasma microbial cell-free DNA sequencing for the diagnosis and surveillance of fever following hematopoietic stem cell transplant

BackgrounFever 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. MethodsThis 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. ResultsAmong 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). ConclusionsPlasma microbial cell-free DNA sequencing shows promise in the surveillance, diagnosis and management of fever in hematopoietic stem cell transplant recipients. Article SummaryPlasma microbial cell-free DNA sequencing increased the diagnostic yield for the infectious etiologies of fever in allogeneic hematopoietic stem-cell recipients by 56% when compared to standard microbiologic testing. Weekly surveillance detected pathogens prior to fever onset.