Evaluation of Plasma Microbial Cell-Free DNA Sequencing to Predict Bloodstream Infection in Pediatric Patients With Relapsed or Refractory Cancer

Abstract

This pilot cohort study estimates sensitivity and specificity of plasma microbial cell-free DNA sequencing for its ability to predict bloodstream infection in patients at high risk of life-threatening infection.

Key Points

Question

Might plasma microbial cell-free DNA sequencing (mcfDNA-seq) predict bloodstream infection (BSI) in immunocompromised patients days before the onset of attributable symptoms?

Findings

This pilot cohort study included 47 pediatric patients with relapsed or refractory cancer. The causative pathogen was identified by mcfDNA-seq in the 3 days before onset of BSI in 12 of 16 episodes; of 33 negative control samples collected from the same patient population, mcfDNA-seq was negative in 27 and identified no common pathogens in 30.

Meaning

In patients with imminent BSI, it appears that mcfDNA-seq can identify clinically relevant pathogens days before onset of attributable symptoms.

Abstract

Importance

Bloodstream infection (BSI) is a common, life-threatening complication of treatment for cancer. Predicting BSI before onset of clinical symptoms would enable preemptive therapy, but there is no reliable screening test.

Objective

To estimate sensitivity and specificity of plasma microbial cell-free DNA sequencing (mcfDNA-seq) for predicting BSI in patients at high risk of life-threatening infection.

Design, Setting, and Participants

A prospective pilot cohort study of mcfDNA-seq for predicting BSI in pediatric patients (<25 years of age) with relapsed or refractory cancers at St Jude Children’s Research Hospital, a specialist quaternary pediatric hematology-oncology referral center. Remnant clinical blood samples were collected during chemotherapy and hematopoietic cell transplantation. Samples collected during the 7 days before and at onset of BSI episodes, along with negative control samples from study participants, underwent blinded testing using a mcfDNA-seq test in a Clinical Laboratory Improvement Amendments/College of American Pathologists–approved laboratory.

Main Outcomes and Measures

The primary outcomes were sensitivity of mcfDNA-seq for detecting a BSI pathogen during the 3 days before BSI onset and specificity of mcfDNA-seq in the absence of fever or infection in the preceding or subsequent 7 days.

Results

Between August 9, 2017, and June 4, 2018, 47 participants (27 [57%] male; median age [IQR], 10 [5-14] years) were enrolled; 19 BSI episodes occurred in 12 participants, and predictive samples were available for 16 episodes, including 15 bacterial BSI episodes. In the 3 days before the onset of infection, predictive sensitivity of mcfDNA-seq was 75% for all BSIs (12 of 16; 95% CI, 51%-90%) and 80% (12 of 15; 95% CI, 55%-93%) for bacterial BSIs. The specificity of mcfDNA-seq, evaluated on 33 negative control samples from enrolled participants, was 82% (27 of 33; 95% CI, 66%-91%) for any bacterial or fungal organism and 91% (30 of 33; 95% CI, 76%-97%) for any common BSI pathogen, and the concentration of pathogen DNA was lower in control than predictive samples.

Conclusions and Relevance

A clinically relevant pathogen can be identified by mcfDNA-seq days before the onset of BSI in a majority of episodes, potentially enabling preemptive treatment. Clinical application appears feasible pending further study.

Trial Registration

ClinicalTrials.gov identifier: NCT03226158