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

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 PARTICIPANTSA 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 MEASURESThe 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 RELEVANCEA 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: NCT03226158JAMA Oncol.

Consolidation of Clinical Microbiology Laboratories and Introduction of Transformative Technologies

“…There are already significant efforts to move next-generation sequencing (NGS) to the heart of the microbiology laboratory as a universal tool for pathogen detection and identification (102), antimicrobial resistance prediction, and molecular epidemiology (103,104), where it has been scientifically demonstrated to be promising (105)(106)(107). However, further studies are needed to better identify the benefits of the integration of NGS into current testing algorithms (108)(109)(110).…”

A Comparison of Blood Pathogen Detection Among Droplet Digital PCR, Metagenomic Next-Generation Sequencing, and Blood Culture in Critically Ill Patients With Suspected Bloodstream Infections

“…Earlier studies have shown that mNGS can reliably detect pathogens from patients with febrile illness (Wylie et al, 2012), respiratory and gastric/ digestive infections (Joensen et al, 2017;Mizrahi et al, 2017), and acute encephalitis/encephalopathy (Kawada et al, 2016). In addition, mNGS can help identify causative microorganisms for patients with suspected BSIs with high sensitivity and specificity (Gyarmati et al, 2016;Brenner et al, 2018;Goggin et al, 2019). ddPCR, as an emerging versatile tool with high sensitivity and excellent accuracy and precision, has been increasingly used in multiple clinical scenarios including BSIs (Li et al, 2018;Abram et al, 2020;Wouters et al, 2020).…”

Plasma Metagenomic Next-Generation Sequencing Assay for Identifying Pathogens: a Retrospective Review of Test Utilization in a Large Children's Hospital

“…There are case reports of mNGS detecting rare pathogens (11)(12)(13) when conventional tests were negative. However, for the vast majority of cases, organisms identified by mNGS were common pathogens that were also detected by conventional testing methods (7,9).…”

“…Case series have shown that mNGS can identify the etiology of infection in patients with complicated community-acquired pneumonia or in immunocompromised patients with invasive fungal disease when traditional or other advanced diagnostic methods are negative (5,6). In a prospective cohort study of pediatric patients with relapsed or refractory cancer, mNGS predicted bloodstream infection 3 days prior to blood culture in 12 of 16 cases (7). mNGS tests bear the promise of being noninvasive, with the ability to detect both uncommon and common pathogens in many different clinical scenarios.…”