The Real-World Clinical Impact of Plasma mNGS Testing: an Observational Study

Abstract

Plasma metagenomic next-generation sequencing (mNGS) testing is a promising diagnostic modality for infectious diseases, but its real-world clinical impact is poorly understood. We reviewed patients who had undergone plasma mNGS at a general hospital to evaluate the clinical utility of plasma mNGS testing. A total of 76.9% (113/147) of plasma mNGS tests had a positive result. A total of 196 microorganisms (58) were identified and reported, of which 75.6% (148/196) were clinically relevant. The median stringent mapped read number (SMRN) of clinically relevant organisms was 88 versus 22 for irrelevant organisms (<i>P</i> = 0.04). Based on the clinically adjudicated diagnosis, the positive and negative percent agreements of plasma mNGS testing for identifying a clinically defined infection were 95.2% and 67.4%, respectively. The plasma mNGS results led to a positive impact in 83 (57.1%) patients by diagnosing or ruling out infection and initiating targeted therapy. However, only 32.4% (11/34) of negative mNGS tests showed a positive impact, suggesting that plasma mNGS testing alone may not be a powerful tool to rule out infection in clinical practice. In the subset of 37 patients positive for both plasma mNGS and conventional testing, mNGS identified the pathogen(s) 2 days (IQR = 0.75 to 4.25) earlier than conventional testing. mNGS enables pathogen identification within 24 h, but given that the detection of clinically irrelevant organisms and nearly half of the tests result in no or a negative clinical impact, more clinical practice and studies are required to better understand who and when to test and how to optimally integrate mNGS into the infectious disease diagnostic workup. <b>IMPORTANCE</b> In this study, we show that although plasma mNGS testing significantly improved the detection rate of tested samples, nearly one in four (24.5%, 48/196) mNGS tests reported organisms were not clinically relevant, emphasizing the importance of cautious interpretation and infectious disease consultation. Moreover, based on clinical adjudication, plasma mNGS testing resulted in no or a negative impact in nearly half (43.5%, 64/147) of patients in the current study, indicating that how best to integrate this advanced method into current infectious disease diagnostic frameworks to maximize its clinical utility in real-world practice is an important question. Therefore, recommending plasma mNGS testing as a routine supplement to first-line diagnostic tests for infectious diseases faces great challenges. The decision to conduct mNGS testing should take into account the diagnostic performance, turnaround time and cost-effectiveness of mNGS, as well as the availability of conventional tests.