Metagenomic Next-generation Sequencing Compared With Blood Culture as First-line Diagnostic Method for Bloodstream Infection in Hematologic Patients With Febrile Neutropenia: A Multicenter, Prospective Study

Abstract

Bloodstream infection (BSI) is a frequent but lethal complication in hematologic patients with febrile neutropenia (FN). However, blood culture (BC) only detects an organism in 20%-30% of patients with FN. We aimed to evaluate the diagnostic performance of metagenomic next-generation sequencing (mNGS) as a first-line diagnostic method in BSI. This study was prospectively performed in 4 Chinese hematologic centers. In patients aged ≥15 years with hematologic diseases, peripheral blood specimens were collected per patient for simultaneous BC and mNGS at the onset of FN. The clinical physician and mNGS analysis team were double-blinded, and the adjudication of the clinical diagnosis was evaluated by another expert panel of 4 specialists. The primary endpoint of this study was the diagnostic performance of mNGS. This study was registered on ClinicalTrials.gov. Three hundred FN events were enrolled, including 62 definite BSI, 61 probable BSI, 116 infectious FN other than BSI, 55 noninfectious FN events, and 6 FN of indeterminate cause. Among 62 definite BSI cases, mNGS identified causative pathogens in 59 (95.2%). Concurrent BC initially detected pathogens in 59 cases, and 3 additional pathogens consistent with mNGS were later identified in repeated BC testing. The sensitivity, specificity, positive predictive value, and negative predictive value of mNGS were 95.2%, 94.6%, 95.2%, and 94.6%, respectively. The diagnostic time of mNGS was significantly shorter than that of BC (39.7 ± 15.0 vs 119.8 ± 31.9 hours, P < .0001). The findings suggest that the mNGS approach has excellent diagnostic performance for the first-line diagnosis of BSI in patients with FN. The study will promote early diagnosis and better management of the patients.

Keywords: blood culture; bloodstream infection; febrile neutropenia; hematologic diseases; mNGS.

Figure 1.

Workflow of the prospective study. BSI, bloodstream infection; FN, febrile neutropenia; mNGS, metagenomics next-generation sequencing.

Figure 2.

Distribution of microbes, comparison of the detection rates, and distribution of the infection sites involved in this study. A, The infection site distribution involved in this study. B, Distribution of microbes detected by mNGS in 62 definite BSI events, 61 probable BSI events, and 116 other infectious FN events. C, Distribution of microbes detected by mNGS and BC. D, Consistency comparison of mNGS and BC in 62 definite BSI events. E, Distribution of microbes and comparison of the detection rates between plasma and blood cell layer. F, The diagnostic time between mNGS and BC. BC, blood culture; BSI, bloodstream infection; CNSIs, central nervous system infections; FN, febrile neutropenia; LRTIs, lower respiratory tract infections; mNGS, metagenomic next-generation sequencing; URTIs, upper respiratory tract infections; UTIs, urinary tract infection.