Combining Metagenomic Sequencing With Whole Exome Sequencing to Optimize Clinical Strategies in Neonates With a Suspected Central Nervous System Infection

Abstract

ObjectivesCentral nervous system (CNS) infection has a high incidence and mortality in neonates, but conventional tests are time-consuming and have a low sensitivity. Some rare genetic diseases may have some similar clinical manifestations as CNS infection. Therefore, we aimed to evaluate the performance of metagenomic next-generation sequencing (mNGS) in diagnosing neonatal CNS infection and to explore the etiology of neonatal suspected CNS infection by combining mNGS with whole exome sequencing (WES).MethodsWe prospectively enrolled neonates with a suspected CNS infection who were admitted to the neonatal intensive care unit(NICU) from September 1, 2019, to May 31, 2020. Cerebrospinal fluid (CSF) samples collected from all patients were tested by using conventional methods and mNGS. For patients with a confirmed CNS infection and patients with an unclear clinical diagnosis, WES was performed on blood samples.ResultsEighty-eight neonatal patients were enrolled, and 101 CSF samples were collected. Fourty-three blood samples were collected for WES. mNGS showed a sample diagnostic yield of 19.8% (20/101) compared to 4.95% (5/101) for the conventional methods. In the empirical treatment group, the detection rate of mNGS was significantly higher than that of conventional methods [27% vs. 6.3%, p=0.002]. Among the 88 patients, 15 patients were etiologically diagnosed by mNGS alone, five patients were etiologically identified by WES alone, and one patient was diagnosed by both mNGS and WES. Twelve of 13 diagnoses based solely on mNGS had a likely clinical effect. Six patients diagnosed by WES also experienced clinical effect.ConclusionsFor patients with a suspected CNS infections, mNGS combined with WES might significantly improve the diagnostic rate of the etiology and effectively guide clinical strategies.

Diagnostic performance of metagenomic next-generation sequencing for the detection of pathogens in bronchoalveolar lavage fluid in patients with pulmonary infections: Systematic review and meta-analysis

“…Metagenomic next-generation sequencing (mNGS) is an unbiased method that can theoretically detect all pathogens in clinical samples, and is especially suitable for the detection of complex, rare, novel, and atypical infectious diseases (Ge et al, 2021, Jin Wenting et al, 2020. Especially for some RNA viruses, mNGS may be the only feasible method of detection (Babiker et al, 2020, van Boheemen et al, 2020.…”

Metagenomics next-generation sequencing for the diagnosis of central nervous system infection: A systematic review and meta-analysis

“…Of which, four studies were retrospective ( 15 , 16 , 18 , 20 ) and eight were prospective ( 9 , 17 , 19 , 21 – 25 ). Studies were conducted in the following countries: China ( 9 , 17 , 22 , 23 ), the United States ( 16 , 18 – 21 , 24 ), Canada ( 15 ), and the unknown ( 25 ). A total of 1,249 participants were analyzed in the 12 studies.…”

“…The 12 included studies were published between 2017 and 2021. Of which, four studies were retrospective (15,16,18,20) and eight were prospective (9,17,19,(21)(22)(23)(24)(25). Studies were conducted in the following countries: China (9,17,22,23), the United States (16, 18-21, 24), Canada (15), and the unknown (25).…”

“…The cerebrospinal fluid (CSF) was used for analysis in all included studies. Most studies were sequenced using Illumia (15)(16)(17)(18)(19)(20)(21)(22)24), but two studies were sequenced using the BGISEQ platform (9,23), and one study could not identify the sequencing platform used (25). The pathogens examined included viruses (10/12), bacteria (12/12), fungi (2/12), and parasites (1/12).…”

Progress in the application of metagenomic next-generation sequencing in pediatric infectious diseases

“…Thus, an efficient and accurate method to identify such pathogens in complex infections would be very important and helpful for clinical practice. Ge et al 21 studied 88 neonates with a suspected central nervous system infection and showed that mNGS had a higher positivity rate than conventional methods. Among the 101 CSF samples collected, 20 (19.8%) showed a positive result by mNGS, whereas the pathogen could only be detected in 5 (4.95%) samples by conventional methods.…”