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Assessment of the Clinical Utility of Plasma Metagenomic Next-Generation Sequencing in a Pediatric Hospital Population.

ABSTRACT: Metagenomic next-generation sequencing (mNGS) of plasma cell-free DNA (cfDNA) is commercially available, but its role in the workup of infectious diseases is unclear. To understand the clinical utility of plasma mNGS, we retrospectively reviewed patients tested at a pediatric institution over 2 years to evaluate the clinical relevance of the organism(s) identified and the impact on antimicrobial management. We also investigated the effect of pretest antimicrobials and interpretation of molecules of microbial cfDNA per microliter (MPM) of plasma. Twenty-nine of 59 (49%) mNGS tests detected organism(s), and 28/51 (55%) organisms detected were clinically relevant. The median MPM of clinically relevant organisms was 1,533, versus 221 for irrelevant organisms (P = 0.01). mNGS test positive and negative percent agreements were 53% and 79%, respectively, and 50% of negative mNGS tests were true negatives. Fourteen percent of tests impacted clinical management by changing antimicrobial therapy. Immunocompromised status was the only patient characteristic that trended toward a significant clinical impact (P = 0.056). No patients with culture-negative endocarditis had organisms identified by mNGS. There were no significant differences in antimicrobial duration retest between tests with clinically relevant organism(s) and those that returned negative, nor were the MPMs different between pretreated and untreated organisms, suggesting that 10 days of antimicrobial therapy as observed in this cohort did not sterilize testing; however, no pretreated organisms identified resulted in a new diagnosis impacting clinical management. Plasma mNGS demonstrated higher utility for immunocompromised patients, but given the detection of many clinically irrelevant organisms (45%), cautious interpretation and infectious diseases consultation are prudent.

SUBMITTER: Lee RA

PROVIDER: S-EPMC7315020 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Assessment of the Clinical Utility of Plasma Metagenomic Next-Generation Sequencing in a Pediatric Hospital Population.

Lee Rose A RA Al Dhaheri Fatima F Pollock Nira R NR Sharma Tanvi S TS

Journal of clinical microbiology 20200624 7

Metagenomic next-generation sequencing (mNGS) of plasma cell-free DNA (cfDNA) is commercially available, but its role in the workup of infectious diseases is unclear. To understand the clinical utility of plasma mNGS, we retrospectively reviewed patients tested at a pediatric institution over 2 years to evaluate the clinical relevance of the organism(s) identified and the impact on antimicrobial management. We also investigated the effect of pretest antimicrobials and interpretation of molecules ...[more]

PMID: 32376666

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Project description:IntroductionMetagenomic next-generation sequencing (mNGS) assay for detecting infectious agents is now in the stage of being translated into clinical practice. With no approved approaches or guidelines available, laboratories adopt customized mNGS assays to detect clinical samples. However, the accuracy, reliability, and problems of these routinely implemented assays are not clear.ObjectivesTo evaluate the performance of 90 mNGS laboratories under routine testing conditions through analyzing identical samples.MethodsEleven microbial communities were generated using 15 quantitative microbial suspensions. They were used as reference materials to evaluate the false negatives and false positives of participating mNGS protocols, as well as the ability to distinguish genetically similar organisms and to identify true pathogens from other microbes based on fictitious case reports.ResultsHigh interlaboratory variability was found in the identification and the quantitative reads per million reads (RPM) values of each microbe in the samples, especially when testing microbes present at low concentrations (1 × 103 cell/ml or less). 42.2% (38/90) of the laboratories reported unexpected microbes (i.e. false positive problem). Only 56.7% (51/90) to 83.3% (75/90) of the laboratories showed a sufficient ability to obtain clear etiological diagnoses for three simulated cases combined with patient information. The analysis of the performance of mNGS in distinguishing genetically similar organisms in three samples revealed that only 56.6% to 63.0% of the laboratories recovered RPM ratios (RPM S. aureus /RPM S. epidermidis ) within the range of a 2-fold change of the initial input ratios (indicating a relatively low level of bias).ConclusionThe high interlaboratory variability found in both identifying microbes and distinguishing true pathogens emphasizes the urgent need for improving the accuracy and comparability of the results generated across different mNGS laboratories, especially in the detection of low-microbial-biomass samples.

Project description:Objectives The aim of this study was to evaluate the diagnostic value of bronchoalveolar lavage fluid (BALF) metagenomic next-generation sequencing (mNGS) versus conventional microbiological tests (CMTs) for pediatric pneumonia. Methods This retrospective observational study enrolled 103 children who were diagnosed with pneumonia and hospitalized at Hubei Maternity and Child Health Care Hospital between 15 October 2020 and 15 February 2022. The pneumonia diagnosis was based on clinical manifestations, lung imaging, and microbiological tests. Pathogens in the lower respiratory tract were detected using CMTs and BALF mNGS (of DNA and RNA). The diagnostic performance of BALF mNGS was compared with that of CMTs. Results In 96 patients, pathogens were identified by microbiological tests. The overall pathogen detection rate of mNGS was significantly higher than that of CMTs (91.3% vs. 59.2%, p = 0.000). The diagnostic performance of mNGS varied for different pathogens; however, its sensitivity and accuracy for diagnosing bacterial and viral infections were both higher than those of CMTs (p = 0.000). For the diagnosis of fungi, the sensitivity of mNGS (87.5%) was higher than that of CMTs (25%); however, its specificity and accuracy were lower than those of CMTs (p < 0.01). For the diagnosis of Mycoplasma pneumoniae, the specificity (98.8%) and accuracy (88.3%) of mNGS were high; however, its sensitivity (42.1%) was significantly lower than that of CMTs (100%) (p = 0.001). In 96 patients with definite pathogens, 52 cases (50.5%) were infected with a single pathogen, while 44 cases (42.7%) had polymicrobial infections. Virus–bacteria and virus–virus co-infections were the most common. Staphylococcus aureus, Haemophilus influenzae, rhinovirus, cytomegalovirus, parainfluenza virus, and fungi were more likely to be associated with polymicrobial infections. Conclusions BALF mNGS improved the detection rate of pediatric pneumonia, especially in mixed infections. The diagnostic performance of BALF mNGS varies according to pathogen type. mNGS can be used to supplement CMTs. A combination of mNGS and CMTs may be the best diagnostic strategy.

Dataset Information

Assessment of the Clinical Utility of Plasma Metagenomic Next-Generation Sequencing in a Pediatric Hospital Population.

Publications

Assessment of the Clinical Utility of Plasma Metagenomic Next-Generation Sequencing in a Pediatric Hospital Population.

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