Routine Metagenomics Service for ICU Patients with Respiratory Infection

Abstract

Rationale Respiratory metagenomics (RMg) needs evaluation in a pilot service setting to determine utility and inform implementation into routine clinical practice. Objectives Feasibility, performance, and clinical impacts on antimicrobial prescribing and infection control were recorded during a pilot RMg service. Methods RMg was performed on 128 samples from 87 patients with suspected lower respiratory tract infection (LRTI) on two general and one specialist respiratory ICUs at Guy’s and St Thomas’ NHS Foundation Trust, London. Measurements and Main Results During the first 15 weeks, RMg provided same-day results for 110 samples (86%), with a median turnaround time of 6.7 hours (interquartile range = 6.1–7.5 h). RMg was 93% sensitive and 81% specific for clinically relevant pathogens compared with routine testing. Forty-eight percent of RMg results informed antimicrobial prescribing changes (22% escalation; 26% deescalation) with escalation based on speciation in 20 out of 24 cases and detection of acquired-resistance genes in 4 out of 24 cases. Fastidious or unexpected organisms were reported in 21 samples, including anaerobes ( n = 12), Mycobacterium tuberculosis , Tropheryma whipplei , cytomegalovirus, and Legionella pneumophila ST1326, which was subsequently isolated from the bedside water outlet. Application to consecutive severe community-acquired LRTI cases identified Staphylococcus aureus (two with SCCmec and three with luk F/S virulence determinants), Streptococcus pyogenes ( emm1- M1uk clone), S. dysgalactiae subspecies equisimilis (STG62647A), and Aspergillus fumigatus with multiple treatments and public health impacts. Conclusions This pilot study illustrates the potential of RMg testing to provide benefits for antimicrobial treatment, infection control, and public health when provided in a real-world critical care setting. Multicenter studies are now required to inform future translation into routine service.

Longitudinal multicompartment characterization of host-microbiota interactions in patients with acute respiratory failure

“…The presence of C.albicans in the LRT may not signify clinical pneumonia by conventional criteria 44 , yet may represent a state of dysbiosis with potential adverse effects from C.albicans on host epithelial integrity and immune response. Taxonomic concordance between amplicon sequencing approaches (Illumina 16S-Seq and ITS-Seq) with rapid metagenomic sequencing with the MiNION device (Oxford Nanopore Technologies, UK) suggests that such microbial profiles could be generated in clinically relevant turnaround times 45 .…”

Evaluating metagenomics and targeted approaches for diagnosis and surveillance of viruses

“…Untargeted Illumina sequencing is also in routine use in a handful of labs for the management of patients with fever of unknown origin, encephalitis, meningitis, and sepsis (10,11,69). Most recently, routine diagnostic ONT metagenomic sequencing of respiratory samples has been proposed for improved management of critically ill patients with pneumonia (12,13). In each case the metagenomic set-ups are multi-step workflows where each stage, from sample collection to computational data analysis, significantly affects the outcome of the test (26,28,70) (Figure 1A).…”

“…Since 2008, short read metagenomics has been trialed by many groups to identify causes of fever and central nervous system diseases, including encephalitis, particularly in undiagnosed immunocompromised patients or outbreaks of unknown aetiology (2)(3)(4)(5)(6)(7)(8)(9)(10)(11). With the recent advent of rapid methods, such as sequencing with Oxford Nanopore Technologies (ONT), metagenomic approaches have been proposed as suitable for rapid detection of unexpected pathogens and antimicrobial resistance in respiratory samples from patients with complex pneumonias receiving intensive care treatment (12)(13)(14)(15)(16)(17)(18). As an augmentation to metagenomics, oligonucleotide panels that enrich for large numbers of pathogens, while potentially reducing the possibilities for detection of an unknown pathogen, have been reported to improve the sensitivity and speed with which known pathogen genomes are detected, making them potentially valuable for infection diagnosis and screening (19)(20)(21)(22)(23)(24).…”

Pulmonary microbiome and transcriptome signatures reveal distinct pathobiologic states associated with mortality in two cohorts of pediatric stem cell transplant patients

“…40,72 Although other factors such as the conditioning regimen may influence microbiome composition, 73 these data argue for the need for judicious use of antibiotics, which might best be achieved with rapid turnaround of clinical metagenomics assays in the future. 74 Certainly for critically ill patients with unclear diagnoses, it will be difficult to feel confident in stopping antibiotics. Therefore, microbiome-restorative therapies in patients necessarily antibiotic-exposed may be a crucial tool.…”