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Outbreak Tracking and Monitoring Emerges as Key Application for NGS in 2012

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In the summer of 2011, the Escherichia coli outbreak in Germany served as a test bed for benchtop sequencing platforms as teams using Life Technologies' Ion Torrent PGM, the Illumina MiSeq, and Roche's 454 GS Junior rushed to be the first to sequence and assemble the strain's whole genome, analyze the data, and detail the evolutionary history of the pathogen, including how it acquired the elements that made it particularly toxic.

This past year, however, saw outbreak sequencing rapidly transition from a technology-demonstration exercise to a key application in which hospitals and public health officials can monitor and track outbreaks.

Sequencing has now been used by academic groups to retrospectively analyze past outbreaks as well as ongoing outbreaks — in some cases even impacting outbreak management — and health officials in both the UK and the US are looking at sequencing's potential in public health settings.

The UK's Health Protection Agency even implemented a protocol for the summer Olympic games that would have used Illumina's MiSeq had an outbreak occurred to guide management and hopefully aid in quickly stemming the outbreak (CSN 8/8/2012).

And pathogen sequencing company Pathogenica this year launched a targeted sequencing-based kit on the PGM that screens for 12 different pathogens common in hospital-acquired infections (CSN 9/26/2012).

Sequencing has advanced so quickly in the public health space because it has clear advantages over traditional pathogen-typing methods such as pulsed-field gel electrophoresis, multilocus sequence typing, and PCR.

Such methods often lack the resolution necessary to tell whether two cases of methicillin-resistant Staphylococcus aureus, for instance, represent a transmission event between patients or are independent events — critical information in deciding how to respond.

As Tara Palmore, the deputy hospital epidemiologist at the National Institutes of Health's Clinical Center, previously told Clinical Sequencing News, "whole-genome sequencing just blows [those] tool[s] out of the water."

Retrospective Analyses Set the Stage

Since the 2011 German E. coli outbreak, a number of groups have begun doing retrospective analyses of past outbreaks to validate next-gen sequencing for such applications and understand better how it could be used and what the hurdles will be for clinical implementation.

For example, a study published in the New England Journal of Medicine in June by the Wellcome Trust Sanger Institute used sequencing to retrospectively study an outbreak of methicillin-resistant Staphylococcus aureus in the neonatal intensive care unit of the Rosie Hospital of the Cambridge University Hospitals system (CSN 6/20/2012).

Julian Parkhill, head of the pathogen genomics team at the Sanger Institute and a senior author of the study, told CSN at the time that had the study been done in real time, it would have changed how the outbreak was managed.

The Wellcome Trust team went on to sequence 12 additional cases of MRSA isolated from infants in a nenonatal unit within a six-month time period and published this study in Lancet Infectious Diseases. The sequencing allowed them to identify 26 additional cases and also to confirm that it had been carried by a staff member, which allowed the outbreak to persist in the unit even after a deep clean.

Since then, Parkhill has been involved in several other outbreak sequencing studies, including most recently a study published in Nature Genetics that sequenced strains of Clostridium difficile from an outbreak in the early- to mid-2000s and two studies from tuberculosis outbreaks published in Lancet Infectious Diseases and the Journal of Clinical Microbiology.

Elsewhere in the UK, Derrick Crook, professor of microbiology at the John Radcliffe Hospital, recently started a pilot project to use sequencing on the MiSeq alongside the hospital's routine methodology, such as pulsed-field gel electrophoresis and multilocus sequence typing, for monitoring outbreaks.

Additionally, he is a member of the Modernizing Medical Microbiology Consortium, a research project funded by the UK Department of Health that includes the University of Oxford, the HPA, and the Wellcome Trust Sanger Institute, which this year received a four-year grant to conduct research toward implementing sequencing in the public health setting.

Building Pathogen Databases

The US Food and Drug Administration has also recognized the role that next-gen sequencing can play in public health epidemiology. It is evaluating a number of different sequencing platforms — including ones from Illumina, Life Technologies' Ion Torrent, Pacific Biosciences, and Roche's 454 — for their use in a public health setting, and the agency recently awarded a grant to Illumina to use its MiSeq to track foodborne pathogens and outbreaks (IS 10/9/2012).

A main component of that project will be to build databases of pathogen genome sequences. These sequences will also contribute to another project, known as the 100K Genome Project, a five-year project involving the University of California, Davis; Agilent; and the FDA, to sequence the genomes of 100,000 foodborne pathogens such as Salmonella, Listeria, and E. coli.

Such databases of pathogen genome sequences will be important in future outbreaks to help quickly identify pathogen strains and their evolutionary history, which is important for understanding how they acquire drug resistance or become more toxic.

In the UK, Sharon Peacock, a professor of clinical microbiology at the University of Cambridge, has been working with colleagues from the Sanger Institute and Imperial College under grants from the UK Clinical Research Collaboration and the Health Protection Agency to develop pathogen databases (CSN 9/5/2012).

Her team has already sequenced the whole genomes of around 3,000 MRSA isolates and plans to do the same with other human pathogens such as vancomycin-resistant Streptococci.

As she previously told CSN: "The dream [is] to really work out if we [can] detect transmission, ultimately in real time, so that we [can] bring to bear control measures."

Real-Time Monitoring

While NGS-based real-time monitoring has not yet become routine, there have been a few notable examples of how sequencing in real-time impacted the management of an outbreak.

In one of the first examples of how this could be done, researchers at the National Institutes of Health used sequencing on the Roche 454 GS FLX during an outbreak of Klebsiella pneumoniae at the NIH Clinical Center to change how the outbreak was managed (CSN 8/22/2012).

While both pulsed-field gel electrophoresis and PCR were used unsuccessfully to try to piece together the transmission route of the pathogen and determine whether it was in fact an outbreak scenario or independent infections, sequencing was able to determine that not only had the infection been transmitted from the first infected patient to other patients, but that the infection had spread from isolates at two different body sites on the patient.

This information made it clear to the hospital staff that additional measures of protection were needed. While they had already isolated the infected patients, they took the additional step of creating a separate ward for infected patients with equipment and staff that was dedicated solely to that ward.

"After seeing how powerful whole-genome sequencing is in the setting of an outbreak and elucidating hospital epidemiology, it's hard to imagine I'll be satisfied going back to our traditional tools," said hospital epidemiologist Palmore at the time.

Despite these rapid successes, there are still a few hurdles to overcome before sequencing will be routine in an outbreak situation. As with the use of next-gen in any clinical setting, data interpretation is still a challenge, as is developing a user-friendly interface that will work in a hospital or other clinical environment.

One of the main thrusts of the UK's Modernizing Medical Microbiology Consortium is to develop such tools that will enable the routine use of sequencing in a clinical outbreak setting as well as protocols for managing the data and implementing it in the HPA and National Health Service hospitals.

By next year, "sequencing will be in use in many centers around the world for typing microorganisms for public health," Oxford's Crook predicted in August.

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