Covid Scotland: Genomic sequencing and the future of infection control

The Victorian hospital is famed as the place where Joseph Lister pioneered antiseptic surgery in the 1860s, so it seems fitting that its scientists today should be on the vanguard of infection control technology of the future.

The GRI team has been sequencing “bugs” - viruses, bacteria and other microbes - since 2017, but investment has been fast-tracked as a result of the pandemic and the lab now has access to £250,000 machines which can unpick 100 samples in less than 24 hours compared to the 32 samples and 57 hours of older models.

READ MORE: Covid modellers set out five possible future scenarios for the virus in Scotland 

“We were going in this direction - we had bid for one of those machines before Covid - but Covid changed the landscape dramatically and accelerated things,” said Dr Alistair Leonard, a senior infection control doctor.

“The potential of sequencing to manage public health became clear. Any organism can be analysed.”

Just as genomic sequencing has enabled scientists to track the emergence and spread of distinct Covid variants, it is expected to become a routine tool to pinpoint mutations in everything from legionella to Clostridium difficile and guide treatment and outbreak responses.

Recently, Brown - an expert in Salmonella - used the technique to identify that two cases of the bacterial infection in Scotland were part of a UK-wide cluster affecting around 90 people.

The outbreak, which sickened some young children and infants, was ultimately traced to a Lithuanian supplier of dead mice: pet owners were falling ill after feeding the infected rodents to snakes and other reptiles.

Sequencing labs across Europe reported matching results and imports into the UK were banned.

As well as rapid and highly accurate monitoring, information new strains and potentially worrying mutations can now be shared and compared internationally in real-time.

“In the past samples would have to be packaged up and mailed around the world,” said Brown.

“Obviously that was much slower, but potentially dangerous too - these are harmful pathogens.”

Derek Brown with one of the GRI labs £250,000 genomic sequencing machines

To date, over 339,000 versions of Salmonella have been logged on the worldwide database.

One particular Salmonella strain, known as XDR, has mutations which make it highly drug resistant. It is becoming more common but does respond to a lesser used antibiotic, azithromycin.

Slowing or preventing the rise of antibiotic resistance is expected to be one of the most important uses of genomic sequencing for public health.

Failing to do so would send humanity back to the "dystopian pre-antibiotic days", notes Leonard, when a quarter of patients died from post-operative infections.

So far thousands of genes associated with antimicrobial resistance have been identified, with more added to the database all the time.

READ MORE: From Joseph Lister to X-rays - how Glasgow Royal Infirmary changed medicine

Leonard believes the next five to 10 years will see a growth in "personalised medicine" to combat infections, driven by increased reliance on genomic sequencing.

"We'll see a tailoring of drugs to particular strains - so an infected patient would be given the most appropriate antibiotic based on rapid sequencing of their bacterial isolates," he said.

Sequencing is also important to understanding outbreaks and transmission, both in the community and in hospitals.

Back in 2012, Dr Diane Lindsay - GRI's legionella expert - worked with colleagues at the Roslin Institute in Edinburgh to investigate a fatal outbreak of legionnaire's disease in the capital linked to cooling towers.

Sequencing revealed a "really surprising" diversity in the genetic make-up of the bacteria causing infections, including unexpected mutations associated with increased virulence.

Dr Diane Lindsay, an expert in legionella

More recently Lindsay has been monitoring an increase in Scottish cases of legionella longbeachae - so-called because it was first isolated from a patient in Long Beach, California.

"It's a bit of a mystery," said Lindsay.

"We're seeing gardeners becoming infected - isolated cases rather than outbreaks. Probably from handling compost."

To understand just how mammoth a task infection control can be it is worth noting that the average person has 10 times as many organisms living on and inside them as they do human cells.

Staphylococci are the most common of all infectious organisms. Around 30 per cent of the population carry Staphylococcus aureus in their nose, and another 30% will pick it up intermittently.

READ MORE: Is Italy's revolutionary mental health model finally coming to Scotland?

Around 5000 to 10,000 samples are isolated from patients every year in Scotland. Mostly it is harmless, but around 200 samples a year are sent to GRI for sequencing if there is suspected cross-transmission.

"It's a sliding scale from harmless to an infection that will kill someone within 72 hours, depending on the strain or the patient's condition," said Dr Andrew Robb, GRI's staphylococci specialist.

"Usually it's not particularly virulent but it's a good indicator for infection control because it is passed on through touch, and on surfaces."

Dr Andrew Robb

One of the advantages of DNA mutations - or RNA mutations in the case of viruses - is that they tend to occur at a fairly predictable rate, depending on the organism, which helps infection scientists to gauge whether a bug is spreading in a particular environment - such as a hospital ward.

Dr Aleks Marek, a consultant microbiologist and senior infection control doctor at GRI, said: "Covid is known not to mutate that quickly, so just because two people have got exactly the same strain and they happen to be in the same place, it doesn't necessarily mean they've given it to each other.

"In the case of Staph aureus, we've been doing whole genome sequencing for a very long time so we have an idea of how long it takes for mutations to develop.

"That gives us an idea that if an isolate is 'this close' to another there probably has been a transmission event, whereas 'this close' probably doesn't mean there's been a transmission.

"Whole genome sequencing can also tell us whether the bacteria causing infection has a resistance determinant, and whether that's arising individually in the community multiple times or whether there's some sort of spread going on.

"So if a particular resistant organism did look very similar in all the samples then we might start to think 'is there some spread?', or the opposite if you've got lots of bugs that look quite different genetically but happen share this one resistance gene.

"That helps to guide our response.

"We're really at the start of the journey with using whole genome sequencing, but more and more organisms are starting to come online. I think over the next while we'll start to use it much more."