In 2020, in the middle of the COVID-19 pandemic, Dr Adela Alcolea-Medina started her PhD project at King’s, co-supervised by Professor Stuart Neil and Professor Jonathan Edgeworth in the School of Immunology and Microbial Sciences and Dr Mark Wilks from Queen Mary University of London. The aim of the project was to develop a ‘metagenomics’ test – a method for detecting genetic material from a range of viruses, bacteria and other microbes from a single clinical sample – that could ultimately help to diagnose infections.
Adela worked on her PhD project part time, alongside her role as a clinical scientist in microbiology at Guy’s and St Thomas’ NHS Foundation Trust in the Synnovis Microbiology laboratory. Having worked in clinical microbiology laboratories for over 10 years, Adela had seen first-hand the limitations of existing methods used to diagnose infections in people admitted to hospital.
“One major limitation is the turnaround time (TAT), which can range from 48 hours to 7 days once the patient sample reaches the lab, depending on the pathogen. Another is the targeted nature of current approaches, such as PCR, which, while sensitive, are limited to detecting only pre-specified pathogens.
“When results are inconclusive, samples are often referred to third-party labs for further testing, which delays diagnosis,” says Adela, who currently works as a Consultant Clinical Scientist for Synnovis at St Thomas’ Hospital, where she leads Next Generation Sequencing initiatives in the Infection Sciences division.
Traditional diagnostics, as well as existing metagenomics tests, also often require more than one sample from a patient, and multiple separate assays to test for the presence of bacteria, fungi and viruses.
“When I learned about metagenomics and the potential of emerging sequencing technologies, I saw an opportunity to revolutionise clinical microbiology by significantly reducing TAT and enabling broad, untargeted pathogen detection from a single sample – ultimately helping to match patients with the treatments they need,” says Adela.
The approach
For metagenomics to be most effective at detecting pathogens, the patient’s own DNA needs to be removed from the sample.
To overcome this, Adela, working with colleagues at King’s College London and Guy’s and St Thomas’ NHS Foundation Trust, found a way to remove the human DNA, whilst preserving genetic material from any bacteria, viruses or fungi present. The method involves physically breaking up the human cells in the sample with tiny beads, and then using an enzyme to break down the human DNA released from the cells.
Sequencing methods are then used to read the codes of the remaining genetic material in the sample, before the sequences are matched to a database of genetic codes of known pathogens.
After developing the workflow, the team validated the method on samples from patients with respiratory infections. Not only was processing samples in this way effective at detecting a broad range of viruses, bacteria and fungi in just one test, but it was significantly faster than existing methods, generating reports on the results within seven hours of receiving the sample.
Adela and the team published the method and findings in Communications Medicine.
Seeing the real-world impact
In 2023, the workflow was put to the test in the clinic. The team launched a pilot trial at Guy’s and St Thomas’ NHS Foundation Trust, using metagenomics testing in real-time to diagnose and treat respiratory infections in patients in intensive care.
The findings of the trial, published this week in The Lancet Microbe, show that the metagenomics test detected the pathogen causing the infection in 30% of patients where standard testing did not, led to a change in antibiotic treatment in 30% of patients, and resulted in 15% of patients being prescribed additional medication to modify the immune response and help their recovery. More than 90% of the tests were returned on the same day, which is significantly faster than standard testing with culture.
The study is the first to show how metagenomics testing for respiratory infections can improve the diagnosis and treatment of patients in intensive care.
“Our findings demonstrate that introducing rapid metagenomic sequencing in the ICU means patients can receive the targeted therapy within hours of admission rather than days,” says Dr Luke Blagdon Snell, Clinical Lecturer in the Department of Infectious Diseases at King’s, who led the pilot trial with Adela. “It can allow detection of organisms that don't grow easily in culture, or those that aren't targeted by standard PCR-based diagnostics.”
Not only can metagenomics testing help to match patients with the treatments they need sooner, but the speed of the diagnosis has also meant that the method has been recognised for its potential to monitor the threat of future pandemics. Last year, following the success of the pilot study and further optimisation of the method, the UK government announced that the test would across the UK to cut the time between new pathogens emerging and action being taken to treat those affected and prevent spread.
“The same metagenomics data is sent to UK public health agencies and can act as an early warning system for emerging drug resistance, epidemics or novel pathogens,” Luke explains.
The method is currently in use in six NHS sites for the diagnosis of respiratory infections and is being piloted across others.
“I feel proud to see the method I developed during my PhD now being implemented in clinical service and piloted across other NHS hospitals in the UK,” says Adela. “It’s very rewarding to see research translate into real-world impact that improves patient care.”