Cutting-edge genomic technology saves girl from rare brain infection

Metagenomics is a cutting-edge sequencing genomic technique that allows for the identification of bacteria and other types of infections, and viruses directly from patient samples. Metagenomics is untargeted, meaning it can look for all types of infections, rather than specific infections.

The recently accredited genomics service, which is the first of its kind in the UK, is already providing clinical teams around the country with vital information about rare infections - allowing for patients to access targeted treatments they desperately need. Patients who want further information should speak to their clinical teams in the first instance.

At the age of 1, Esther became unwell and was losing weight. She lost the movement in her arm, began struggling to hold her head up and was in a lot of pain.

Her local hospitals referred her to Great Ormond Street Hospital for consideration of a bone marrow transplant after genetic testing found she had severe combined immunodeficiency (SCID) caused by MHC class II deficiency. This is an exceptionally rare cause of SCID, a condition where the immune system doesn’t develop properly leaving patient very vulnerable to even mild viral infections.

Esther continued to lose her abilities and was no longer able to swallow. GOSH clinicians suspected an unusual infection and requested a brain biopsy and used the metagenomics testing service to discover she had Astrovirus, which was causing brain damage.

There had only been a handful of these cases around the world. There were no standard treatments available and so a multi-disciplinary team decided to trial Esther on a combination of anti-viral medicines, predicted to work against the Astrovirus. Given the success of Esther’s treatment, her team will now share their findings in the hope of helping other patients around the world.

Esther’s mum Charlotte said: “We were told it was very unlikely Esther would reach her second birthday and we should make the most of time we have left with her, so we moved to a children’s hospice.

“But she then began to stabilise, and we were able to go home, which we never expected.”

Esther is now 6 and her condition has not only stabilised but her family are slowly seeing some improvements.

Charlotte said: “She is severely disabled and will be affected for the rest of her life but it’s incredible she’s here and we do just take every day as it comes. She lives a great life, she goes to school full time, she’s a very sociable little girl and loves music.”

Speaking about the testing, Charlotte said: “It was our choice to do the testing, and we would do or try anything we could do to try and help Esther. Now we know that this testing and finding might help another child in a similar situation – it feels amazing.”

The GOSH metagenomics service was established to investigate the benefits of this type of sequencing in infections within ‘sterile sites’ where infectious agents are normally not present – such as the brain, the central nervous system, the liver or in the fluid behind the eye.

Professor Judith Breuer, Professor of Virology at UCL and Honorary Consultant Virologist at GOSH, said: “We have been developing our metagenomics service at GOSH and UCL for over 10 years now and we are incredibly proud to be the first UK accredited service. We are now able to offer this vital genomic testing to patients around the country, and it is amazing to see the impact it is already having.”

The team have worked collaboratively with clinicians at GOSH and across the country to develop a diagnostic standard of test ensuring it is available to patients. Currently, the service is used as a final test, when clinicians suspect an infection, but traditional diagnostic techniques have not been able to identify the pathogen. Even where no pathogen is identified, a negative test gives the clinical team confidence to stop antimicrobials or administer strong drugs to suppress inflammation.

Dr Julianne Brown, Principal Clinical Scientist of the GOSH metagenomics service, said: “Being part of the GOSH metagenomics service, since its origins, has meant I have had the privilege of watching it grow from research to an established, accredited clinical service that tests 6 samples a week for patients across the country. It is only thanks to the collaboration between dedicated scientists and clinical teams that a service like this is possible.”

In early 2019, whilst a medical student, Ellie began to have significant problems with her right eye. After initial tests she was diagnosed with uveitis, a condition that causes inflammation of the eye. Despite continued treatment, Ellie’s symptoms continued to worsen. At its worst she was having monthly infusions, daily tablets and was having to apply hourly steroid eye drops. Her condition was not behaving as expected but all tests looking for any infections had come back negative.

After learning about metagenomic sequencing, her clinical team at Moorfields worked with the GOSH team to have a sample from Ellie’s eye tested. The sequencing revealed Ellie had a very specific strain of Leptospirosis, a bacterial infection, in her eye which was the cause of all her inflammation.

Ellie was given a 3-week course of antibiotics and the infection completely cleared, she was able to begin weening herself off her steroid eye drops and in March was able to celebrate her wedding day – eye drop and infection free.

She said: “I will never be able to thank the teams that continued to fight to find answers for me enough. Metagenomics has truly been game-changing for me. I spent Boxing Day of 2023 in hospital, thinking about whether it was time to have my eye removed. Now I can’t even imagine being back in that place, I am able to get back to focusing on my life – being able to have that for my wedding day is a priceless gift.”

Carlos Pavesio, consultant ophthalmologist at Moorfields Eye Hospital, said: “We are delighted that this new service enabled us to identify Ellie’s infection and treat it. As a result of this, we were able to address the source of her recurrent inflammation. We are excited about the opportunities this opens up and have already initiated a clinical trial on the use of metagenomics for hard to diagnose eye infections.”

While the metagenomics service at GOSH now provides diagnostic testing that can be used as part of a clinical pathway, its establishment was only possible due to continued research investment and the close connection between Professor Breuer’s research team at UCL ICH and the clinical teams within GOSH. Early work setting up the service was supported by Great Ormond Street Hospital Charity, the Reuben Foundation and a Wellcome Trust fellowship to Dr Sofia Morfopoulou, and the research has benefited from continuous support from the National Institute for Health and Care Research GOSH and University College London Hospital Biomedical Research Centres.

The teams at GOSH and UCL GOS ICH are working in nationwide collaborations, which are at the forefront of using metagenomics in innovative ways, such as in critical care and immune responsiveness in central nervous system infections.

For example, GOSH is participating in the NHS England Severe Presentation of Infectious Disease Genomic Network of Excellence, co-lead by NHS Central and South Genomics, NHS North Thames Genomic Medicine Service and NHS South East Genomics and delivered by NHS trusts across the country.

Through the network, Professor Breuer and her team have developed a new metagenomics method that is even more sensitive and quicker than the current accredited service, potentially capable of detecting a pathogen in a sterile site within a single day. This exciting development is now being tested to determine whether the speed of results will enable metagenomics to move to being a first-line diagnostic test for patients like Ellie where the test needs to both rule in and rule out infection to enable more precise treatment.

In parallel, Professor Breuer and her team are also working closely with colleagues at Guy’s and St Thomas’ NHS Foundation Trust (GSTT), who are leading a national programme to introduce metagenomics sequencing to identify respiratory infections and support national surveillance of outbreaks and future pandemics. The test, initially developed and piloted at GSTT, can identify the cause of respiratory infections in under seven hours, allowing for earlier and more personalised treatment. With funding from the Office of Life Sciences, the test is now being deployed at up to 30 sites across the UK, including GOSH.

Professor Dame Sue Hill, Chief Scientific Officer for England and Senior Responsible Officer for Genomics in the NHS said: "The application of this cutting-edge genomic technology represents a significant leap forward in infectious disease diagnosis and treatment.

“By identifying previously undetectable pathogens, targeted treatments can now be given to patients in need.

“This is yet another example of the exceptional progress the NHS is making in the field of metagenomics, supported by the work we are delivering through our metagenomics network of excellence."