mNGS sepsis V 1.0
Research type
Research Study
Full title
The impact of a single diagnostic test (Metagenomic sequencing, mNGS) on clinical management of sepsis and meningitis in children
IRAS ID
316759
Contact name
Kathryn Harris
Contact email
Sponsor organisation
Barts Health NHS Trust
Duration of Study in the UK
3 years, 0 months, 0 days
Research summary
Research Summary
Sepsis affects 25,000 children in the UK every year. A patient has septicaemia (blood-poisoning) when germs are in the blood-stream. Sepsis can also be caused by infection of other organs in the body, for example meningitis which is an infection of the fluid around the brain and spinal cord (cerebrospinal fluid).
Blood samples taken from patients can be tested in the laboratory to find out what germ is causing the infection, and this information is used to decide on the best treatment, normally antibiotics.
The most common way to find germs in the laboratory is to ‘grow’ them on agar plates, this can take several days, will not find viruses and does not work well if the patient has already been given antibiotics. Another way to identify germs is to look for their DNA using lots of separate tests. However, this type of test can’t tell which antibiotics will work and make it difficult to rule-out infection, therefore many patients receive unnecessary treatment with antibiotics. This produces side-effects for the patient and contributes to an increase in bacteria becoming resistant to antibiotics.
We will use a new test that can look at all DNA in a patient’s sample. Computer programs will be used to find any DNA in the sample that does not belong to the patient, as this is likely to be from the germ causing the infection. The genome of the germ contains information about which antibiotics will treat the infection. If no germ DNA is found then we may be able to use this test to rule-out infection, and stop unnecessary antibiotic treatment.
We will collect samples from children who might have an infection. Following ethical approval at participating centres, we will perform the new test on the study samples, and test them in the usual way.Summary of Results
Sepsis and serious infections of the blood or brain can be life-threatening in children. Doctors need to identify the germ causing the infection as quickly as possible so that they can choose the right treatment. However, current laboratory tests do not always find the cause. Blood and cerebrospinal fluid cultures can take several days and may be negative, especially if a child has already received antibiotics or if the infection is caused by a virus or a difficult-to-grow bacterium.
This study evaluated a new test called metagenomic next-generation sequencing, or mNGS, for diagnosing serious infections in children. Unlike standard tests, which usually look for specific germs, mNGS reads genetic material in a sample and can potentially detect bacteria, viruses, fungi and other organisms in a single test. The study used Oxford Nanopore sequencing on blood and cerebrospinal fluid samples from children under 16 years old who were being investigated for sepsis or another acute infection at The Royal London Hospital, Barts Health NHS Trust.
A total of 291 children were recruited, and 262 had at least one valid mNGS result. The mNGS test detected a potential pathogen in 98 children. However, not every organism detected by sequencing was judged to be the true cause of illness. To understand the clinical importance of the results, infection specialists reviewed the children’s medical notes and compared the mNGS findings with routine diagnostic tests.
After this review, mNGS was considered to have found a clinically significant pathogen in 37 children. In 13 of these cases, all routine diagnostic tests were negative, meaning mNGS provided additional information that would not have been available from standard testing alone. In other cases, mNGS supported routine test results, partly agreed with them, or detected a different organism that was thought to better explain the child’s illness. For example, mNGS sometimes detected important bacterial or viral infections when blood cultures or routine tests were negative or showed organisms likely to be contaminants.
The study also showed that negative mNGS results may be useful. In many children, no pathogen was found by mNGS, and this matched the routine test results and clinical assessment. In the future, a reliable negative result could help doctors consider stopping unnecessary antibiotics earlier in selected patients, although this would need further evaluation.
Overall, this study suggests that mNGS could be a useful additional test for children with suspected serious infection, particularly when routine tests are negative, inconclusive, or do not cover the likely cause. However, the results must be interpreted carefully by specialists, because sequencing can detect harmless organisms, contaminants, or germs that are present but not causing the illness. The test is therefore not a replacement for routine diagnostics, but it may add valuable information when used alongside existing tests and clinical judgement.
Further work is needed to improve the speed of the test and to identify which groups of children are most likely to benefit from it in routine clinical care.REC name
Wales REC 6
REC reference
22/WA/0341
Date of REC Opinion
25 Nov 2022
REC opinion
Further Information Favourable Opinion