Rapid Genetic Test Prevents Hearing Loss in Newborns With Sepsis

Becky McCall

June 15, 2018

A point of care genetic test, designed to optimise the selection of newborns for the antibiotic treatment of sepsis, promises to prevent cases of irreversible hearing loss.

By identifying the gene variant known as mitochondrial m.1555A>G, the rapid bedside test determines which infants are prone to antibiotic-related deafness before the recommended combination of gentamicin and a beta-lactam antibiotic is given.

Gentamicin, an aminoglycoside, is a powerful treatment for life-threatening cases of sepsis, but it is associated with the potential side effect of irreversible hearing loss and the risk is worse in early childhood. In a susceptible infant, a single dose can cause profound sensorineural hearing loss.

The work is being presented at the 2018 meeting of the European Society of Human Genetics (ESHG) by academic clinical fellow in genomic medicine, Dr John McDermott, from the Manchester Centre for Genomic Medicine. His colleague Prof Bill Newman, professor of translational genomic medicine at the University of Manchester, spoke to Medscape News UK. The test has been developed jointly with Genedrive plc, a molecular diagnostics company.

Gene Variant

The mitochondrial m.1555A>G variant has a prevalence of 1 in 500 newborn babies and it predisposes the individual to profound hearing loss after gentamicin administration, often requiring cochlear implantation. "The mutation has been known for around 20 years but if we want to test for this variant in clinical practice currently it take 2-3 days to obtain a result," explained Newman. "The problem is that a baby [with sepsis] needs to receive the antibiotic within an hour of admission. We've now made a test that takes only 30-40 minutes to determine if the child is susceptible to gentamicin-related hearing loss."

Worldwide there are over a million neonatal deaths from sepsis annually, and in the UK alone, 90,000 babies per year are admitted to neonatal intensive care units with sepsis. With a prevalence of the mitochondrial variant of one in 500, use of the new test would prevent hearing loss in 180 babies annually in the UK.

There are a number of treatment options for sepsis in newborn babies. The combination of penicillin (beta-lactam compound) and gentamicin is preferred and recommended by the National Institute for Health and Care Excellence (NICE) due to its narrow spectrum of activity and lower risk of the development of antibiotic resistance. "The alternative antibiotic options are very good and cheap but they are more likely to lead to the development of resistance because they have a broad-spectrum profile. Gentamicin works very well and the priority is to get on top of the baby's sepsis straight away because they can die from it," said Newman.

He went on to point out that the overarching driver for the development of the test was consideration of where in genetic medicine a result is needed very quickly, and where clinical decision-making opportunities lie. "We identified that the question around who should be treated with gentamicin was viable and we worked with Genedrive, a company that make point of care tests, to find a solution." He explained that the process uses asymmetric polymerase chain reaction (PCR) tests to make multiple copies of the gene variant sourced from a cheek swab of the baby's saliva. The DNA is extracted, undergoes the PCR test and in this way provides specific information on the mitochondrial m.1555A>G variant only. "We believe it is 100% reliable. We've done lots of positive and negative controls and it all comes out correctly. We tried blood samples but a cheek swab is the most convenient option in the real-life setting."

Point of Care Testing (POCT)

The test epitomises a new way of thinking in healthcare around rapid bedside testing. "It allows you to extract DNA from whatever material you choose to use and then generate the test there and then. This technology has wide applications, and could be used for identifying infections, for example, tuberculosis. Also, it could be used in the field because it can be charged up and taken to where it is needed."

He added that there were distinct advantages with this point of care test. "We are keen to see how it works in the neonatal setting but there might be times when a patient enters A&E or might be seen in general practice and genetic information is needed very quickly so we are starting to think about the other applications too."

At present, this test is the proof of concept in a scenario where there is very strong evidence to support it, said Prof Newman. "The result of this test is very clear and you know exactly what to do on the basis of it. If the baby has the variant then don't give gentamicin, but something different. In this setting, the test needs to be one that doesn't demand a lot of interpretation and complicated algorithms."

Next, the researchers plan to undertake a multi-centre feasibility study introducing the test into several neonatal centres around the UK, starting in two large neonatal units in Manchester, and one in Liverpool, and will expand across England at a later date. All children admitted to these centres will be tested for the genetic variant and antibiotics will be tailored accordingly. Other aspects of implementation will need to be investigated, including access, how the funding is provided, and the health economic argument that determines the value of the medicine in clinical practice. 

"We want this test to be widely available in around 2 years," remarked Prof Newman. "But more study is needed before that. It is important that when we introduce this test it doesn't interfere with all the other things that need to be done for a newborn baby. We need to be able to effectively incorporate the test into standard care." 

Commenting on the work, chair of the ESHG conference, Professor Joris Veltman, director of the Institute of Genetic Medicine at Newcastle University, said: "This study shows us the importance of rapid genetic tests to prevent severe side effects from the use of antibiotics in a small group of sepsis patients who carry a mutation in their DNA. Identifying those patients within an hour can now allow doctors to prescribe alternative drugs in this group of patients, whereas the majority of patients can safely use the standard antibiotics."

COI: Both Bill Newman and John McDermott have nothing to disclose
Presented Saturday 16th June 2018 at the European Society of Human Genetics (ESHG).
Abstract no: C01.3. Development of a point of care pharmacogenetic test to avoid antibiotic related hearing loss in neonates

 

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