Nothing leaves parents with a feeling of dread like a baby or a young child with unreasonably high fever. In such scenarios, there is but one choice: heading straight to the hospital so that clinicians can distinguish mild, self-resolving viral infections from severe bacterial ones. But methods currently used in hospitals are far from 100 % reliable. With PERFORM (Personalised Risk assessment in febrile illness to Optimise Real-life Management across the European Union), project partners aimed to solve the three main problems posed by these methods: the high number of children unnecessarily treated with antibiotics; the fact that some severe bacterial infections are still missed; and the long time required to get test results. “The vast majority of children admitted to emergency departments have trivial illnesses that do not require any treatment. But amongst them are also a small number of bacterial infections that can progress into life-threatening conditions like septicaemia, meningitis, pneumonia, osteomyelitis and septic arthritis,” says Michel Levin, coordinator of PERFORM and professor of Paediatrics and International Child Health at Imperial College London. Doctors need to rule out such scenarios, but the go-to solution – bacteria culture that can take 24 to 48 hours – can’t be applied to difficult-to-access sites like the lungs. The result? Too many children still undergo unnecessary treatment with broad spectrum antibiotics simply because the presence of bacteria couldn’t be ruled out or get sent home without treatment only to come back with aggravated symptoms.
From genes and proteins to rapid testing
The PERFORM consortium faces this challenge head-on by tapping into the potential of a new technique called blood RNA sequencing. “Instead of culturing the bacteria or using molecular methods to identify the pathogen, we propose to identify bacterial infection by using the child’s immune response to this pathogen,” Levin explains. “The fundamental concept is that identifying the specific host response to bacteria can help us distinguish bacterial from trivial viral infections.” Doctors and researchers from across Europe tested two distinct methods on blood samples from 6 000 children: one detecting the genes being switched in response to bacteria or viruses, and one detecting the proteins produced in response to the two types of infections. “Not only did we show that the pattern of RNA expressed in a blood sample can accurately distinguish bacterial from viral infection, but we also found that only three to five genes were needed to do so. The same goes with proteins: we only need a small number,” Levin adds. This wasn’t an easy process. Each patient studied generated millions of RNA or peptide sequences. Bringing these down to a very small number required sophisticated computational methods, and there is still the challenge of turning these genes into a rapid test that can deliver results in 1 hour. Biotechnology company bioMérieux is already hard at work developing a prototype device. Besides this groundbreaking testing method, the project also generated large amounts of data on the patterns and cases of febrile illness. The team notably found that many children suffering from severe and life-threatening bacterial infections also have viruses in their nose or throat. “This suggests that bacterial infection and viral infection are not two distinct conditions. Viral infections may in fact alter the child’s resistance or response to infection, which in turn allows bacterial infections to develop. This shows how the presence of a virus in a child’s nose or throat does not exclude the possibility of a severe bacterial infection,” Levin notes. PERFORM is set for completion in June 2021, but a follow-up project – DIAMONDS – is already under way. The new project will investigate the hypothesis that all infectious and inflammatory diseases can be diagnosed rapidly and accurately with gene signatures. Eventually, both projects should help ease parents’ and clinicians’ concerns while avoiding inappropriate use of antibiotics in children.
PERFORM, children, fever, febrile illness, virus, bacteria, diagnosis, RNA sequencing, testing method