Feverish children – bacteria or virus?

Every year, thousands of children throughout Britain are taken to their local GP or A&E with a high temperature. They may have no other symptoms but they are clearly unwell.

The difficulty that the clinician faces is trying to make a rapid assessment as to whether the child has a virus – by far the most common cause of high temperature – or a bacterial infection -which is rarer but potentially more dangerous, possibly leading to septicaemia, pneumonia or meningitis. Yes, there are signs that could indicate a bacterial infection, but they are not infallible. Tests to determine this with certainty can take days to get a result, as is the case with taking a blood or spinal fluid sample and growing bacteria in culture until they can be identified. This usually takes around 48 hours. Molecular tests which can pinpoint viruses take hours but they don’t exclude the possibility that a child has a bacterial secondary infection as well.

The fact is that most clinicians make a judgement call, and they usually get it right. However, mistakes do happen, as we know from newspaper reports about children with undiagnosed meningitis who end up in a serious condition.

The more experienced I get as a paediatrician, the more I realise just how difficult it is to tell the causes of fever apart. So it is not surprising that many doctors resort to prescribing antibiotics to feverish children ‘as a failsafe’ just in case the cause is bacterial. Even when feverish children are assessed in hospital, they are often admitted and treated with intravenous antibiotics when the doctor is uncertain whether the illness is caused by a bacteria or not.

It’s not ideal, particularly when we are so worried about the explosion of antibiotic-resistant bacteria caused by over-use of antibiotic medication.

This conundrum is behind a £14m research project called PERFORM funded by the EU, which I am leading, which hopes to develop a rapid test to allow doctors to quickly indentify bacterial infection in children. We need a test which gives results in minutes, not hours or days, and the tests needs to be be very accurate. To achieve this, we are looking at the problem in a new way. Instead of trying to identify the pathogen itself (bacteria or virus), we are now looking at how the patient’s immune system reacts to different infections. We are pinning our hopes on data which shows that bacterial illnesses can be identified by the particular pattern of genes activated in a child’s immune system which are different from genes activated by viruses.

This approach has already been shown to work in other situations. For example, our previous studies (also funded by the EU) showed that we can distinguish TB from other infections, by the specific pattern of genes activated in blood which we detected using microarray technology – a method that enables all genes to be examined simultaneously in a few drops of blood.

Now we have to show that this approach can be extended to different types of bacterial infection across a broad spectrum of patients. Our study will look at 60,000 children in total across Europe and West Africa who are brought into hospitals or clinics suffering from high fever. Children in resource-poor regions of Africa are at even greater risk of serious bacterial infections, as well as other causes of fever such as Malaria so our study will include children from both Europe and Africa.

Over five years, we will focus on 10,000 children in particular and take blood samples which we will use to try and find the key genes activated when the child’s immune system reacts to bacterial infections. Our hope is that we will be able to narrow the field down from a potential 40,000 gene sequences, to just one or two which are specific for bacterial infection.

Once we have identified the gene “signature” which accurately identifies bacterial infection, we will be looking at ways to turn this information into a simple, low cost test. It is not feasible to use the microarray or sequencing technology we are using in our research study in every suspicious case as these sophisticated technologies are too costly for routine use. The gene “signature” of bacterial infection is based on RNA which is made when the DNA of each gene is activated by the infection. There are a number of methods to detect RNA, by binding it to the corresponding DNA. One possibility is that we will detect the gene signature of bacterial infection by electrical signals that are released when each gene is detected. An electrical signal could be uploaded onto hand held digital devices like mobile phones. An alternative approach is to detect the RNA in our bacterial infection “signature” by the release of coloured molecules when the RNA is recognised . We could thus develop a test like the current pregnancy tests, where colour change on a strip of paper or in solution indicates the presence of the RNA signature of bacterial infection.

I am optimistic that this collaborative effort involving many European, African and UK partners will achieve its goals and help to reduce both the problem of over-prescribing of antibiotics and missed diagnoses of bacterial infection such as meningitis in very sick children.