Hi Reddit! We are researchers from PERFORM, a European Commission funded project led by Imperial College London.

Diagnosing child fever

The management of febrile patients (patients having or showing symptoms of fever) is one of the most common and important problems facing healthcare providers.

There is currently a lack of means to correctly diagnose the cause of fever for children who arrive at the emergency department.

This lack of a rapid and accurate tool and algorithm for diagnosis means:

  • a high number of children are unnecessarily treated with antibiotics
  • some severe bacterial infections are missed
  • A long time is needed to get test results which may not be very informative.

A one-hour diagnostic tool

At the PERFORM project (Personalised Management of Febrile Illness) we are working to develop a rapid, one-hour prototype that can distinguish whether the fever is a symptom of a bacterial or viral infection. This is achieved by measuring the expression of genes and the abundance of proteins in the blood using novel molecular techniques.

You can read more at the European Commission project page:

Personalised Risk assessment in febrile illness to Optimise Real-life Management across the European Union (European Commission)

Team members in this AMA:

  • Professor Michael Levin
  • Dr Myrsini Kaforou
  • Dr Jethro Herberg
  • Dr Aubrey Cunnington

We’re looking forward to answering your questions about our research and the diagnostic tool. We aren’t able to offer clinical advice, so would always recommend you go to your healthcare providers if seeking healthcare advice.

Key papers

Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children and Diagnosis of Bacterial Infection Using a 2-Transcript Host RNA Signature in Febrile Infants 60 Days or Younger (JAMA Network)

Impact of a clinical decision rule on antibiotic prescription for children with suspected lower respiratory tract infections presenting to European emergency departments: a simulation study based on routine data (National Library of Medicine)

Variation in hospital admission in febrile children evaluated at the Emergency Department (ED) in Europe: PERFORM, a multicentre prospective observational study (PLoS One)

Respiratory Tract Infection Management and Antibiotic Prescription in Children: A Unique Study Comparing Three Levels of Healthcare in The Netherlands (National Library of Medicine)

Variation in antibiotic prescription rates in febrile children presenting to emergency departments across Europe (MOFICHE): A multicentre observational study (PLoS One)

Proof: https://twitter.com/imperialcollege/status/1392496049185607690

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UPDATE [1PM ET / 6PM BST]: Thanks very much for your great questions everyone. We’re heading off for now but will be checking back in tomorrow, so please do submit any more questions you may have.

And a big thanks to r/IAmA for hosting this AMA!

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PERFORMing Live webinar

If you’d like to hear more about our research, please join us on 29 June for our final free webinar, where the PERFORM2020 consortium will be sharing major results from this 5-year project followed by a plenary discussion to answer audience questions.The webinar is free and open to all, register via Eventbrite: https://www.eventbrite.com/e/turning-personalised-management-of-children-with-fever-into-a-reality-tickets-151178369573

Comments: 157 • Responses: 26  • Date: 

tashawook240 karma

Hi there. I work in a Pediatric emergency department in the public sector in South Africa and this type of test would be extremely useful in our context. One of the biggest diagnostic challenges for us is differentiating febrile seizures from possible meningitis as our lumbar puncture results have a turn around time of about 24 hours. This leads to unnecessary admissions and iv antibiotic use. My question is therefore, world this test be applicable to cns infections and how long until this test could be rolled out globally?

ImperialCollege152 karma

Hello tashawook . Thanks for your question about febrile convulsions (those are the fits/seizures that some children have when they develop a fever).

We have developed this test based on blood samples from a wide range of patients, and some of them had meningitis. So yes - we do believe that it will work to identify children with a bacterial infection, even if it is in association with meningitis.

If a child comes in with a febrile convulsion and it is not related to a bacterial infection, the test should tell us that. But it won’t tell us whether or not meningitis is present - after all meningitis might be caused by a virus.

So - another question which we are working on is to see whether a test can tell us where the infection is in the body - and it sounds like that would be really helpful in the situation that you’re describing.

We are really make this test globally available and affordable - we are working on that!

Lupicia36 karma

Interesting! I have three kids, so I've encountered a fair share of fevers that our pediatrician has had to deal with, though none so bad as to land them in the ER. That's wonderful that you're developing a rapid tool that can help avoid over-prescribing antibiotics for viral causes and also picking up on smoldering bacterial infections that need them.

First, in your experience, can some fevers seem to lack viral or bacterial etiology? (Teething? Immunizations? Expansion forces of the universe?) Can your test identify one that's neither bacterial nor viral... and what do you do then?

Second, does your test help diagnose chronic, low-grade fevers that need antibiotics but would otherwise be missed because the child's fever never spiked high, or is your test mostly for severe fever?

ImperialCollege29 karma

Lupicia, this is a great question! In order to be certain that our test works, we have to start by assessing how well it performs in patients with a definite cause of illness. But we also found that doctors can only make a definite diagnosis with current tests in less than 50% of children with fever, even when they are seriously ill. So this leaves a lot of fever unclassified by current tests, and we hope that our test can help to classify these better.

We are also using data from the same studies to see if we can make new classifications of the causes of fever, so watch this space!
You are absolutely right - fever is an important sign in some childhood conditions that are not related to bacterial or viral infection. For instance, our team has been working on Kawasaki disease for many years - this is an important condition to diagnose quickly - but there is no diagnostic test available - and we have worked out a test to diagnose Kawasaki disease that uses this same technology.

Regarding your second question, children don’t need to have a fever for these tests to work, we are testing them in any children with suspected infection, and may even detect the cause before development of symptoms.

catboy_majima29 karma

What did you eat for breakfast?

ImperialCollege64 karma

Great question catboy_majima, thanks for keeping us on our toes. In no particular order: cinnamon and raisin bagel, cereal without enough milk, crumpet with marmite, coffee, orange juice, greek yoghurt with strawberries, avocado on toast, home-made granola with coconut yoghurt. This was not eaten by just one person!

forever_erratic25 karma

Sounds like an important goal! I'm a microbial ecologist; my questions are mostly about exceptions.

1) a quick scan of the lit seems like FAM89A is upregulated during immune response to bacterial presence, hence your using it as a bacterial signature. But what if immune response is depressed? Have you addressed the interaction between immune system quality and false negatives? A similar question could be asked about the viral marker.

2) RNA is notoriously difficult to keep from degrading. Presumably your tests are pretty controlled; how well do you think practitioners are going to be able to adhere to RNA working standards in real scenarios?

3) Are these genes conserved enough so that your tool (qPCR I assume? Er, no, looks like microarray) will detect all of humanity's transcripts?

4) Presumably you don't intend to sell microarrays as diagnostic tools, but won't cost be an important factor here?

5) Sometimes time is of the essence, and I wonder about the balance of reducing antibiotic usage vs. overtreating but dealing more quickly with critical clinical situations. Abx resistance is super important, I agree, but I wonder if other avenues are more important for reduced usage (e.g. agriculture).

Really cool stuff, thanks!

ImperialCollege23 karma

Thanks for really interesting and important questions.

1) First your question on FAM89A as a marker of bacterial infection: as our signatures are based on white blood cells being activated in blood in response to different infections, you are correct that severe immune deficiency that causes severe depletion of specific cell lines, or treatment with high doses of immune-supressing drugs is likely to affect the result. In PERFORM we are currently evaluating the use of the RNA bacterial/viral signature in immunosuppressed patients. In some groups we have looked at (e.g. neutropenia and HIV), we still find we can distinguish individual infections. We also aim to build minimal redundancy in the signatures to eliminate the false negatives.
2) Regarding RNA stability, for discovery of the signatures we collect the blood into PAXgene tubes or Tempus tubes which are RNA stabilising fluids. Once in the fluid and then in the freezer, the RNA can remain stable for a very long time. However we are aiming for the tests in clinical practice to work on blood collected directly from a finger prick and immediately analysed, without the need for any RNA preservation at all.
3) Yes, the genes selected to be in our small “signatures” are selected from studies involving hundreds of patients, to find the most consistently expressed and conserved genes. Some redundancy is built into the signatures to allow for heterogeneity in gene expression.
4) Cost is an important issue. We are aiming for a cheap test which can be used at the point-of-care, ie. the location where the patient is being treated rather than in a lab elsewhere. We are working with lots of technology partners to try to achieve this. In order for us to get to our ultimate goal of a simple, rapid, cheap and portable test, we have to first test that the general method of diagnosis works well and is safe using existing technologies.
5) Although reducing antibiotics misuse is an important goal, our real aim is to ensure that patients with severe bacterial infections are rapidly diagnosed and treated. And at the same time patients with inflammatory conditions that may take a lot of time to reach a final diagnosis with the current test, can be diagnosed earlier.

Ryanosaurus_WRECKS22 karma

Where could this type of technology have the biggest impact? Is this something that we could see in every hospital? Or is it more geared towards developing / rural regions where there may be less (lab-based) diagnostic capability?

ImperialCollege17 karma

Hello Ryanosaurus_WRECKS, thank you for your question. We are currently exploring technologies that are both appropriate for developing/rural regions and high-resource settings, as diagnostic challenges exist in all settings. We are also aiming to design different platforms based on the prevalence of disease in different populations. Our test is based on measuring the way the patient responds differently to bacteria or viruses, through different patterns of gene expression and protein levels in blood. Therefore different technologies that rapidly and accurately measure molecules from the blood can be used to diagnose disease in different settings.

HeidiGluck19 karma

My son has Pfapa fevers, has outgrown it now. Do you plan on the test identifying this too? Was a very horrible time for years. Peds very dismissive, rheumy took it seriously and sent him to the hospital with very messed up lab values- sed rate over 100, etc. Please add this as part of your test so other children do not have to suffer with this not being caught and treated by doctor's. Was a nightmare for him and us!

ImperialCollege27 karma

Thanks for sharing your experience with us. Yes we agree paediatricians have difficulty diagnosing conditions like Pfapa (for others on the thread this is a childhood inflammatory disorder which causes severe and frequently recurring fevers).

We have evidence that all infectious and inflammatory diseases have unique ”signatures” in blood that can be used to diagnose them. So far we have studied the most common inflammatory diseases (such as Kawasaki disease, and Juvenile Rheumatoid arthritis, and found they have clear molecular signatures. We are trying to include diseases like Pfapa in our current EU funded DIAMONDS study.

We are optimistic that we will identify tests for each inflammatory and autoimmune disease, but we can only be certain after we have studied the gene signature of many children with each disorder.

Flakkarin18 karma

Thanks for your work! Why is it especially important to perform these kinds of rapid tests for children? Could adults also benefit?

ImperialCollege34 karma

Great question Flakkarin. Yes, adults could benefit too. In fact we are investigating the development of the same type of test for adults. We focussed initially on children because fever is the most common reason why children are brought to hospital. In children it is often difficult to distinguish the cause of fever, but this is also a big problem in elderly adults too. The principles of the test should apply to anyone.

Snoo8025917 karma

Thanks for your great work. Would the test only be able to be performed by a clinician, or is it something parents or carers could perform at home (before they even take the child to A&E)?

ImperialCollege32 karma

Hello Snoo80259, thank you for your question. We are currently exploring different platforms to measure the molecules that give us the answer including measuring straight from finger prick blood, which would then allow the test to potentially be used in pharmacies or by parents. Another idea we are exploring is whether the type of diagnostics we are doing can be run on saliva instead of blood. It turns out that your saliva does contain human RNA molecules - these are the same molecules that we are measuring on blood. That would make it a really non-invasive test - and definitely more kid-friendly!

the_slate15 karma

Why only children? Is there a reason it doesn’t work in adults, or is it just more valuable in children due to lack of well developed immune systems?

ImperialCollege8 karma

ImperialCollege13 karma

Also, we have begun work on Children, as we are a group of Paediatricians, and our original studies were focused on children. However the approach is equally applicable to adults. In our follow on study funded by the European Commission the DIAMONDS study we will be including both children and adults.

schlingfo8 karma

"There is currently a lack of means to correctly diagnose the cause of fever for children who arrive at the emergency department"

I would take issue with that statement. A large percentage of febrile pediatric cases I encounter can be safely classified as viral illness with a good H&P. The key is being able to explain to parents why antibiotics aren't necessary for the 5 year old with one day of fever and cough who happens to have a sibling at home with the same symptoms that are now better.

With that said, for those kiddos who you think may have something more than just a virus going on, how exactly is the sample collected? Is it a fingerstick POC? Or, is it something more invasive?

ImperialCollege7 karma

Thanks for an interesting question. We agree that the vast majority of children are correctly diagnosed by careful history and examination, by experienced paediatricians.

Unfortunately, there are daily tragedies of children sent home from emergency departments, or from their GP, with clinicians reassuring parents that “it's a virus” only to return critically ill with sepsis or meningitis.

Also every paediatric department admits many children for ”rule out sepsis” workup with cultures and lumbar puncture, and most of these children do not turn out to have bacterial infection.

It is the junior doctor, at midnight, who sends children home with reassurance, that could be most helped by a rapid test.

nait_jello8 karma

Do you know how much the test is expected to cost? And why is it be better than current tests being used in the hospital for detection of bacteria, like CRP?

ImperialCollege7 karma

At the moment we are working with different technology partners to be able to come up with versatile tests for different settings that address clinical needs appropriately (rural setting vs high-resource settings for example). Cost indeed is an important issue. We are aiming for a cheap test which can be used at the point-of-care, ie. the location where the patient is being treated rather than in a lab elsewhere. In order for us to get to our ultimate goal of a simple, rapid, cheap and portable test, we have to first test that the general method of diagnosis works well and is safe using existing technologies.
C-Reactive Protein (CRP) is commonly measured by doctors to help them discriminate between the causes of fever. When it is very high it usually indicates a bacterial infection (but can also happen in inflammatory diseases). When it is very low it makes it much less likely that there is a severe bacterial infection. But when it is somewhere in the middle, it doesn’t help much at all! Unfortunately the group with CRP in the middle is very common, and so we definitely need better tests to discriminate the cause of fever.

ikonikon7 karma

Thank you for working on such an important topic!
Does the test work for COVID-19?
What about bacteria and viruses that it has not been trained on - can it still classify them correctly?

ImperialCollege9 karma

Thanks ikonikon, this is a very topical question. We have some new data that indicates the answer is yes! We can identify COVID-19 infection as a viral infection using our existing test, and we are now working to see if we can discriminate between COVID-19 and other common viruses causing similar symptoms.

We didn’t include COVID-19 when were developing the test, because it didn’t exist at that time, but the evidence so far looks like we can classify bacteria and viruses that were not used to “train” the test

ThisIsZane5 karma

Hey hope I’m not too late. I actually have something you might find interesting! When I was about 5 years old I developed a mild fever and it would not go away. What started as a simple doctors visit turned into many specialist visits because my fever started lasting weeks. After nearly TWO MONTHS of a constant mild fever (confirmed by our pediatrician and the specialists) our doctor finally told my mom to stop taking my temperature and return to school.

About two weeks later she took it again and it was gone. I have memories of countless blood tests and MRI’s. They never found out what the cause was and I’ve been rather healthy ever since!

I have always been curious what the heck went on. Have you guys ever heard of anything like this?

ImperialCollege3 karma

Thanks for sharing your experience. We realise that sometimes the cause of fever can’t be identified and in our ongoing work we are trying to find ways to address this.

You might like to see our answer to Lupicia. https://www.reddit.com/r/IAmA/comments/nbhvf0/we\_are\_researchers\_developing\_a\_onehour\_test\_to/gxzgg3m?utm\_source=share&utm\_medium=web2x&context=3 .

sock_templar5 karma

Hi team! Great work!

My question is: how expensive do you think this test would be to be used in underdeveloped countries where giving antibiotics isn't even a possibility due to lack of govt funding?

ImperialCollege5 karma

Thank you for your question! We answered a similar question here which might be useful. https://www.reddit.com/r/IAmA/comments/nbhvf0/we_are_researchers_developing_a_onehour_test_to/gxzqq5d?utm_source=share&utm_medium=web2x&context=3 but do let us know if you have further questions :)

Yellow_dress3 karma

Hi! What is the toughest question you have to answer about pediatric febrile illness?

ImperialCollege7 karma

The toughest question has come from our large scale studies of thousands of children, which has shown that infections are not either bacterial or viral, but often a complex mix of the two. This has changed our thinking, from how do you distinguish bacterial from viral infection, to how do we identify the patients who need antibiotics , even if we can identify a virus in their throat. Infection is more complex than we thought before we commenced PERFORM.

caosmom3 karma

How will you deal with the skepticism that Theranos has caused?

ImperialCollege5 karma

Thanks for an important question about scientific credibility.
Our studies are based on years of careful scientific study, and recruitment of thousands of patients into our EU funded studies. Each step in our development of the concept of using RNA signatures for diagnosis of infectious and inflammatory diseases has been based on peer reviewed publications in leading scientific journals and transparency. Furthermore, all the RNA expression data our tests are based on are made publicly available at the time of publication, so other scientists world wide can reproduce our work.
We believe in open access and sharing of data.

10thunderpigs3 karma

But can't fevers also stem from autoimmune disorders? Would your test take this into account?

ImperialCollege4 karma

Hi 10thunderpigs - we've answered a similar question on inflammatory and autoimmune disease here https://www.reddit.com/r/IAmA/comments/nbhvf0/we_are_researchers_developing_a_onehour_test_to/gxzq6bp?utm_source=share&utm_medium=web2x&context=3 but do let us know if you have further questions :)

Damnit_Bird2 karma

Do you think you could collaborate with veterinary medicine in the future to have a similar test for pets? Fever of unknown origin is a common problem in cats and some breeds of dogs.

ImperialCollege3 karma

Hi Damnit_Bird. That’s a great question - and not one we’ve yet thought of tackling. The short answer is yes, the approach should work across species, and there is a lot of research published on how animals respond to infection.

So far the discovery work we have done to ‘discover’ which genes are changed in different illnesses with fever has been done in humans (not pets!) - this requires painstaking work to take samples from good numbers of patients with all the different common and important conditions associated with fever. This would likely need to be repeated for each species - but I’m sure there are veterinarians out there doing this work and I think that if we can get this rolled-out for humans, animals will follow.

kenyan-girl2 karma

Hi! I'm a doctor working in a resource limited setting in rural Kenya. For example, our lab only runs full haemograms, no other tests. In such an environment, do you think the rapid test would be helpful given our lack of other lab tests to give clinical correlation? Thank you

ImperialCollege1 karma

Hi kenyan-girl. It is a top priority for us to develop a test platform that is affordable, and that can be used in settings in which there is not significant testing infrastructure already in place. If we can achieve this, then we can have the most impact on healthcare from a global perspective.

Whilst the discovery of our biomarker signatures has relied on resource-rich technological approaches, we believe that the signatures can be translated into useful tests that, even if they rely on advanced technology, can be run on simple devices in any setting. We are working with our technology partners to achieve this aim.

binaryblade2 karma

How often is it lupus?

ImperialCollege1 karma

Thank you binaryblade. Lupus is a good example of an autoimmune condition which can present with fever, and mimic an infectious condition. Particularly in children, where it is quite rare, the diagnosis can be easily missed.

However, lupus is an example of a condition for which there is already data showing that it has its own unique ‘signature’ in blood of gene expression (ie which genes are switched on or off) so we are aiming to capitalise on that to include lupus as a diagnostic condition built into our tests (see our EU-funded DIAMONDS project: https://www.diamonds2020.eu)

Kim_John_Wick1 karma

[deleted]

ImperialCollege7 karma

The current test technology gives an answer in just under one hour. But we are already working to reduce this to 20 minutes in a handheld device - we think this is possible!

WaveyLAD1 karma

Hi, just wanted to say great work so far! I work in a Paeds ED and we often do bloods for your study on top of our normal bloods and I speak often with our research nurse about this study! So it’s pretty cool to see an ama about something I’ve indirectly helped and been apart of!

My question is(and in layman’s terms please I’m still only a medical student) is the idea to build a giant “database” of the types of exact infection that is causing the fever that could then be cross referenced in the path lab or something that would be able to be used in our department that could give us a quick result? i.e practically speaking how would this work in clinical medicine?

Thanks in advance and keep up the good work!

ImperialCollege2 karma

Hi WaveyLAD! We are thrilled that you’re helping recruit to our study - THANK YOU SO MUCH. All of our work relies on the efforts of many dedicated people working at the front-line - particularly in ED where the children first come in with fever. Engaging members of the public in research - particularly children, and particularly when they are ill - can be really challenging, and requires skill and dedication. So thank you again!

Your question addresses a key part of our DIAMONDS project - we are working with the European Molecular Biology Laboratory (EMBL) to build a European Diagnostic Transcriptomic Library - an online resource for researchers to look up how the host responds to a range of illnesses. The resource will allow linking the clinical data (ie the details of how patient was when they had their blood sample taken) to the changes in gene expression in their blood.

This aims to be a ‘dictionary’ of how the body responds to different illnesses, particularly those associated with fever. When we design tests for different conditions, we draw on this complete and extensive disease dictionary. We think that the tests would be run locally - with a result coming from an in-built algorithm that is designed and based on the online library.

Yellow_dress1 karma

It seems that there are more than one questions- bacterial or viral, infection or inflammation, severe or mild disease. Are more than one test needed?

ImperialCollege2 karma

Thank you for a great question - this is exactly what we are trying to do. We are aiming to develop a single test that answers the severity question as well as the cause of fever question at the same time from a drop of blood. Please see more at https://www.diamonds2020.eu/

RVAEMS3991 karma

Which specific viral illnesses does your test identify that we are currently unable to test for?

ImperialCollege3 karma

Thanks for the question. You are correct that we can currently detect many viruses by finding Viral DNA or RNA. The problem is that we can detect viruses in the throat, nose, and blood of healthy children, and in a similar proportion of children with severe bacterial infections as those with viral infections. What this tells us is that detecting the viral pathogen does not help us to be sure about the cause of fever or know if the child has a severe bacterial infection as well.
Our new approach detects the human host response to the pathogen, and is able to identify a range of different viruses that children get ill with. So even if a child or adult has the flu virus or common cold virus in their nose and throat, if they ALSO have a bacteria invading the lungs or blood, our test will identify this infection.
Our PERFORM study has shown we need a paradigm shift in thinking about infection. Most infections are not simply bacterial or viral, but may be a complex interaction of the two. What is important to identify is those infections where a bacteria is making the patient ill, even if there are viruses present in the patient’s airway.

celica18l1 karma

This is fascinating!

My son had atypical Kawasaki disease and had a fever for over 20 days.

Could a test like this help streamline diagnoses similar to Kawasaki disease when all the typical symptoms may not be present at the same time?

He never had more than two symptoms at any given time.

ImperialCollege2 karma

Hi celica18l. Sorry to hear that your son had a delayed diagnosis of Kawasaki disease. This is a common problem as Kawasaki disease can look very much like other, more common infection problems, and yet the treatment is completely different, and at the moment there is no diagnostic test for it.

Our team are very interested in Kawasaki disease - and one of the central aims of this project has been to bring in a test for this condition - which if not diagnosed and treated quickly can lead to permanent damage to the coronary arteries.

We have developed a diagnostic ‘signature’ for Kawasaki disease, and we are actively working on translating this into a test using the same approach as for the infectious (bacterial vs viral) illnesses. (https://www.imperial.ac.uk/news/187547/genetic-signature-kawasaki-disease-paves-first/)