New blood test distinguishes serious illness from mild infection in children with cancer

A new study has found a blood test that can distinguish between children whose fever is a sign of serious illness and need to be admitted to hospital, and those who do not and therefore are safe to go home.

Challenge of Managing infections in paediatric cancer patients

It was an early experience as a then-junior doctor that sparked Professor Phillips’ longstanding interest in infectious complications in children with cancer.

He was regularly seeing paediatric cancer patients who came into hospital because they had a high temperature.

Chemotherapy can weaken the immune system, making children more susceptible to life-threatening infections. When an infection occurs, children need to be admitted to hospital for antibiotics quickly.

Professor Bob Phillips, Senior Lecturer in Paediatric Oncology at Hull York Medical School and an Honorary Consultant in Paediatric Oncology at Leeds Children’s Hospital
Professor Bob Phillips, Senior Lecturer in Paediatric Oncology at Hull York Medical School and an Honorary Consultant in Paediatric Oncology at Leeds Children’s Hospital

However, there are a range of reasons why a child’s temperature can be raised when they are having chemotherapy, including: side effects of medication or chemotherapy, the body is fighting off an infection trying to take hold, or they have a mild infection like a common cold.

Professor Phillips said, “We treated all children with powerful intravenous antibiotics for seven days and ordered chest X-rays for all of them – regardless of the underlying cause of their high temperature. However, there was one child who kept coming back every other week, and I thought this is ridiculous.”

"All children were treated with powerful intravenous antibiotics; I thought there must be a better way"
Professor Bob Phillips

Professor Phillips, who is now a Senior Lecturer in Paediatric Oncology at Hull York Medical School and an Honorary Consultant in Paediatric Oncology at Leeds Children’s Hospital, wanted to change this.

Now, a new study led by Professor Phillips has found a blood test that can distinguish between children whose fever is a sign of serious illness, and those who do not and therefore are safe to go home.

And using the blood test in combination with a new protocol to identify children that are safe to go home, the study found it could cut the average stay in hospital down to two days, with some able to leave in as little as eight hours.

Dr Bob Phillips talking with colleagues at Leeds Children's Hospital

The Challenge of Distinguishing Serious Infections

It is standard practice in the NHS to keep paediatric cancer patients with a fever in hospital for up to a week, while antibiotics are administered in case the high temperature is a symptom of a serious infection.

The condition, called febrile neutropenia (FN), can occur when cancer treatment causes white blood cell count to drop to dangerously low levels, leaving children vulnerable to infections. A high temperature often accompanies FN.

Only 20%–30% of all patients with FN will have a serious bacterial infection (1). However, identifying the patients who genuinely require antibiotics is challenging.

“Well children were being stuck in hospital unnecessarily for days”
Professor Bob Phillips

All children are given antibiotics, regardless of what has caused their high temperature. However, not all children will need antibiotics, and some may be receiving too much.

This can lead to negative side effects from antibiotics, developing an antibiotic resistance, and being kept in hospital longer than needed which puts an additional strain on families.

Professor Phillips said, “This approach to treating infection is very safe, meaning nearly all severe infections can be cured.

"But it also means that well children, who may just have a cold, get stuck in hospital for days having powerful antibiotics, until their temperature settles.”

Dr Bob Phillips with a patients at Leeds Children's Hospital

The Blood test breakthrough

Currently, in adults admitted to intensive care, blood tests that can detect inflammation due to bacterial infections are used to guide treatment with antibiotics.

But it is not known if these markers are the same for immunosuppressed individuals. In these cases, the immune system doesn’t work as well, so it wasn’t understood if cancer patients produce these markers as effectively and as efficiently as an otherwise-well person.

Professor Phillips’ previous NIHR-funded research examined the usefulness of a new blood test that measured the biomarker procalcitonin (PCT). PCT, a protein in the blood, may be a useful tool to determine if a cancer patient is at low risk of serious bacterial infection and can therefore safely have antibiotics discontinued.

Armed with this knowledge, the researchers received funding by Yorkshire children’s cancer charity Candlelighters to conduct a pilot study, to investigate whether measuring PCT levels could help guide safely stopping antibiotics where they were not needed in children with FN.

"The blood test could make a big difference to children who don’t have a serious infection, allowing them to go home earlier"
Professor Bob Phillips

The study enrolled 28 patients with 13 episodes of FN. Their PCT levels were measured daily during each FN episode, and researchers used these to identify the point at which intravenous antibiotics could be stopped. The study found that in half of the episodes without clear evidence of infection, antibiotics were successfully reduced.

Professor Phillips said of the results, "Frequent fevers are a distressing and sometimes life-threatening complication of childhood cancer. Our study shows that procalcitonin blood tests could make a big difference.”

He continued, "The blood test could cut unnecessary treatment with antibiotics and reducing an already intense mental and physical toll."

The study is published in the BMJ Open: PAnTher Cub: procalcitonin-guided antibiotic therapy for febrile neutropenia in children and young people with cancer - a single-arm pilot study.

The study funder Candlelighters artwork in a play area at Leeds Children's Hospital
The study funder Candlelighters artwork in a play area at Leeds Children's Hospital

Candlelighters CEO Emily Wragg said, “In the 1970's when Candlelighters was formed, the survival rate for children's cancers was just 10%. The five-year survival for all childhood cancers diagnosed in Yorkshire is now at 86%, a fantastic improvement made possible by investments in research from organisations like ours.”

“Now, more must be done to ensure not only that more children survive, but they survive with fewer long-term side effects and have an improved quality of life while undergoing treatment.

"This research allows children to enjoy as much normal life as possible"
Emily Wragg, CEO of Candlelighters

"Frequent and long stays in hospitals are so disruptive for families, impacting mental health and finances, with parents needing to take time off work.

"Research like this is vital to make a positive difference to children and their families, allowing them to spend more time at home amongst their family and friends."

Clown stickers on a wall in a children's hospital ward

Looking to Future large-scale testing

The study had positive engagement from patients, their families, and doctors. From previous experience, Professor Phillips was expecting around 50% of families and doctors to take part in the trial. However, 38 of the 42 families approached agreed to take part, and doctors followed the trial 4 out of 5 times.

The promising results of this pilot study, and the willingness of families and doctors to take part in the research, mean that the researchers are developing a bid for a national, large-scale randomised trial.

Speaking on the success of the uptake, Professor Phillips said “We know from working with families and PPI groups what research is important to them. Even so, we normally get around 50% uptake in trials. There’s something about this study that has an understandability to it. It allows people to believe it, in a way that other studies didn’t.”

Professor Phillips said, "We found most of the doctors didn’t always stick to stopping if the blood test result was low in the first couple of months of the trial period. As they got the confidence to try it, and saw that the outcome was ok, they gained confidence in the new approach."

They hope that the findings will demonstrate it is possible to shorten the antibiotic usage for a large number of children, with its consequent benefits to them.

Professor Phillips said, “We are now working up a bid for a full national clinical trial to compare using the PCT blood test to suggest when antibiotics are needed, versus the standard approach to testing and antibiotics. We’ll be able to batten down whether this is a safe, cost effective and better approach for patients.”

For more information about this research, contact Professor Bob Phillips or visit the Centre for Health and Population Sciences.

References

(1) Miedema KGE, Tissing WJE, Abbink FCH, et al. Risk-adapted approach for fever and neutropenia in paediatric cancer patients--a national multicentre study. Eur J Cancer 2016;53:16–24. doi:10.1016/j.ejca.2015.10.065