Raising AWaRe-ness of antimicrobial stewardship challenges in pediatric emergency care: results from the PERFORM study assessing consistency and appropriateness of antibiotic prescribing across Europe 

For the first time, in a large cohort of children (2,130 febrile episodes) across Europe, we analysed antibiotic use in the context of the WHO AWaRe criteria.  

We demonstrated that a significant proportion of children with suspicion of infection in European Emergency Departments (EDs) receive systemic antibiotics including substantial use of Watch antibiotics. Many patients with viral illness, who are unlikely to benefit from antibiotics, receive empiric antibiotics at presentation to the ED. The proportion of patients with febrile episodes receiving Watch antibiotics was higher in the ‘viral’ group compared to the ‘bacterial’ group. 

Our data demonstrate that diagnostic uncertainty contributes to inappropriate antibiotic use for viral infections. While in the majority of cases, the presumed aetiology was correct and treated appropriately, when bacterial or viral aetiologies were not clearly identified, >50% of patients with febrile episodes from the ‘viral’ group received empiric antibiotics. 

Relationship between molecular pathogen detection and clinical disease in febrile children across Europe: a multicentre, prospective observational study 

Fever is amongst the most common conditions for which children attend medical care.   Management of febrile children is focused on identifying the small number of children with severe and potentially life- threatening bacterial infections, amongst the greater number of children with self-resolving viral infections. Our study evaluated the diagnostic process for febrile children, utilising current best practice at each institution, supplemented by centralised molecular testing for bacterial and viral pathogens in blood and mucosal surfaces. 

After studying 5,952 febrile children, a definite diagnosis of either bacterial infection or viral infection was only established in 14% and 10% of the cohort respectively. The remaining 76% of patients could not be assigned as having either bacterial or viral infection.  After application of both centralised molecular pathogen detection methods and best practice at local hospitals, viruses were detected in a high proportion of patients with confirmed bacterial infection as well as in those with features of viral infection. 

Our study suggests that diagnosis and management of febrile children based on pathogen detection is not successful in many cases, as identification of a virus in samples from a febrile patient offers little reassurance that they do not have a bacterial infection.  Our study reinforces the need for an alternative approach. PERFORM is developing diagnostic approaches based on the host response, using host blood protein and RNA expression to diagnose infection. 

A multi-platform approach to identify a blood-based host protein signature for distinguishing between bacterial and viral infections in febrile children (PERFORM): a multi-cohort machine learning study.

We have shown that host protein biomarkers have clear potential to further improve the diagnosis of bacterial and viral infections in children with fever.

This study is the first to mine high-dimensional host proteomic data, obtained by measuring proteins in the blood of children recruited in the PERFORM study, from a range of countries and health-care settings.

We describe and validate a six-protein signature which could be developed into a rapid point-of-care diagnostic test with high accuracy, using blood as a specimen, which in comparison to specimens that need to be obtained from the actual sites of infection, is easy-to-access.

We have also contributed three high-quality, high-dimensional proteomic datasets that are publicly available for reuse by the research community.

Characterisation of the blood RNA host response underpinning severity in COVID-19 patients

The severity of COVID-19 disease can vary between patients, ranging from asymptomatic infection to life-threatening disease.

In this study, we used RNA sequencing to examine the genes switched on or off in the blood of adult patients with varying degrees of COVID-19 severity, who were recruited through the GEN-COVID study group.

By performing comparator analysis while accounting for known epidemiological factors that influence severity (i.e. age, sex), we showed that increasing COVID-19 severity was characterised by more inflammation with the involvement of specific cell types (neutrophils and macrophages).

We identified many genes and biological pathways that are associated with differing COVID-19 severity, amongst which there could be potential novel targets for immunomodulatory therapies for preventing severe COVID-19. It is worth noting that this study started early into the COVID-19 pandemic relying on recruitment, laboratory and data analysis pathways established as part of our PERFORM study.

“A simple blood test which may be able to rapidly diagnose the cause of a child’s illness could be ‘transformative’, say researchers.” Imperial College News, The Guardian, BBC.