Title: Impact of Clostridium difficile on clinical outcomes in hospitalised infants with diarrhoea (CD-COT)
Funder: Health Education England

Abstract: Impact of Clostridium difficile on clinical outcomes in hospitalised infants with diarrhoea (CD-COT) Background: Clostridium difficile is the leading infectious case of antibiotic-associated diarrhoea, and a significant cause of morbidity and mortality. It causes a spectrum of disease from mild, self-limiting diarrhoea to life-threatening pseudomembranous colitis as a result of the action of C. difficile toxin action. Management of CDI requires substantial medical and nursing input, costly infection control measures and is a considerable burden on healthcare resources. While CDI is well-described in adults, the picture is less clear in children, and infants (C. difficile toxin in diarrhoea has not been established. Due to the lack of robust evidence, current guidelines do not recommend testing of infants. This leaves healthcare professionals with little guidance on when to test for CDI, interpretation of results or management of C. difficile toxin positive participants, potentially leading to sub-optimal management of this group. Aims: Determine how and when C. difficile toxin is tested for in infants, and how results are used; Clarify the role of C. difficile in infants by prospectively determining if the clinical outcomes of infants with C. difficile toxin in their stools are worse than those who are toxin negative; Determine what risk factors influence toxin positivity to create a stronger case definition for testing in infants; Characterise C. difficile strains involved in colonisation or infection of infants.Methods: Current UK practices around diagnosing and managing infants with CDI will be determined using an on-line survey of UK NHS consultant microbiologists and paediatricians with descriptive statistical analysis. A multi-centre, non-interventional study will determine any differences in clinical outcome in infants with all-cause diarrhoea who are positive for C. difficile toxin versus those who are negative. Samples will be tested for C. difficile (glutamate dehydrogenase assay, PCR for C. difficile toxin genes), C. difficile toxin and other gastrointestinal pathogens (Biofire). C. difficile isolates will be characterised by PCR ribotyping, Whole Genome Sequencing and antimicrobial susceptibility testing.Primary outcomes (time to resolution of diarrhoea) and secondary outcomes (mortality, length of hospital stay) will be subject to univariate analyses. Multivariate analyses of 30 day mortality, need for rehydration therapy, colectomy and morbidity (laboratory markers). Risk ratio analyses will determine risk factors associated within toxin positivity and poorer outcomes in a case-control study. Delivery: Recruitment will take place over 2 years, followed by 6 months for laboratory analyses and a further 6 months for full results analyses. Impact and Dissemination. We anticipate that the results of this study would influence local policy, and national and international guidance on CDI in infants, and form a baseline for future infant CDI management studies. Results will be disseminated on ClinicalTrials.gov; via the Paediatric C. difficile network (established as part of the clinical Lectureship); industry partner updates; through the Leeds NIHR Medtech in vitro diagnostic co-operative; at national and international conferences and in peer-reviewed publications.

Lay abstract: Clostridium difficile is a bacterium that causes diarrhoea, particularly in elderly hospitalised patients on antibiotics. It is a very unpleasant condition that can be very debilitating and require nursing and medical support, which is costly to the NHS as well as difficult for the patient. Sometimes the disease is fairly mild and resolves but sometimes it can be more serious, and even fatal. Normally, the millions of bacteria in our guts prevent disease-causing bacteria like C. difficile, from causing a problem. However, antibiotics that we may take for an infection elsewhere (eg chest infection) can damage these defences, allowing C. difficile to move in, grow and produce toxins (poisons) that affect the gut lining, resulting in diarrhoea. Hospitals diagnose C. difficile infection (CDI) by detecting the toxin in faeces (poo). It is important to detect the toxin, rather than the bacteria because it can be present without producing toxin or causing symptoms. We know a lot about how and why C. difficile causes disease in adults, but relatively little about what role it plays in children, particularly infants (children under 1 year old). Although many infants may carry the bacteria in their guts, there is no clear understanding of what the presence of C. difficile toxin in infant diarrhoeal faeces means. Because of this lack of clarity, current UK guidelines discourage testing in infants and this means that doctors and nurses do not have any rules to guide them on when they should test for C. difficile toxin in these patients.In order to find out what doctors are doing at the moment with regard to these patients in the absence of guidance, I will send a survey out to all doctors involved in diagnosing the causes of diarrhoea in children . The survey will ask doctors when and how they test infants for C. difficile toxin; what they think the test results mean and how they use those results to care for the infant. This will tell us what is currently being done to diagnose and manage these patients.We will then do a study to determine what the presence of C. difficile toxin in infant diarrhoeal faeces means: does it contribute to the diarrhoea symptoms or play no role at all? We will look for C. difficile toxin in all infant diarrhoeal faeces sent to the routine diagnostic laboratory. We will compare how quickly diarrhoea gets better in infants WITH toxin compared to those WITHOUT toxin in their faeces. This will help us to build a much clearer picture of the importance of C. difficile toxin in infants with diarrhoea.We will also look at other measures of wellness (results of blood tests will also be used to see whether infants with toxin progress less well. We will examine patient notes to see if there are factors (eg an underlying condition such as cancer, being on other treatments, breast or bottle feeding) that may be linked to infants having toxin in their diarrhoeal faeces and those who do not get better as quickly. This will help us to know which infants should be tested for C. difficile toxin. Lastly, we will examine the C. difficile bacteria we recover with DNA fingerprinting and antibiotic susceptibility testing. This will tell us what types of C. difficile are present in infants, and their resistance to certain important antibiotics. I will communicate the results of the study to health professionals at conferences and through publishing in journals, and through the Paediatric C. difficile Network of health professionals, patients/carers and the public that I will establish during the course of the lectureship.

Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFECTION;ORAL AND GASTROINTESTINAL