Title: Can current C. difficile diagnostic assays be repurposed to predict recurrent CDI?
Funder: Health Education England

Abstract: Background: Clostridioides (previously Clostridium) difficile is a bacterium that causes debilitating diarrhoea via toxin production, with 12,275 primary cases/year in the UK (2018-19) and a mortality rate ~17%. Primary C. difficile infection (CDI) with the bacterium is preceded by disturbance to the normal gut bacteria, most commonly by antibiotics taken to treat an infection. CDI is also treated by antibiotics, potentially causing further damage to the normal gut bacteria. A patient with a primary case of CDI has ~25-30% chance of having a second case within 2-8 weeks, despite appropriate treatment; known as recurrence (rCDI), and each episode of recurrence increases the chance of another episode (fig 1.1). These escalating multiple recurrences cause patients to become debilitated and frail, with massive impacts on their quality-of-life, and increased risk of dying. While new treatments aimed at rCDI exist, they are expensive and deciding who to give these drugs to is difficult. There is now new information of a potential relationship between the amount of bacteria in the sample and if they may go on to have rCDI. However, most of this information has come from studies not robustly designed to answer this question. This study aims to determine if a diagnostic test, alone or in a clinical prediction model could predict rCDI, and collect the data required to design a future clinical trial using a new test to guide treatment and reduce rCDIMethods (Figs 1.2 and 1.3): I will recruit patients diagnosed with CDI and then re-test them 5-7 days later, to see if there are still high levels of bacteria/toxin present. All participants complete stool/ drug diaries over 12 weeks, whether in hospital or at home. If they develop symptoms of diarrhoea during follow up they will be asked to provide a stool sample to confirm rCDI. By comparing the result of the second tests in those who do/do not develop rCDI I will determine if we can predict rCDI. I will conduct interviews with healthcare professionals to determine how they currently interpret the complicated CDI laboratory reports, and how they might interpret/use laboratory reports which include a prediction of recurrence. To aid this I will develop an online pretend clinic and ask the clinicians to talk through their thought processes as they review and treat the patients. Delivery Recruitment:18 months; follow up;12 weeks (to capture rCDI): analysis:5 months. Interviews: year one/two. Impact and Dissemination (fig 1.4).Dissemination activities will be targeted and optimised to facilitate engagement with several groups and maximise impact, including; PPI, public engagement, feedback to clinical/academic/industrial colleagues, and a final educational event for all stakeholders.The outputs from this study have the potential to positively impact the lives of CDI patients, with a test that may help guide treatment options; PPI indicated that patients prefer to be informed about potential risks/treatment options. If a future interventional clinical trial, partnering the test with a treatment intervention, can reduce rCDI, this will have considerable benefits for the quality of life for CDI patients, and decrease healthcare costs.

Lay abstract: The bacterium C. diff makes a toxin, like a poison, that causes our gut lining to become leaky, so you get runny poo, which can be very serious; roughly 1-2 out of 10 people who get the infection die. The normal gut bacterial that we all have gives us some protection to this bacterium, but if we take drugs to treat an infection (antibiotics) like a chest infection, the gut bacteria can also be reduced in number. This leaves space for the C. diff bacterium to live and grow in our gut. Unfortunately, because we also use the same drugs to treat C.diff this can make the damage to the normal gut bacteria worse. Someone who has had C.diff has a 1 in 4 chance of having the infection again within 2-8 weeks; this is called recurrence. For someone that has recurrence once, they have 4 in 10 chance of having recurrence a second time and then they have a 2 in 3 chance of having recurrence a third time. These repeated infections can make people very poorly, unable to live their lives normally and means there is an increased chance of dying from the infection. There are some new treatments aimed at reducing the chance of someone getting recurrence but they are very expensive and it is difficult to know who to give these drugs to. All of the tests we use to tell if someone has an infection give a yes/no answer. There is now new information that there may be a relationship between the amount of bacteria in the sample and how sick the patient is, and possibly, if they will go on to have a recurrent infection. But, most of this information has come from analysis of old studies that were not designed to actually answer this question. This study will try to find out if tests we already use to find the first infection with C.diff can also be used to predict if someone will get recurrence. If we could predict recurrence, we would know who to give the new treatments to. I will recruit patients who have CDI and then test their poo again 5-7 days after their first poo sample was tested, to see if there are still high levels of bacteria/bacterial components present, even though they are on treatment. I will then monitor them for 12 weeks (by asking them to record toilet trips in a diary to see if they develop a recurrent infection). By comparing the result of those second tests in those who do and do not develop a recurrent C.diff infection I will find out if we can predict recurrent CDI. I will also ask healthcare professionals what they think about the complicated laboratory reports on C. diff test that we use at the moment. Later on in the study I will then ask how they might use laboratory reports which include information on if a person might get recurrence or not. To help me understand their thoughts I will ask them to tell me all of their thoughts as soon as they have them, not only what they think I would like to hear; this is called Think Aloud. I will also use an online pretend clinic to talk through how they understand and use the test results. The main aim of this project is to find a test that can predict recurrence and collect the data required to design a future clinical trial where a new test will be used to guide treatment and see if it reduces the number of people who get recurrence.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION