Title: Predicting Risk In Management of Infection in Orthopaedics (PRIMIO): developing risk-prediction model and a pre-operative strategy based on risk factors, to reduce recurrence of orthopaedic infection after treatment
Funder: Department of Health and Social Care

Abstract: Background Orthopaedic infection is potentially curable with elective surgery and antibiotic treatment, but recurs in around 1 in 5 patients. It affects more than 2200 new sufferers annually, and is rising in the UK, with an increase of 300% projected by 2030. It includes post-traumatic osteomyelitis, diabetic foot infection and prosthetic joint infection; it is the most common serious complication of orthopaedic surgery, and costs the NHS over 50 million per year to treat. Infection recurrence necessitates high-risk surgery or life-long antibiotic suppression, resulting in antibiotic resistance, side-effects and increasing costs. One in eight sufferers report a quality of life worse than death, and many experience chronic intractable pain. The recurrence of orthopaedic infection results from pathogens winning a 'race to the surface' of bone and implants against the immune system after surgery, so immunity and healing in the peri-operative period are crucial for cure. Smoking, hyperglycaemia, malnutrition, obesity and excessive alcohol consumption are frequently observed in patients with orthopaedic infection, and have a recognized effect on immunity and healing. However, the risk of infection recurrence attributable to these factors is not known. Pre-operative smoking cessation and glycaemic control interventions prevent surgical site infections, but interventions for other risk factors have not been studied. Additionally, many patients refused to engage with reported interventions, which were labour and resource intensive. A strategy selected specifically to support patients with orthopaedic infection enact pre-operative behaviour change is necessary to improve treatment outcomes. Aims Analysis of the risk of orthopaedic infection recurrence attributable to modifiable risk factors, in order to create and validate a risk prediction model for clinical use. Qualitative study of the barriers and facilitators to risk factor modification experienced by patients undergoing orthopaedic surgery for infection, to guide the selection of a pre-operative intervention. Methods A multi-centre prospective study of 600 patients treated for orthopaedic infection, involving participants in an existing randomised controlled trial, will examine the impact of modifiable risk factors on infection recurrence. Multivariable logistic regression modelling with discrimination analysis, internal and external validation will be used to construct a risk prediction model. Thematic analysis of semi-structured interviews with a diverse patient group, with reference to a validated theoretical framework, will guide the choice of a pre-operative intervention to support behaviour change. Population Adults receiving surgical treatment for orthopaedic infection: the pathogenesis and risk of recurrence after treatment is similar for different orthopaedic infections. Outcome Recurrence of orthopaedic infection will be ascertained by an independent endpoint committee blinded to treatment and possible risk factors. Ascertainment will include international criteria for diagnosis of orthopaedic infection. All-cause mortality will also be recorded. Clinical Application This study will benefit patients with orthopaedic infection by providing accurate, personalised pre-operative information to guide treatment decisions, and selecting a multi-faceted intervention to support behaviour change to reduce the risk of re-infection, thus reducing re-operation, antibiotic use, and rehabilitation costs. This may serve as a framework for pre-operative intervention in other settings. It will facilitate risk stratification for the testing of future treatments for orthopaedic infection.

Lay abstract: Bone and joint infection is difficult to cure Bone and joint infection is a significant issue, affecting more than 2200 new sufferers each year, and costing over 50,000,000 per year to treat in the UK alone. Infection returns in many adults even after intensive treatment with surgery and antibiotics, and ongoing infection is very painful; one in eight sufferers report a quality of life worse than death. People whose infection returns may need life-long antibiotics to suppress it, which can lead to antibiotic resistance, and many patients have severe side effects from long term antibiotic courses. Failed treatment may also mean more surgery, which has more than twice the risk of death of a joint replacement operation. More people could be cured The body's ability to heal and fight infection around the time of surgery is crucial. This is when bacteria can stick to bone and implants: once stuck, it is impossible to get rid of them without more surgery. Healing is known to be jeopardised by smoking, high blood sugar, being underweight or overweight, and alcohol use. Many people with bone or joint infection have at least one of these factors, but we don't know how much they affect whether infection comes back after treatment. Help with stopping smoking and controlling blood sugar before surgery is safe and prevents infections. However, many people refuse the support offered, and help for other risk factors before surgery has not been studied. We do not have a good understanding of what supports or prevents people with bone and joint infections from making changes before surgery. Support before surgery could help This study aims to find out how much the risk of bone and joint infection returning depends on factors a person may be able to change before surgery, and how to best support people to make these changes. This will allow us to select a strategy to support people before surgery, and to help patients by making accurate information available before treatment for bone and joint infection. Support before surgery could mean more people are cured of infection, especially those living in difficult circumstances. If it works for bone and joint infection, it may be useful for people having other surgery. Knowing the risk may also help plan tests of new treatments for bone and joint infection in people who need them most. How will the study be done? Patients having surgery for bone and joint infection will be asked about risk factors around the time of their operation, through an existing clinical trial. They will have checks up to 12 months after the operation through routine clinic visits or phone calls to see if their infection has come back. We will use a statistical model, that has been used before to make reliable risk predictions, to investigate how great the risk is from different factors. The model will be re-analysed to make sure that not too much risk is put down to the factors we measured, so it is more accurate. It will then be checked for another group of patients to make sure it works accurately. Another group of patients with bone and joint infection will be asked about what made it easy or difficult for them to control risk factors before surgery. Private interviews with these patients, who will be chosen to represent different experiences and views, will be recorded with permission. Information that may identify the patient will be removed. We will include patient representatives in analysing what supported or prevented people from making changes, and use this to plan a strategy together, to help people before surgery.

Research activity codes: 6.4 SURGERY;7.1 INDIVIDUAL CARE NEEDS
Health categories: INFECTION