Award Title: Improving health care burden amongst sepsis survivors by reducing infection-related rehospitalisation
Funder: Department of Health and Social Care

Abstract: Background Sepsis is defined as life-threatening organ dysfunction caused by dysregulated host responses to infection. The incidence of critical care (ICU) treated sepsis is increasing while improvements in management have reduced mortality. Every year generates an estimated 60/100,000 population new sepsis survivors in England, who are at risk for impaired health status, hospital readmission, and increased risk of dying in the year following sepsis.Approximately 30% of sepsis survivors have unplanned rehospitalisation within 30 days that increases to 65% by one-year, with two-thirds being infection-related. My PhD studies revealed acute loss of memory lymphocytes in septic patients alongside other features of immunosuppression. Concept These studies explore impaired immune competence as a biological mechanism underpinning infection-related rehospitalisation in sepsis survivors. To the best of my knowledge, this will be the first pilot randomised controlled trial (RCT) that focuses on how the immune system recovers following hospital discharge and uses vaccination as a controlled antigen challenge to augment immune system recovery in sepsis survivors. Aims Aim 1: Investigate the epidemiology of infection-related rehospitalisation to identify predictors, risk factors, pathogens and timing in sepsis survivors A pilot RCT of pneumococcal vaccine in sepsis survivors addresses the aims 2, 3 and 4. Aim 2: ascertains how the innate and adaptive immune systems recover over time in sepsis survivors Aim 3: tests the biological effect of pneumococcal vaccine in sepsis survivors Aim 4: Identify factors that could guide the design of an effective vaccination strategy and inform key outcomes to a necessary degree of precision for designing future definitive RCT in sepsis survivors (feasibility). Plan of investigation Aim 1 will be addressed by retrospective cohort studies using data from the Intensive Care National Audit & Research Centre Case Mix Programme Database linked to the Health & Social Care Information Centre Database. After identifying septic patients who survive their hospitalization and patients who have a subsequent infection related rehospitalisation, I will describe the incidence and timing of infection related re-hospitalization and insure that these are distinguishable from other causes of rehospitalisation. Using sensitivity analyses and matched control populations, I will explore the causal role of sepsis in infection related rehospitalisation. The NIHR Health Informatics Collaborative Critical Care (NHIC) Theme databases will be used to describe pathogens in infection-related rehospitalisation in sepsis survivors. At the completion of aim 1, I will understand the factors that identify sepsis survivors who are at high risk of developing infection and likely to survive one-year, which will form the target population for testing vaccination effects. Aims 2, 3 and 4 are addressed using the double blind and placebo-controlled pilot RCT of pneumococcal vaccine. The sample size to help refine the end points to necessary degree of precision for informing definitive efficacy trial will be used. Both groups will undergo regular blood sampling during one-year follow-up period to assess how vaccination alters leukocyte subsets and their function. Detailed immunological profiling of the placebo group will address Aim 2. Comparisons of immune characteristics between the vaccinated and placebo group answers whether vaccination improves the immune recovery seen in sepsis survivors, which addresses Aim 3. As pilot RCT, implementation issues, potential barriers, event rates, and population averaged treatment effects will be explored, which addresses Aim 4. Potential Patient and NHS benefits If vaccine related memory loss is persistent in sepsis survivors, this will require devising vaccination schedules in these patients. If vaccination reduces infection-related rehospitalisation in sepsis survivors, this could translate into reduced antibiotic use, and better life expectancy. Vaccination is a low-risk and low-cost intervention.

Lay Abstract: Background Sepsis is a life-threatening dysfunction of the body organs triggered by an infection. This common condition accounts for ~25% of adult intensive care unit (ICU) admissions, with mortality rates of 30-40%. In 2012 sepsis affected approximately 85 cases per 100,000 population in the UK, and this incidence is increasing. Many sepsis survivors have an impaired quality of life and 1-in-6 do not survive one year after their hospital discharge. Sepsis survivors are at much higher risk of infection-related rehospitalisation. Exact reasons are unclear. I recently found that loss of specialized white blood cells responsible for immune memory against common bacteria is commonplace during sepsis. This defect is likely to weaken the body's defences and thus predispose the individual to repeated bouts of infection. Long-term persistence of this defect, persistence of acutely impairment seen in the immune system during sepsis alongside changes in bacterial flora following hospitalisation are potential reasons underlying infection-related rehospitalisation in sepsis survivors. Infection-related rehospitalisations in sepsis survivors create a vicious cycle of deteriorating health and increased health care costs. This project will test a safe, low-cost, and feasible intervention to break this cycle by augmenting recovery of the damaged immune system in sepsis survivors to prevent infection-related rehospitalisations. These studies are designed to understand the salient features of infection-related rehospitalisations and immune system recovery in the year following hospital discharge in sepsis survivors. My project tests two hypotheses. First, that a subgroup of sepsis survivors at particularly high risk for Infection-related rehospitalisations can be identified using routinely collected clinical variables. Second, that vaccination augments recovery of the damaged immune system in sepsis survivors. Aims Aim 1: Investigate the epidemiology of infection-related rehospitalisation to identify predictors, risk factors, pathogens and timing The aims 2, 3 and 4 are addressed by pilot randomised controlled trial (RCT) of pneumococcal vaccine in sepsis survivors. Aim 2: Ascertain how the innate and adaptive immune systems in sepsis survivors recover over time using placebo group samples Aim 3: Test the biological effect of pneumococcal vaccine in sepsis survivors using vaccine group samples Aim 4: Identify factors that could guide the design of an effective vaccination strategy and inform key outcomes to a necessary degree of precision for designing future definitive RCT in sepsis survivors. Design and methods used First aim is addressed by linking the Health and Social Care Information Centre (HSCIC) database to two data sources using admissions between 2009 and 2016: Records from the Intensive Care National Audit and Research Centre database and the NIHR Health Informatics Collaborative Critical Care Theme database. The epidemiology of rehospitalisation episodes including its incidence, timing, and risk factors amongst sepsis survivors will be studied. Common bacteria responsible for infection-related rehospitalisation will also be identified. Comparing characteristics of sepsis survivors to non-sepsis survivors would identify true magnitude of risk for infection-related rehospitalisation due to sepsis. The target population for the pilot RCT will be informed by this study. To the best of my knowledge, this will be the first pilot RCT that focuses on understanding how the immune system recovers in sepsis survivors and whether vaccination helps with recovery. This will inform whether vaccination could be used to reduce infection-related rehospitalisation in a future definitive trial. The intervention arm of the RCT will receive pneumococcal vaccine and there will be a blinded placebo arm. Both groups will undergo regular blood sampling and detailed assessment of immune system changes during one-year follow-up period. Immune changes in the placebo arm will address Aim 2. Comparing immune changes between the vaccinated and placebo arm will inform whether vaccination improves immune function in sepsis survivors (Aim 3). Feasibility and other outcome data will inform future study design (Aim 4). Patient and Public involvement Sepsis survivors have already been involved in discussions in preparation for this grant. I plan to include patients and their carers as members of the project advisory group to inform the trial protocol, help with preparation of patient information leaflets, and consent forms. Dissemination The findings will be disseminated to the public, health care professionals and scientists by publishing in peer-reviewed journals and professional organisation websites (such as ICNARC and the Intensive Care Society), and by discussion with patient support groups (e.g. at UK Sepsis Trust meetings).

Research Activity Codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health Categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM