Title: The Role of Immunosuppression in an antibiotic Stewardship intervention and its association with Clinical outcomes and antibiotic use: RISC-sepsis
Funder: Medical Research Council

Abstract: Sepsis is a life threatening condition due to infection in which the immune system has an abnormally over-active and under-active response (immunosuppression). Patients who have pronounced immunosuppression have a higher risk of getting further infections while in hospital, have a longer stay in hospital and even have a higher rate of death._x000D_ _x000D_ Patients with sepsis require treatment with antibiotics and the length of antibiotic course is often fixed. A trial (called ADAPT-sepsis) is currently underway to see whether two markers that can be measured in blood or ‘biomarkers’ (called procalcitonin (PCT) and c-reactive protein (CRP)), can reduce antibiotic use in patients with sepsis. The biomarkers will be measured daily while the patient receives antibiotics (approximately 1 week). These biomarkers are generally high at the start of the illness and when they fall to a certain level, the clinician will be advised to stop antibiotics. Patients will be allocated at random to one of three interventions – PCT-guided antibiotic use, CRP-guided antibiotic use or usual care. The purpose is to see if using these biomarkers will reduce antibiotic use._x000D_ _x000D_ This study will be a sub-study within this trial. The study will identify patients with immunosuppression and answer the question:_x000D_ _x000D_ Does immunosuppression make biomarker-guided antibiotic use (the ADAPT-sepsis intervention) ineffective?_x000D_ _x000D_ The primary objective is to determine whether patients with immunosuppression have more antibiotics, more hospital-acquired infections and a longer stay in intensive care and hospital, than patients without immunosuppression._x000D_ _x000D_ Identification of patients, consent, randomisation and collection of clinical data will all occur as per the trial. This sub-study will involve taking additional blood samples on 4 days, when blood will be collected for the trial anyway._x000D_ _x000D_ Immunosuppression is determined by measuring cell markers on different types of white blood cells. These markers reflect certain cell functions and if these levels are abnormal (high or low), then the cell function is impaired. Importantly these abnormal levels are linked to poor clinical outcomes. These cell markers will be measured by a method called flow cytometry._x000D_ _x000D_ The levels of cellular markers will then be analysed with the trial outcomes (antibiotic duration in the biomarker-guided antibiotic use period, antibiotic use at 28-days, length of intensive care and hospital stay and hospital-acquired infection)._x000D_ _x000D_ The project will influence patient care in two ways. Firstly, if we can show that the PCT/CRP intervention does not work in patients with immunosuppression, this could lead to developing a ‘precision-medicine’ strategy. These markers of immunosuppression could be used to identify patients without immunosuppression (low risk patients) who would benefit from biomarker-guided antibiotic use._x000D_ Secondly, if it shows that as PCT and CRP levels fall, patients also recover from immunosuppression, it would give clinicians greater confidence in this biomarker approach. This would lead to shorter courses of antibiotics which could reduce antibiotic resistance, NHS costs and could improve other clinical outcomes.

Lay abstract: Background_x000D_ _x000D_ Sepsis is a syndrome of dysregulated pro-inflammatory and anti-inflammatory responses to infection. ADAPT-sepsis is a multi-centre, randomised controlled trial (RCT) that aims to determine whether a procalcitonin (PCT) and C-reactive protein (CRP)-guided approach to antibiotic prescribing will reduce antibiotic use at 28-days while maintaining equivalent 28-day mortality. Established cellular markers of leucocyte function indicate sepsis-induced immunosuppression and are associated with adverse clinical outcomes._x000D_ _x000D_ Research question_x000D_ _x000D_ Does sepsis-induced immunosuppression render the biomarker-guided antibiotic discontinuation intervention ineffective?_x000D_ _x000D_ Hypothesis_x000D_ _x000D_ Sepsis induced-immunosuppression will be associated with longer duration of antibiotics, due to persistently raised PCT and CRP, and be associated with more hospital-acquired infections and thereby further increase antibiotic use at 28 days (ADAPT-sepsis primary outcome)._x000D_ _x000D_ Aim and objectives_x000D_ _x000D_ Aim:_x000D_ To determine whether patients with sepsis-induced immunosuppression have more antibiotics and different trial outcomes in ADAPT-sepsis._x000D_ _x000D_ Primary objective:_x000D_ Determine differences in duration of antibiotics during the ADAPT-sepsis biomarker-guided antibiotic phase, antibiotic use at 28-days, hospital-acquired infection, and length of ICU and hospital stay between patients with sepsis-induced immunosuppression and patients without._x000D_ _x000D_ Secondary objective:_x000D_ Monitor cell surface markers of leucocyte function during the time-course of the ADAPT-sepsis biomarker-guided antibiotic phase._x000D_ _x000D_ Methods_x000D_ _x000D_ This study will include 180 sequential patients from a sub-set of sites participating in ADAPT-sepsis. During the trial intervention period (when blood is sampled daily), additional samples will be taken. Samples will be transferred to Newcastle University for measurement of cell surface markers by fluorescence-based flow cytometry. Markers will include monocyte HLA-DR, neutrophil CD88, programmed cell death 1 (PD1), and the percentage of regulatory T cells. Patients will be dichotomised by presence or absence of sepsis-induced immunosuppression. Differences in antibiotic use and trial outcomes between these groups will be determined._x000D_ _x000D_ Impact_x000D_ _x000D_ If this study demonstrates that the biomarker-guided antibiotic use intervention is ineffective on patients with sepsis-induced immunosuppression, this could lead to developing a precision-medicine approach to antibiotic stewardship. Patients without sepsis-induced immunosuppression could be identified by near-patient testing and the biomarker-guided antibiotic intervention can be focused in these patients._x000D_ Demonstrating that cellular markers of immune function normalise in tandem with PCT and CRP will reinforce the biomarker recommendations for clinical practice and improve uptake of the intervention, resulting in reduced antibiotic usage in ICU.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM