Title: The clinical and cost-effectiveness of contemporary diagnostics for patients with suspected Hospital-Acquired Pneumonia (HAP).
Funder: Department of Health and Social Care

Abstract: Background Hospital-Acquired Pneumonia (HAP) is common, frequently fatal and there is sparse evidence to support its management. Recent guidelines have called for studies focussed on diagnostics. There are problems diagnosing the condition; HAP diagnosis relies on a chest x-ray but misinterpretation leads to over-diagnosis. There are also problems diagnosing the cause of HAP; sputum culture takes too long to meaningfully impact upon antibiotic decisions. Together, these diagnostic inadequacies lead to poor clinical outcomes and over use of extended-spectrum antibiotics. CT scans are more accurate than chest x-rays at diagnosing pneumonia but there are no studies to demonstrate impact on outcome in HAP. The close to patient test, 'FILMARRAY Pneumonia Panel' (FAPP) can identify 28 pneumonia pathogens from a respiratory sample in 75 minutes - but clinical and cost-effectiveness in an NHS setting has not been evaluated. Research question What is the best design for a multi-centre trial to demonstrate the effectiveness of low-dose, thoracic CT scans and the FAPP in patients with suspected HAP? Methods The Fellowship will comprise three phases. In phase one; I will start a clinical trials MSc, qualitative and health economics training and foster industry collaboration by visiting BIOFIRE in Salt Lake City. I will conduct patient and public involvement (PPI) and staff workshops to discuss the feasibility study then work with Liverpool Clinical Trials Centre to finalise the protocol, obtain approvals and set sites up. In phase two, I will conduct a two centre Liverpool / Watford), randomised, factorial, feasibility trial of FAPP and/or CT scans vs standard care for patients with suspected HAP with 12 months of recruitment and 3 months of follow-up. The study will benefit from my current work to incorporate FAPP results into our HAP treatment guidelines. I will conduct an embedded qualitative study to provide 'in practice' evidence of patients' experiences of participating in the study and staff experiences of following the protocol. I will embed a resource and costing analysis of HAP to inform a cost-effectiveness analysis for a definitive trial. I will co-supervise a PhD student who will investigate longitudinal and topographical changes in respiratory tract pathogens in HAP. In phase three, I will spend 3 months analysing quantitative and qualitative data to determine if a definitive trial is feasible. I will then spend 6 months on dissemination and development of the protocol amongst a network of hospitals interested in recruiting to a definitive trial. I will consult with patients and staff across the network to ensure the design works. I will link network trusts to our Advancing Quality Alliance (AQuA) HAP programme in order to incorporate hospital episode statistics into the analysis plan for the definitive trial. At the end of phase three, I will spend 3 months writing papers and submitting an expression of interest to HTA for a multi-centre trial. Impact This Fellowship will produce a patient-centric design for a definitive HAP diagnostic trial by demonstrating feasibility and incorporating knowledge from qualitative work and PPI and equip me to become a research leader in HAP.

Lay abstract: Hospital-Acquired Pneumonia (HAP) refers to a type of severe lung infection that develops while a patient is in hospital or has been recently discharged. My aim is to design a clinical trial to see if modern diagnostic investigations can safely reduce unnecessary antibiotic use in patients suspected of HAP. Currently, doctors use chest x-rays to make the diagnosis, but these are difficult to interpret and a third of patients suspected of HAP receive antibiotics when they have an alternative diagnosis. Patients tell us they are worried about misdiagnosis and a solution might be to replace the chest x-ray with a CT scan since these show the lungs in more detail. Once a diagnosis of HAP is made, doctors would like to identify the bacteria responsible before starting treatment, so we can choose the right antibiotic. However, current tests are too slow to determine the initial treatment, so guidelines suggest we cover a range of possible bacteria by using at least two powerful antibiotics. Patients tell us they are concerned, because these antibiotics increase the risk of potentially fatal side effects and promote antibiotic resistance. The BIOFIRE FILMARRAY pneumonia panel (FAPP) is a new test that can identify the cause of HAP very quickly. If we can work out the best way to use the FAPP, we can give antibiotics more effectively and slow the development of antimicrobial resistance. I will conduct a feasibility study to design a definitive trial to discover whether using CT scans or the FAPP, or both together, helps improve antibiotic use and patient recovery whilst being cost effective. Using a random process, we will divide patients suspected of having HAP into four groups:- Group 1 will have the standard chest x-ray and follow standard guidelines. Group 2 will have sputum tested by the FAPP enabling doctors to use a new section of the treatment guideline based on FAPP results. Group 3 will not have the FAPP test but will replace the standard chest x-ray with a CT scan. Group 4 will have both the CT scan and use the FAPP test. This study will enable us to compare antibiotic use and recovery time in the patients who received 'usual' care with those who had one or both of the new tests. Our preliminary work shows HAP is more likely to develop in patients who are poor, elderly, and have dementia and finding the best way to explain the study to patients and families will be crucial. Before we seek NHS ethical approval, we will work with patients and carers to prepare clear explanations of the study and explain why no one will be disadvantaged. We have shown HAP develops on all wards and many people will have a stake in how these studies might run. Therefore, before we start the feasibility study, we will ask patients and hospital teams their opinions about how our study design could be more effective. Then, during the study, we will interview patients and staff about how it is working in real life so that we can further refine the design. During the feasibility study, we will list the costs associated with HAP so we can design a process for measuring the effect of CT scans and FAPP on costs in the definitive trial. This feasibility study will tell us if a full trial is possible and how big it needs to be. We will explain any full trial design to interested hospitals so their patients and staff can help refine the design to suit their circumstances. At the end of the Fellowship, we will seek funding for the definitive study.

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