Joy Allen, William Jones, Michael Power, Stephen Rice, Greg Mantiapolous, Mark Wilcox, and Ashley Price

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1 What is the potential for point of care diagnostics to improve testing protocols for C. difficile infection, with particular reference to the English NHS? Joy Allen, William Jones, Michael Power, Stephen Rice, Greg Mantiapolous, Mark Wilcox, and Ashley Price NIHR 23 rd April 2018

2 Overview Clinical background Clinical problem Current diagnostic testing and recommendations for testing Understanding the value of point of care testing for Clostridium difficile Research questions Study methodology Preliminary findings Implications for further research Summary and conclusions

3 The NIHR MICs Leading NHS organisations have been awarded funding to host NIHR MICs. Over 14 million has been awarded across 11 NIHR MICs. NIHR Medtech and In vitro diagnostics Co-operatives (MICs) build expertise and capacity in the NHS to develop new medical technologies and provide evidence on commercially-supplied in vitro diagnostic (IVD) tests. Ncl MIC is a partnership between: NuTH Newcastle University Facilitates evidence on: - Clinical validity - Clinical utility - Value for money - Affordability of in vitro diagnostic medical devices (IVDs) and diagnostic medical technologies

4 Clostridium difficile infection Clostridium difficile (C. diff) is an anaerobic, gram-positive, spore-forming bacterium that can be found in people s intestines. C. diff is recognized as the main cause of infectious diarrhoea that develops in patients after hospitalisation and antibiotic treatment 7, (2009)

5 The clinical problem Clostridium difficile infection (CDI) is one of the most common healthcareassociated infections worldwide Can cause complications leading to longer stays in hospital, increased morbidity, mortality and excess cost to the healthcare provider Clinical features of CDI are indistinguishable from those of other gastrointestinal infections There is no single test with sufficient accuracy for detecting toxigenic CDI

6 Tests used to diagnose C. diff Class of test Target for test Considerations for use Glutamate dehydrogenase (GDH) enzyme immunoassays (EIA) GDH present in both toxin producing and nonproducing C. diff High sensitivity, low specificity Can be used to rule out CDI. Cannot be used alone to diagnose CDI.

7 Tests used to diagnose C. diff Class of test Target for test Considerations for use Glutamate dehydrogenase (GDH) enzyme immunoassays (EIA) Molecular tests (NAAT or PCR) GDH present in both toxin producing and nonproducing C. diff Toxin gene test - detect the presence of C. diff and the genes that produce the toxins. High sensitivity, low specificity Can be used to rule out CDI. Cannot be used alone to diagnose CDI. Rapid and very sensitive Do not distinguish between infection and colonisation.

8 Tests used to diagnose C. diff Class of test Target for test Considerations for use Glutamate dehydrogenase (GDH) enzyme immunoassays (EIA) Molecular tests (NAAT or PCR) GDH present in both toxin producing and nonproducing C. diff Toxin gene test - detect the presence of C. diff and the genes that produce the toxins. High sensitivity, low specificity Can be used to rule out CDI. Cannot be used alone to diagnose CDI. Rapid and very sensitive Do not distinguish between infection and colonisation. Toxin enzyme immunoassays (EIA) Toxin - directly detect A and B toxins in the stool sample. Relatively rapid. Low sensitivity Cannot be used alone to diagnose CDI.

9 Validation of tests for C. diff Lancet Infect Dis 2013; 13: Prospective, multi centre study, 4 UK laboratories N = 12,420 faecal samples for comparative testing, N = 6522 in patient episodes with clinical data available. Validation of reference tests for C. diff Develop optimum diagnostic algorithm

10 Comparing tests for CDI Comparing the accuracies of tests for CDI is challenging because a variety of operational definitions of CDI have been used. A fair comparison of tests requires that they use the same reference standard i.e. the same (operational) definition of CDI.

the type of sample; the types of tests that should be used; and what

11 Two-step algorithm for accuracy and efficiency To optimise accuracy of the algorithm, the guidance also outlines who should be tested and the type of sample; the types of tests that should be used; and what healthcare providers should do, depending on the outcome of the tests.

12 C. diff testing in UK NHS Majority of tests for C. diff are performed by the laboratory Potential for two main time to result delays: Transport of samples to the lab Batch testing within the lab Infect Dis Ther Dec; 3(2): Audit of data from a large tertiary hospital (2015/2016) Transit and testing times for C. difficile Average (hrs) Trust specimen transit time 14:38 Laboratory turnaround time 03:52 Total time until result becomes available N = 3797 samples, N(tested) = :31 (Target <18hrs)

13 C. diff testing in UK NHS Majority of tests for C. diff are performed in the laboratory Potential for two main time to result delays: Transport of samples to the lab Batch testing within the lab Infect Dis Ther Dec; 3(2): Audit of data from a large tertiary hospital (2015/2016) Transit and testing times for C. difficile Average (hrs) Trust specimen transit time 14:38 Laboratory turnaround time 03:52 Total time until result becomes available N = 3797 samples, N(tested) = :31 (Target <18hrs)

14 The evidence gap What are the clinical and economic benefits of a point of care PCR test for the toxin B gene of C. difficile?

15 Research questions In which clinical settings (in the UK NHS) would a POCT for C. diff toxin B gene be most likely to be cost-effective? For which patient population would the POCT be most likely to provide benefits for patients and savings for the NHS? How would a rapid test for C. diff improve the patient diagnostic and care pathways? What evidence would regulators, policy makers, and guidance developers require for including a POCT for C. diff toxin B gene into testing protocols?

Methods Review national guidelines and audit data from a large tertiary hospital to understand the current environment Interview ~15 experts to elicit

16 Methods Review national guidelines and audit data from a large tertiary hospital to understand the current environment Interview ~15 experts to elicit their opinions on the clinical, laboratory, and public health issues Model the economics to identify the variables most likely to drive cost-effectiveness

17 Diagnosis and management of diarrhoea Best practice recommendation: Isolate Review clinical features and risk factors Decide: infective or noninfective cause Test and treat accordingly

18 Whose opinion? Experts: Clinical consultants: Microbiology, Infectious Diseases, Acute Medicine, Public Health, Healthcare Scientist: Infection Prevention and Control Laboratory: Enteric lead for Microbiology Nursing: Infection control What works, what doesn t?

19 Management of patients with diarrhoea in UK hospitals EXPERT OPINION Positive opinions Increased knowledge and education of importance of infection control Lab process for CDI testing much faster than in the past All diarrhoea stool samples are tested for CDI Negative opinions Not enough side rooms for isolation Competing reasons for isolation Delays in transporting sample to the lab Timely identification of non-infective cause Prevalence is v low so perhaps testing inappropriately [Preliminary results] Sample collection not always straightforward

Issues around isolation Single rooms are thought to reduce the risk of healthcare associated infections Medical Assessment Units (MAUs) and A&E departments in UK NHS have limited single room

20 Issues around isolation Single rooms are thought to reduce the risk of healthcare associated infections Medical Assessment Units (MAUs) and A&E departments in UK NHS have limited single room provision for patients. Competing reasons (infective/non-infective) for use of single rooms; triage necessary. If patient admitted to ward, lack of side room availability can mean patients unable to be admitted; other infection control measures can be put in place or they may remain in MAUs/A&E. However, single rooms becoming commonplace in newer hospitals in the UK (aim 50% by DoH).

21 Potential value for POC test for C. diff toxin B Opinions of ID consultants Rapid results may help to promptly exclude CDI, and potentially: Increase efficiency of use of isolation facilities and infection control resources Facilitate cohorting infective patients. Improve appropriateness of use of other diagnostic investigations Reduce lengths of stay in isolation and hospital Increased diagnostic certainty may allow prompt initiation of CDI treatment (in a small proportion of patients) Information for patients available with minimum delay [Preliminary results]

22 Potential value for POC test for C.diff toxin B Concerns of interviewees Removing symptomatic patients from single room isolation based solely on a test for the presence of the C. diff toxin B gene. - If laboratory based: throughput limitations (issue for large hospital laboratories) - If POC based: - infection control concerns - training required for staff, - usability, - storage, - connectivity, - staff acceptability - Over/under testing - Cost of testing [Preliminary results]

23 Settings and populations Settings where a rapid POCT for C. diff toxin B gene could add value: Admissions or medical assessment suite of large hospital Laboratory setting of small hospitals with lower throughput Patient populations that might benefit from the test: Those in which the test is cost-effective Use economic modelling to identify them Explore the utility of a clinical risk score

24 Conclusions preliminary - Department of Health recommends a two step algorithm for diagnosis and management of C. diff. - Requirement to isolate all patients with infectious diarrhoea conflicts with constraints on side room resources. - Delays in transporting samples to laboratories increase the time to actionable result may be common, but can be improved. - A POCT PCR test for C. diff has the potential to aid clinical decision making particularly for infection control. - A POCT for C. diff would be substantially more useful if it included other causes of infective diarrhoea. - Patients and clinicians do not like waiting for diagnostic test results.

25 Some quotes As with all things, nobody likes change... this is a new thing which has to be a bit more effort and a bit more training. That s not necessarily a barrier.it has to be overcome. What we ve found from the point of care is people like instant results. The nurses quite like this, they re their patients as well and they like to know what s going on with them. It s really useful because it reinforced the utility of doing it

Acknowledgements Interviewees The study team Provided funding for

Methodologist Dr Ashley Price, ID Consultant, Infection theme Lead NIHR

practice lead Professor Mark Wilcox Professor of Medical Microbiology,

Methodologist Mr Stephen Rice, Senior Health Economist Institute of

26 Acknowledgements Interviewees The study team Provided funding for investigator initiated study Mr Will Jones, IVD Evaluation Methodologist Dr Ashley Price, ID Consultant, Infection theme Lead NIHR Newcastle MIC Dr Michael Power, Deputy Director, Evidence based practice lead Professor Mark Wilcox Professor of Medical Microbiology, Uni of Leeds, NIHR Leeds MIC Dr Gregory Maniatopoulos, Senior Mixed Methodologist Mr Stephen Rice, Senior Health Economist Institute of Health and Society, Newcastle University Prof. Luke Vale, Health Foundation Chair in Health Economics

Stephen.Lynn@nuth.nhs.uk Website: www.newcastle.

27 Thank you Stephen Lynn (Industry Liaison lead) Website:

Clinical Microbiology, Cork University Hospital, Wilton, Cork, Ireland; 3 Dept. of Clinical

Clinical Microbiology, Cork University Hospital, Wilton, Cork, Ireland; 3 Dept. of Clinical A prospective, three-centre study to determine the efficacy of the EntericBio realtime C. difficile Assay (EBCD) for the detection of toxigenic C. difficile in stool samples. B. Lucey 1*, L. Blake 2, M.