Despite the use of high resolution CT scanning, the diagnosis of IFD is problematic as infection often presents with non-specific clinical and radiological signs/symptoms. As a result, diagnosis is frequently delayed and associated with high mortality rates (40-100%). Consequently, empirical use of antifungal agents in these patients is commonplace and results in many patients without IFD receiving unnecessary anti-fungal therapy. Furthermore, as definitive (microbiological) evidence of IFD is rarely obtained, the decision to discontinue therapy is often difficult. Audits in haemato-oncology units in the UK have shown an incidence rate of proven IFD of 6.5%, while over 50% of patients are treated with antifungals during febrile neutropenia episodes. In one review of the effectiveness of a UK antifungal stewardship programme, 82% of empirical therapy was deemed unnecessary.
The overuse of antifungal drugs has serious consequences for the individual patient and for the wider NHS in terms of toxicity, drug interactions, cost and the promotion of resistance. The NHS England antifungal budget is ~£150M and increasing year-on-year, with the majority spent in haemato-oncology units (£87M). Globally, antifungal resistance is spreading rapidly, including the emergence of new, multi-drug resistant fungal pathogens associated with increased mortality. Reports of increasing azole-resistant infections caused by Aspergillus fumigatus – the commonest cause of invasive aspergillosis in the UK – and rapid spread of the MDR organism, Candida auris, are of significant clinical concern.
In recent years the development of assays for detection of fungal DNA (Aspergillus PCR) and cell wall antigens (galactomannan and β-D-glucan) has facilitated the early, rapid diagnosis of IFD. These fungal biomarker all have very high negative predictive values (NPV) allowing the exclusion of IFD. By combining these assays, performance is further enhanced. A meta-analysis of combined Aspergillus PCR/GM for the screening of blood from high-risk haematology patients generated sensitivity of 99% and a NPV of >99%. Conversely, when both tests were positive, specificity (98%)/positive predictive value (88%) were good indicators of disease. NHS England and the Scottish Antimicrobial Prescribing Group have identified antifungal stewardship in haemato-oncology patients as a priority and the Public Health England ESPAUR group has recently commented on the lack of both antifungal stewardship and the availability of rapid fungal diagnostics in NHS Trusts.
The NIHR-HTA has requested study proposals to improve antifungal stewardship in haemato-oncology patients using rapid tests for fungal infection. In response, Dr Samir Agrawal, Consultant in Stem Cell Transplantation at Barts and I, along with more than 20 UK-wide colleagues in haematology, microbiology, ID, paediatrics, mycology reference laboratories, the Warwick CTU and patient representatives have developed the I-SAVE Study. We are proposing a multi-centre randomised controlled trial to determine the safety (mortality), efficacy (reduced antifungal therapy), cost-effectiveness of and compliance with a diagnostic-guided management strategy using galactomannan (GM), PCR for Aspergillus (A-PCR), (1,3)-beta-d-glucan (BDG) and lateral flow assays for Aspergillus in adult and paediatric haemato-oncology patients at high-risk of IFD. The two arms are (a) standard-of-care (SoC) at each centre; (b) biomarker-guided antifungal management. Biomarker testing will be done in real-time using centralised laboratories with extensive experience in performing these assays. The NIHR has requested a full application from the I-SAVE Study group.
The British Society of Blood and Barrow Transplantation, including the paediatric subgroup, has sent a Feasibility Survey to all transplant centres in the UK.
Documents to download
If any BSAC members are interested we would encourage them to complete the feasibility study and return, or address any questions to:
Dr Samir Agrawal, Barts Health NHS Trust, Samir.email@example.com
Dr Varun MEHRA, King’s College Hospital, Varun.firstname.lastname@example.org
Prof Adilia Warris, MRC Centre for Medical Mycology, A.email@example.com
Prof Brian Jones, Institute of Infection, Immunity and Inflammation, University of Glasgow, firstname.lastname@example.org