Advice

The technology

The technology

The Fungitell assay (Associates of Cape Cod) is an in vitro diagnostic test for the qualitative detection of (1–3)‑beta‑D‑Glucan (BDG) in serum. BDG is a major cell-wall component of most pathogenic fungi and tiny quantities are released into circulation during infection. Detection of elevated levels of BDG is designed to help the presumptive diagnosis of invasive fungal diseases and could help guide antifungal treatment in at‑risk patients, such as people with stem cell transplants or intra-abdominal candidiasis, and people having steroids or other immune-suppressing treatment.

Fungitell is a kinetic colourimetric assay that works with computer software. If BDG is present in a serum sample, the Fungitell reagent reacts with the BDG and turns yellow. The rate of this colour change is measured against a standard curve of BDG concentrations to produce estimates of concentration in the sample. The results range from non-detectable (less than 31 pg/ml) to over 500 pg/ml and are displayed as a value on the computer screen. The sample must be diluted and retested for any values over 500 pg/ml. Fungitell can detect the presence of many pathogenic fungal infections including candidiasis, aspergillosis and fusariosis, but cannot differentiate these by type. Fungitell cannot identify fungal infections caused by certain fungal species such as Cryptococcus, the yeast phase of Blastomyces dermatitidis or Mucorales such as Absidia, Mucor and Rhizopus.

One Fungitell kit comprises 2 flat-bottom microtiter plates and all necessary reagents. Each microtiter plate is set up with 5 standards, 1 negative control and up to 21 patient samples, all in duplicate (following the recommended protocol), meaning that 1 kit can provide test results for up to 42 patients. Additional equipment needed for the test would be readily available in most pathology laboratories. If needed, other consumables are available from the manufacturer on request.

To use Fungitell, 0.5 ml of serum is needed per patient which is then centrifuged. The serum samples, negative control and standards are pipetted into a microtiter plate. Fungitell reagents are added and the plates are agitated in an incubating plate reader at 37°C. The mean rate of change is calculated using measurements of optical density recorded over 40 minutes. Samples that are cloudy, off-colour, or turbid can be diluted in reagent grade water, retested and the dilution factor accounted for when reporting of the results.

Fungitell test values of 80 pg/ml or more in at-risk patients are interpreted as positive for BDG. However, a positive result cannot fully determine the presence of fungal disease and Fungitell should be used with other diagnostic procedures. A Fungitell test value of less than 60 pg/ml should be interpreted as negative; values from 60 pg/ml to 79 pg/ml suggest a possible fungal infection. Although Fungitell gives results using clinically validated thresholds, the test is described as qualitative rather than quantitative. This is because many clinical factors, including total fungal burden, site of infection and type of fungus, can cause the reactivity of BDG to vary. The thresholds given are therefore not definitive.

Invasive fungal diseases fall into 3 categories: possible, probable and proven, based on a combination of host factors, clinical criteria and mycological criteria (EORTC/MSG diagnostic criteria). Repeat testing is recommended before diagnosis and during surveillance when stopping antifungal treatment is the aim.

Full information of the Fungitell test procedure, quality control and accuracy and precision data can be found in the instructions for use.

Innovations

The Fungitell assay takes 1 hour compared with culture-based fungal diagnostic methods, which often take weeks to produce a result.

Using the test could inform clinical decisions on prescribing or stopping treatment with antifungal drugs. Tests that improve clinical decision-making in antifungal prescribing have the potential to support antimicrobial stewardship.

Current NHS pathway

Diagnosing fungal infections in secondary care is currently done using radiological assessment, mycological cultures, histological examination and microbiological investigation including polymerase chain reaction (PCR) and BDG and galatomannan biomarker tests. Blood cultures are currently the standard method for diagnosing fungal infections. The use of histology, radiology or PCR depends on patient health, type of fungal infection and the centre in which treatment is done. Tests for rapidly identifying bloodstream bacteria and fungi have been previously addressed in the NICE diagnostic guidance on LightCycler SeptiFast Test MGRADE, SepsiTest and IRIDICA BAC BSI assay. However, insufficient evidence was found to recommend routine adoption of these similar molecular diagnostic tests in the NHS.

The decision to prescribe antifungal therapy for suspected invasive fungal disease in secondary care is made by a clinician, and is generally based on medical history, clinical examination and assessment of risk plus the results of diagnostic tests. Antifungal treatment strategies include prophylactic, fever-driven (empiric), diagnosis-driven (pre-emptive) and targeted therapy (Ruping et al. 2008).

The most common invasive fungal diseases treated in secondary care in the NHS are invasive candidiasis, invasive aspergillosis, and Pneumocystis pneumonia.

These diseases are associated with high morbidity and mortality rates and many patients die before diagnosis. Current diagnosis with blood cultures take up to 4 weeks from the time they arrive in the laboratory to provide a result which would delay starting appropriate treatment. Empirical antifungal therapy is therefore usually started in high-risk patients. Non-culture-based test methods which can help rule out fungal infection could help to stop unnecessary antifungal therapy earlier and reduce the considerable toxicity and costs of the treatment, and potentially contribute to a reduction in the development of resistance.

Fungal diagnosis using BDG was included in the revised EORTC/MSG diagnostic criteria for probable invasive fungal infections.

Guidelines from the European Society for Clinical Microbiology and Infectious Diseases on the diagnosis and management of Candida diseases (2012) recommend considering the Fungitell test for candidaemia detection in adults as well as for ruling out infection. These guidelines recommend starting antifungal therapy based on strong clinical suspicion and the use of an echinocandin as first-line therapy. Diagnostic tests should be used to rule out infection and to stop unnecessary therapy.

NICE is aware of the following CE‑marked devices that appear to fulfil a similar function as Fungitell:

Population, setting and intended user

Fungitell would be used for people who are suspected of, or at high risk of, invasive fungal disease. High-risk people in secondary care are typically those with haematological malignancies, HIV or bone marrow or organ transplants. Fungitell would most likely be used in conjunction with current diagnostic procedures as a rule-out test for invasive fungal diseases and to guide antifungal therapy. In pre-emptive treatment strategies, it could be used to prevent unnecessary antifungal prescription. In empiric treatment strategies it could help inform a decision to stop antifungal treatment earlier.

The test would be carried out in secondary or tertiary care clinical laboratories and run by qualified laboratory staff after training on the test and system.

Costs

Technology costs

One Fungitell kit includes all necessary reagents for duplicate tests on 42 individual patient serum samples (21 duplicate samples on 2 sequential plates). In this scenario, the cost of the test per patient would be £17.55 (excluding VAT). In practice, the cost of the test per patient will vary depending on the number of patient samples run per plate, using 1 kit. If fewer than 42 duplicate tests are run, a whole plate must still be used and so the cost per patient would increase. Additional costs include readily available laboratory consumables such as pipette tips, glass dilution and storage tubes, an incubating plate reader, and proprietary consumables purchased from the company if needed. Other costs associated with the test include staff costs, maintenance contracts and additional quality assurance requirements.

Table 1 Current UK costs of the Fungitell test and optional components

Description

Cost (excluding VAT)

Additional information

Fungitell test kit

£737.05

Includes 2 microtiter plates and all reagents to run up to 42 tests.

Additional equipment supplied by the company if needed

Certified beta-glucan-free pipette tips

£85.50

£96.35

1,000 microlitre tips (768 tips).

250 microlitre tips (960 tips).

Purchased separately.

Certified beta-glucan-free glass dilution tubes

£11.75

50 tubes per pack.

Purchased separately.

Biotek ELx808iu plate reader instrument

Price provided on an individual basis.

Usually based on a rental and kit purchase agreement with the company.

Annual service and calibration agreement for the Biotek ELx808iu plate reader

£1,200.00

Per year.

The company also provides onsite training including equipment installation, analyst training and data interpretation at no extra cost.

Costs of standard care

A range of diagnostic test methods may be used alongside medical history, clinical examination and assessment of risk to prescribe antifungal treatment for invasive fungal disease. The unit costs of microbiological tests at a reference laboratory range from £55 to £59 per patient sample. The cost per hour of a band 5 healthcare or biomedical scientist, who would carry out the test, is £33 to £35 (Personal Social Services Research Unit, 2016).

Resource consequences

Five NHS centres and 2 public health laboratories currently use Fungitell in England and Wales and these numbers are understood to be increasing.

Fungitell would be used as an adjunct to current diagnostic procedures and represents additional acquisition and staff time costs. These costs could be offset if it led to a reduction in unnecessary use of antifungal therapy or antifungal-associated adverse events, such as allergic and gastrointestinal reactions. Adverse effects vary depending on treatment type: some drugs have predictable side effects or drug-to-drug interactions and need additional monitoring; others have few adverse effects. One specialist commentator stated that in their large UK tertiary referral teaching hospital (1,000 beds), they see antifungal-associated adverse events on a weekly basis. This is despite the fact that they conduct therapeutic drug monitoring on site and have a very experienced team advising on the use of antifungals. Severe adverse drug reactions are rare. Fungitell could also contribute to good antimicrobial stewardship. Antimicrobial stewardship is an important issue in healthcare and a number of guidelines have been published in relation to this (for example, NICE's guideline on systems and processes for effective antimicrobial medicine use and Public Health England's start smart – then focus).

Frequently prescribed antifungals include:

  • anidulafungin (£299.99 per 100‑mg vial)

  • caspofungin (£416.78 per 70‑mg vial; £327.67 per 50‑mg vial)

  • micafungin (£341.00 per 100‑mg vial; £196.08 per 50‑mg vial)

  • fluconazole (£29.28 per 200‑mg vial; price varies according to dosage and medicinal form)

  • voriconazole (£460.32 for 28×200‑mg tablets)

  • liposomal amphotericin B (£821.87 for 10×50‑mg vials).

The patent for caspofungin expired in April 2017 and generic versions may be available in the future, which would reduce any calculated cost saving. However it would not limit other benefits of reducing the unnecessary use of antifungal agents.

One economic study was identified from the literature search which evaluated the cost effectiveness of active BDG surveillance with pre-emptive antifungal therapy in patients admitted to adult intensive care units (Pang et al. 2017). The test used in this study was usually Fungitell. A Markov model was designed to simulate the outcomes of active BDG surveillance with pre-emptive therapy (surveillance group) and no surveillance (standard care group). Costs were higher in the BDG surveillance group compared to the standard-care group. The surveillance group had a lower candidiasis-associated mortality rate and lost fewer quality-adjusted life years than the standard-care group. The study concluded that BDG surveillance with pre-emptive therapy was cost effective. The study was based on the perspective of Hong Kong healthcare providers' results and therefore may not be generalisable to UK practice.

One conference abstract reported a resource impact study using Fungitell to stop antifungal treatment in a UK tertiary referral teaching hospital (Richardson et al. 2015). Following a 4‑month study period, they reported that the monthly expenditure on antifungal therapy in the adult intensive care unit setting was reduced by €3,800, or £2,714 (using a historical conversion rate of £1=€1.40 from 30 June 2015).