{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:04:29Z","timestamp":1792803869570,"version":"4.5.0"},"reference-count":118,"publisher":"National Institute for Health and Care Research","issue":"3","license":[{"start":{"date-parts":[[2013,2,1]],"date-time":"2013-02-01T00:00:00Z","timestamp":1359676800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/www.nationalarchives.gov.uk\/doc\/non-commercial-government-licence\/non-commercial-government-licence.htm"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Health Technol Assess"],"abstract":"<jats:sec id=\"abs1-1\"><jats:title>Background<\/jats:title><jats:p>There is increasing evidence that invasive fungal disease (IFD) is more likely to occur in non-neutropenic patients in critical care units. A number of randomised controlled trials (RCTs) have evaluated antifungal prophylaxis in non-neutropenic, critically ill patients, demonstrating a reduction in the risk of proven IFD and suggesting a reduction in mortality. It is necessary to establish a method to identify and target antifungal prophylaxis at those patients at highest risk of IFD, who stand to benefit most from any antifungal prophylaxis strategy.<\/jats:p><\/jats:sec><jats:sec id=\"abs1-2\"><jats:title>Objectives<\/jats:title><jats:p>To develop and validate risk models to identify non-neutropenic, critically ill adult patients at high risk of invasive<jats:italic>Candida<\/jats:italic>infection, who would benefit from antifungal prophylaxis, and to assess the cost-effectiveness of targeting antifungal prophylaxis to high-risk patients based on these models.<\/jats:p><\/jats:sec><jats:sec id=\"abs1-3\"><jats:title>Design<\/jats:title><jats:p>Systematic review, prospective data collection, statistical modelling, economic decision modelling and value of information analysis.<\/jats:p><\/jats:sec><jats:sec id=\"abs1-4\"><jats:title>Setting<\/jats:title><jats:p>Ninety-six UK adult general critical care units.<\/jats:p><\/jats:sec><jats:sec id=\"abs1-5\"><jats:title>Participants<\/jats:title><jats:p>Consecutive admissions to participating critical care units.<\/jats:p><\/jats:sec><jats:sec id=\"abs1-6\"><jats:title>Interventions<\/jats:title><jats:p>None.<\/jats:p><\/jats:sec><jats:sec id=\"abs1-7\"><jats:title>Main outcome measures<\/jats:title><jats:p>Invasive fungal disease, defined as a blood culture or sample from a normally sterile site showing yeast\/mould cells in a microbiological or histopathological report. For statistical and economic modelling, the primary outcome was invasive<jats:italic>Candida<\/jats:italic>infection, defined as IFD-positive for<jats:italic>Candida<\/jats:italic>species.<\/jats:p><\/jats:sec><jats:sec id=\"abs1-8\"><jats:title>Results<\/jats:title><jats:p><jats:italic>Systematic review<\/jats:italic>: Thirteen articles exploring risk factors, risk models or clinical decision rules for IFD in critically ill adult patients were identified. Risk factors reported to be significantly associated with IFD were included in the final data set for the prospective data collection.<jats:italic>Data collection<\/jats:italic>: Data were collected on 60,778 admissions between July 2009 and March 2011. Overall, 383 patients (0.6%) were admitted with or developed IFD. The majority of IFD patients (94%) were positive for<jats:italic>Candida<\/jats:italic>species. The most common site of infection was blood (55%). The incidence of IFD identified in unit was 4.7 cases per 1000 admissions, and for unit-acquired IFD was 3.2 cases per 1000 admissions.<jats:italic>Statistical modelling<\/jats:italic>: Risk models were developed at admission to the critical care unit, 24 hours and the end of calendar day 3. The risk model at admission had fair discrimination (c-index 0.705). Discrimination improved at 24 hours (c-index 0.823) and this was maintained at the end of calendar day 3 (c-index 0.835). There was a drop in model performance in the validation sample.<jats:italic>Economic decision model<\/jats:italic>: Irrespective of risk threshold, incremental quality-adjusted life-years of prophylaxis strategies compared with current practice were positive but small. Incremental costs of the prophylaxis strategies compared with current practice were positive for most strategies, although a few strategies were cost saving. Incremental net benefits of each prophylaxis strategy compared with current practice were positive for most, but not all, of the strategies. Cost-effectiveness acceptability curves showed that risk assessment and prophylaxis at the end of calendar day 3 was the strategy most likely to be cost-effective when the risk threshold was 1% or 2%. At a lower risk threshold (0.5%) it was most cost-effective to assess risk at each time point; this led to a relatively high proportion of patients receiving antifungal prophylaxis (30%), which may lead to additional burden from increased resistance. The estimates of cost-effectiveness were highly uncertain and the value of further research for the whole population of interest is high relative to the research costs.<\/jats:p><\/jats:sec><jats:sec id=\"abs1-9\"><jats:title>Conclusions<\/jats:title><jats:p>The results of the Fungal Infection Risk Evaluation (FIRE) Study, derived from a highly representative sample of adult general critical care units across the UK, indicated a low incidence of IFD among non-neutropenic, critically ill adult patients. IFD was associated with substantially higher mortality, more intensive organ support and longer length of stay. Risk modelling produced simple risk models that provided acceptable discrimination for identifying patients at \u2018high risk\u2019 of invasive<jats:italic>Candida<\/jats:italic>infection. Results of the economic model suggested that the current most cost-effective treatment strategy among non-neutropenic, critically ill adult patients admitted to NHS adult general critical care units is a strategy of risk assessment and antifungal prophylaxis at the end of calendar day 3, but this finding is highly uncertain and future studies should consider the potential impact of increased resistance.<\/jats:p><\/jats:sec><jats:sec id=\"abs1-10\"><jats:title>Funding<\/jats:title><jats:p>Funding for this study was provided by the Health Technology Assessment programme of the National Institute for Health Research.<\/jats:p><jats:p><jats:italic>A previous version of this report was published in February 2013. The report was subsequently modified to reflect a substantial reduction in the unit cost of fluconazole that took place between the original analysis being conducted and the publication of the report.<\/jats:italic><\/jats:p><\/jats:sec>","DOI":"10.3310\/hta17030","type":"journal-article","created":{"date-parts":[[2014,10,13]],"date-time":"2014-10-13T11:53:29Z","timestamp":1413201209000},"page":"1-156","update-policy":"https:\/\/doi.org\/10.3310\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":47,"title":["Development and validation of a risk model for identification of non-neutropenic, critically ill adult patients at high risk of invasive Candida infection: the Fungal Infection Risk Evaluation (FIRE) Study"],"prefix":"10.3310","volume":"17","author":[{"given":"D","family":"Harrison","sequence":"first","affiliation":[{"name":"Intensive Care National Audit and Research Centre, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H","family":"Muskett","sequence":"additional","affiliation":[{"name":"Intensive Care National Audit and Research Centre, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Harvey","sequence":"additional","affiliation":[{"name":"Intensive Care National Audit and Research Centre, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Grieve","sequence":"additional","affiliation":[{"name":"London School of Hygiene and Tropical Medicine, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Shahin","sequence":"additional","affiliation":[{"name":"Intensive Care National Audit and Research Centre, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Patel","sequence":"additional","affiliation":[{"name":"Intensive Care National Audit and Research Centre, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z","family":"Sadique","sequence":"additional","affiliation":[{"name":"London School of Hygiene and Tropical Medicine, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Allen","sequence":"additional","affiliation":[{"name":"London School of Hygiene and Tropical Medicine, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Dybowski","sequence":"additional","affiliation":[{"name":"Inferspace, Pinner, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Jit","sequence":"additional","affiliation":[{"name":"Health Protection Agency, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Edgeworth","sequence":"additional","affiliation":[{"name":"St Thomas' Hospital, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Kibbler","sequence":"additional","affiliation":[{"name":"Royal Free Hospital, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Barnes","sequence":"additional","affiliation":[{"name":"Cardiff University, Cardiff, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N","family":"Soni","sequence":"additional","affiliation":[{"name":"Chelsea and Westminster Hospital, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Rowan","sequence":"additional","affiliation":[{"name":"Intensive Care National Audit and Research Centre, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"6221","published-online":{"date-parts":[[2013,2]]},"reference":[{"key":"key20160715112357622_ref1-bib1","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1513\/pats.200510-110JH","article-title":"Fungal infections","volume":"3","author":"Kauffman","year":"2006","journal-title":"Proc Am Thorac Soc"},{"key":"key20160715112357622_ref1-bib2","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1017\/S0950268801005507","article-title":"Emerging trends in the epidemiology of invasive mycoses in England and Wales (1990\u20139)","volume":"126","author":"Lamagni","year":"2001","journal-title":"Epidemiol Infect"},{"key":"key20160715112357622_ref1-bib3","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1086\/421946","article-title":"Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study","volume":"39","author":"Wisplinghoff","year":"2004","journal-title":"Clin Infect Dis"},{"key":"key20160715112357622_ref1-bib4","volume-title":"Fungal Diseases in the UK \u2013 The current provision of support for diagnosis and treatment: assessment and proposed network solution. 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