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

Abstract

BackgroundThere 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.ObjectivesTo develop and validate risk models to identify non-neutropenic, critically ill adult patients at high risk of invasiveCandidainfection, who would benefit from antifungal prophylaxis, and to assess the cost-effectiveness of targeting antifungal prophylaxis to high-risk patients based on these models.DesignSystematic review, prospective data collection, statistical modelling, economic decision modelling and value of information analysis.SettingNinety-six UK adult general critical care units.ParticipantsConsecutive admissions to participating critical care units.InterventionsNone.Main outcome measuresInvasive 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 invasiveCandidainfection, defined as IFD-positive forCandidaspecies.ResultsSystematic review: 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.Data collection: 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 forCandidaspecies. 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.Statistical modelling: 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.Economic decision model: 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.ConclusionsThe 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 ‘high risk’ of invasiveCandidainfection. 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.FundingFunding for this study was provided by the Health Technology Assessment programme of the National Institute for Health Research.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.

Early invasive fungal infections and colonization in patients with cirrhosis admitted to the intensive care unit

“…The overall incidence of IFD (acquired immediately before ICU admission and early in the ICU) in this large multicentre cohort of patients with chronic liver disease was 1%, which is slightly higher than the whole FIRE study cohort (0.6%) [12], but not significantly higher when compared with the control cohort of patients (CVD) with similar ICU mortality …”

Invasive candidiasis in critical care setting, updated recommendations from “Invasive Fungal Infections-Clinical Forum”, Iran

“…Since most of the diagnostic tests lack proper specificity and the culture result normally requires a long time, diagnosis of IFIs and IC in particular remains a challenge. Cumulating evidence suggest that institution of appropriate antifungal therapy upon initial clinical suspicion of IFIs is crucial for a positive outcome [8] .…”

“…Furthermore, based on a main febrile despite adequate antibiotic therapy and are characterized as high risk [7,8,11] .…”

“…Timely management of IFIs based on risk stratification and empirical approach is shown to be of meaningful clinical benefit, meanwhile dependence on the culture results and relying on fungal biomarkers may delay clinical decisions and lead to potential complications, morbidity and mortality in such patients [5,6] . There are risk prediction models which suggest empirical approach for patients who are supposed to significantly benefit from empirical antifungal therapy [7,8] . Despite the validated clinical impact of applying IFIs' predictive tools such as Candida Score [9,10] , many clinicians seem not to be consistently using them in routine practice [11] .…”

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“…10 Pseudomonal, enterococcal or Acinetobacter sepsis, abdominal sources of infection, acute kidney injury, cancer, heart failure, immunosuppression and cirrhosis are all independent predictors of poor outcome. 9 …”