Clinical PotpourriA prospective study of fungal biomarkers to improve management of invasive fungal diseases in a mixed specialty critical care unit
Introduction
Globally, invasive fungal diseases (IFD) are recognised as a major and frequent complication during treatment of critical care patients (CrCP). Candida spp. are the most common fungal pathogens although recently Aspergillus spp. have emerged as important pathogens in this cohort [1], [2], [3], [4], [5], [6], [7]. The main challenge is making a timely diagnosis of IFD since delayed initiation of appropriate antifungal therapy has been shown to increase morbidity and mortality [8], [9], [10].
Candida species have been reported as the 5th leading cause of nosocomial bloodstream infections (BSIs) in CrCP [11]. However, given the poor sensitivity of blood cultures, the true incidence of candidemia may be greater [12]. In addition, intra-abdominal candidiasis (IAC) may be an under-diagnosed clinical syndrome due to the non-specificity of clinical signs and the difficulty of interpretation of culture results from intra-abdominal samples where cultured Candida spp. could be interpreted as colonizers of the intestinal tract [13].
Invasive aspergillosis (IA), most commonly caused by A. fumigatus, has been increasing in incidence in CrCP who do not have the traditional host factors for this disease [2], [4], [6], [14], [15]. Like invasive candidiasis (IC), the clinical presentation and radiological findings of IA in non-neutropenic patients are non-specific, therefore a high index of suspicion is necessary when a patient is not responding to broad-spectrum antibacterial agents. Blot et al. [16] have proposed a diagnostic algorithm for invasive pulmonary aspergillosis (IPA) in CrCP where patients were classified as proven, putative IPA (which from hereon will be referred to as probable IPA) or Aspergillus colonization. This algorithm requires isolation of Aspergillus species from a respiratory specimen when not all patients with IPA will satisfy this mycological criterion. Importantly, the algorithm excludes fungal biomarkers such as galactomannan (GM) or (1-3)-β-d-glucan (BDG). Of particular interest is the increased recognition that patients with COPD, most of whom are receiving corticosteroids, are at risk for IPA during critical care [6], [17], [18]. Diagnosis of IPA in this cohort is also challenging. To address this, Bulpa et al. have proposed definitions for diagnosis of IPA in COPD patients but these require further clinical validation [17].
Given the difficulty with diagnosis of IFD and the low sensitivity of fungal cultures, other approaches have been investigated. Two key advances are fungal antigen detection and molecular assays to detect fungal DNA in clinical samples. Several studies have investigated the potential usefulness of BDG and GM antigen in the diagnosis of IFD both in neutropenic and non-neutropenic patients [19], [20], [21], [22]. These biomarkers (BM) have been included as mycological criteria in the European Organisation for Research and Treatment of Cancer/National Institute of Allergy and Infectious Disease Mycoses Study Group (EORTC/MSG) revised definitions of IFD [23]. Detection of fungal DNA was not included as this was stated to require further standardisation and validation although in the recently proposed revisions to these guidelines, PCR for the detection of Aspergillus and Pneumocystis jirovecii are likely to be included (PL White, Personal Communication). The potential usefulness of these biomarkers for early diagnosis of IFD and their impact on the management of non-neutropenic critical care patients needs further evaluation.
To address these deficiencies, a prospective observational study was performed to document the incidence of IFD in our CrCP, to enumerate the host factors associated with an increased risk for acquiring IFD and to determine the performance of BDG, GM and our in-house Aspergillus fumigatus specific real time polymerase chain reaction (qPCR) assay for diagnosis of IFD in CrCP. Detection of Candida DNA was not included because we did not have an in-house assay for this fungal pathogen.
Section snippets
Materials and methods
This study was conducted at St. James’s Hospital (SJH) Dublin Ireland, a 1010 bed tertiary referral centre. Our 23 bed critical care unit (CrCU), which includes the general intensive care (GICU) and high dependency (HDU) units, is a mixed specialty unit.
Patient demographics
The demographic and clinical characteristics of the patients are summarised in Table 1.
A total of 100 patients were recruited, of whom 67 were males. The average age at enrolment into the study was 64.4 years (Range, 20–85). The average length of stay was 31 days (Range, 10–121 days). The most frequent reasons for admission were for ventilatory and/or circulatory support.
Proven IFD
There were 13 patients with proven IFD, nine with proven IC, one with proven IA, and one each with Saccharomyces cerevisiae
Discussion
This prospective study investigated IFD in a mixed specialty CrCU and the role of BMs in their diagnosis and management. Consistent with other studies, Candida spp. were the most common fungal pathogen. We also demonstrated that patients who acquired IFD while receiving critical care had a significantly longer duration of stay in the unit. In addition, although not statistically significant, a greater proportion of patients with proven and probable IFD died within 30 days of diagnosis (Table 1).
Authors' contribution
Study Design: AT, TRR, KD, DC, TRR.
Data collection: AT, KD, EAJ, MP, EJ, PLW, JS, JL, TRR.
Data analysis: AT, MP, PLW, JS, TRR.
Writing of manuscript: AT, KD, EAJ, MP, EJ, PLW, JS, JL, DC, TR, TRR.
Research funding
This work was in part supported by the Department of Clinical Microbiology Trinity College Dublin and an unrestricted educational grant from Pfizer Healthcare Ireland who was not involved in the design or conduct of the study or the writing of this manuscript.
Conflict of interest
EJ received sponsorship from Bio-Rad for a GM symposium.
PLW is a founding member of the EAPCRI, received project funding from Myconostica, Luminex, and Renishaw diagnostics, was sponsored by Myconostica, MSD and Gilead Sciences to attend international meetings, on a speaker's bureau for Gilead Sciences, and provided consultancy for Renishaw Diagnostics Limited.
TRR is a member of the advisory board for Gilead Sciences and Basilea. He has also received lecturing fees and travel grants from Pfizer
Acknowledgement
We wish to thank Dr. Geraldine Moloney (Research Fellow, Department of Clinical Microbiology, Trinity College Dublin) for her advice on the statistical analyses required for the study.
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