Elsevier

Journal of Critical Care

Volume 40, August 2017, Pages 119-127
Journal of Critical Care

Clinical Potpourri
A prospective study of fungal biomarkers to improve management of invasive fungal diseases in a mixed specialty critical care unit

https://doi.org/10.1016/j.jcrc.2017.03.025Get rights and content

Highlights

  • Invasive fungal disease in critical care leads to longer duration of stay and is associated with increased mortality.

  • Diagnostic criteria which incorporate fungal biomarkers and risk factors unique to critical care patients is needed.

  • Fungal biomarkers such as serum 1–3 beta-d-glucan can contribute to antifungal stewardship programs in critical care.

Abstract

Purpose

The diagnosis of invasive fungal diseases (IFD) in critical care patients (CrCP) is difficult. The study investigated the performance of a set of biomarkers for diagnosis of IFD in a mixed specialty critical care unit (CrCU).

Methods

A prospective observational study in patients receiving critical care for ≥ 7 days was performed. Serum samples were tested for the presence of: (1-3) - β-d-glucan (BDG), galactomannan (GM), and Aspergillus fumigatus DNA. GM antigen detection was also performed on bronchoalveolar lavage (BAL) samples. The patients were classified using published definitions for IFD and a diagnostic algorithm for invasive pulmonary aspergillosis. Performance parameters of the assays were determined.

Results

In patients with proven and probable IFD, the sensitivity, specificity, PPV and NPV of a single positive BDG were 63%, 83%, 65% and 83% respectively. Specificity increased to 86% with 2 consecutive positive results. The mean BDG value of patients with proven and probable IFD was significantly higher compared to those with fungal colonization and no IFD (p value < 0.0001).

Conclusion

New diagnostic criteria which incorporate these biomarkers, in particular BDG, and host factors unique to critical care patients should enhance diagnosis of IFD and positively impact antifungal stewardship programs.

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.

References (56)

  • K.H. Vandewoude

    Invasive aspergillosis in critically ill patients: attributable mortality and excesses in length of ICU stay and ventilator dependence

    J Hosp Infect

    (2004)
  • O.A. Cornely

    ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients

    Clin Microbiol Infect

    (2012)
  • M. Bassetti

    How to manage aspergillosis in non-neutropenic intensive care unit patients

    Crit Care

    (2014)
  • S. Blot et al.

    Fungal sepsis in the ICU: are we doing better? Trends in incidence, diagnosis, and outcome

    Minerva Anestesiol

    (2013)
  • J. Delaloye et al.

    Invasive candidiasis as a cause of sepsis in the critically ill patient

    Virulence

    (2014)
  • R. Dutkiewicz et al.

    Aspergillus infections in the critically ill

    Proc Am Thorac Soc

    (2010)
  • P. Eggimann

    Invasive Candida infections in the ICU

    Mycoses

    (2012)
  • W. Meersseman

    Invasive aspergillosis in critically ill patients without malignancy

    Am J Respir Crit Care Med

    (2004)
  • A.M. Tortorano

    Invasive fungal infections in the intensive care unit: a multicentre, prospective, observational study in Italy (2006–2008)

    Mycoses

    (2012)
  • M. Morrell et al.

    Delaying the empiric treatment of candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality

    Antimicrob Agents Chemother

    (2005)
  • M. Bassetti

    A multicenter study of septic shock due to candidemia: outcomes and predictors of mortality

    Intensive Care Med

    (2014)
  • H. Wisplinghoff

    Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study

    Clin Infect Dis

    (2004)
  • P. Montravers et al.

    Intra-abdominal candidiasis: the guidelines-forgotten non-candidemic invasive candidiasis

    Intensive Care Med

    (2013)
  • G. Dimopoulos

    Invasive aspergillosis in the intensive care unit

    Ann N Y Acad Sci

    (2012)
  • G. Morace et al.

    Fungal infections in ICU patients: epidemiology and the role of diagnostics

    Minerva Anestesiol

    (2010)
  • S.I. Blot

    A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients

    Am J Respir Crit Care Med

    (2012)
  • P. Bulpa et al.

    Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease

    Eur Respir J

    (2007)
  • F. Ader

    Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease: an emerging fungal disease

    Curr Infect Dis Rep

    (2010)
  • F. Persat

    Contribution of the (1  3)-beta-d-glucan assay for diagnosis of invasive fungal infections

    J Clin Microbiol

    (2008)
  • A. Sulahian

    Use and limits of (1-3)-beta-d-glucan assay (Fungitell), compared to galactomannan determination (Platelia Aspergillus), for diagnosis of invasive aspergillosis

    J Clin Microbiol

    (2014)
  • V.R. Aquino

    The performance of real-time PCR, galactomannan, and fungal culture in the diagnosis of invasive aspergillosis in ventilated patients with chronic obstructive pulmonary disease (COPD)

    Mycopathologia

    (2012)
  • J. Acosta

    Prospective study in critically ill non-neutropenic patients: diagnostic potential of (1,3)-(beta)-d-glucan assay and circulating galactomannan for the diagnosis of invasive fungal disease

    Eur J Clin Microbiol Infect Dis

    (2012)
  • B. De Pauw

    Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group

    Clin Infect Dis

    (2008)
  • D. Harrison

    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

    Health Technol Assess

    (2013)
  • P. Eggimann et al.

    Candida colonization index and subsequent infection in critically ill surgical patients: 20 years later

    Intensive Care Med

    (2014)
  • J. Springer

    Comparison of serum and whole blood specimens for the detection of Aspergillus DNA in high-risk haematological patients: a multicenter evaluation

    J Clin Microbiol

    (2013)
  • P.L. White

    Evaluation of Aspergillus PCR protocols for testing serum specimens

    J Clin Microbiol

    (2011)
  • J. Springer

    Pathogen-specific DNA enrichment does not increase sensitivity of PCR for diagnosis of invasive aspergillosis in neutropenic patients

    J Clin Microbiol

    (2011)
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