Clinical Infectious Diseases

SUPPLEMENT ARTICLE

EORTC/MSGERC Definitions of Invasive Fungal

Diseases: Summary of Activities of the Intensive Care Unit
Working Group

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Matteo Bassetti,1,2, Elie Azoulay,3,4 Bart-Jan Kullberg,5 Markus Ruhnke,6 Shmuel Shoham,7 Jose Vazquez,8 Daniele Roberto Giacobbe,1 and
Thierry Calandra9
1
Infectious Diseases Unit, Ospedale Policlinico San Martino–IRCCS, Genoa, Italy, 2Department of Health Sciences, University of Genoa, Genoa, Italy, 3Medical ICU, APHP, Saint-Louis Hospital,
Paris, France, 4Université de Paris, Paris, France, 5Department of Medicine and Radboudumc Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands,
6
Division of Hematology, Oncology and Palliative Care, Department of Internal Medicine, Helios Klinikum Aue, Aue, Germany, 7Johns Hopkins University School of Medicine, Baltimore, Maryland,
USA, 8Department of Medicine, Division of Infectious Diseases, Medical College of Georgia/Augusta University, Augusta, Georgia, USA, and 9Infectious Diseases Service, Department of Medicine,
Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland

The EORTC/MSGERC recently revised and updated the consensus definitions of invasive fungal disease (IFD). These definitions
primarily focus on patients with cancer and stem cell or solid-organ transplant patients. They may therefore not be suitable for in-
tensive care unit (ICU) patients. More in detail, while the definition of proven IFD applies to a broad range of hosts, the categories
of probable and possible IFD were primarily designed for classical immunocompromised hosts and may therefore not be ideal for
other populations. Moreover, the scope of the possible category of IFD has been diminished in the recently revised definitions for
classically immunocompromised hosts. Diagnosis of IFD in the ICU presents many challenges, which are different for invasive can-
didiasis and for invasive aspergillosis. The aim of this article is to review progresses made in recent years and difficulties remaining
in the development of definitions applicable in the ICU setting.
Keywords. invasive aspergillosis (IA); invasive candidiasis (IC); biomarker; definition; histology.

Diagnosing invasive fungal diseases (IFD) in intensive care units a formal framework for defining IFD with a variable certainty
(ICU) presents many challenges, which are different for the 2 of diagnosis. “Proven” IFD requires that a fungus be detected
most frequent IFD encountered in nonneutropenic critically ill by blood culture or histology/culture of a specimen of tissue
patients: (1) invasive candidiasis (IC) and (2) invasive aspergil- taken from a normally sterile clinical site. This category of IFD
losis (IA). Especially for the latter, difficulties arise from the het- can apply to any host whether or not immunocompromised. By
erogeneity of the population admitted to the ICU, including a contrast, “probable” IFD is dependent on the setting/popula-
large proportion of immunocompetent hosts in whom classical tion and hinges on 3 elements—namely, a host factor that iden-
host factors predisposing to IFD (eg, neutropenia, hematolog- tifies the patients at risk, clinical features consistent with the
ical malignancies, or organ transplantation) are not present. This disease entity, and mycological evidence that includes culture
heterogeneity implies variable and frequently unclear risk pro- and microscopy but also indirect tests, such as antigen detection
filing, in turn affecting several key aspects (eg, difficulty in meas- and molecular tools (polymerase chain reaction [PCR]) [7, 8].
uring the true prevalence of the disease and the performance of Progress and difficulties encountered by the EORTC/MSGERC
diagnostic tests) necessary for defining IFD in a standardized ICU Working Group in developing definitions for IC and IA in
fashion from both clinical and research standpoints [1–6]. The ICU patients are briefly reviewed in the present work.
objective of the EORTC/MSGERC ICU Working Group was to
try to overcome these difficulties and provide definitions for IC
INVASIVE CANDIDIASIS
and IA that are relevant for ICU patients.
Following the EORTC/MSGERC approach, definitions were Background
developed according to 2 levels of probability of IFD—namely, Invasive candidiasis is the most common fungal disease among
“proven” and “probable” IFD [7, 8]. This approach establishes ICU patients [6, 9–11]. It occurs when Candida species, which
are frequent colonizers of cutaneous and mucosal surfaces, gain
access to deeper, normally sterile sites. Invasive candidiasis
Correspondence: M. Bassetti, Clinica Malattie Infettive, Ospedale Policlinico San Martino—
IRCCS, L. go R. Benzi 10, 16132 Genoa, Italy (matteo.bassetti@unige.it). comprises candidemia and deep-seated tissue candidiasis [12].
Clinical Infectious Diseases®  2021;72(S2):S121–7 Deep-seated candidiasis arises either from hematogenous dis-
© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society
semination or from procedures that lead to direct inoculation
of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
DOI: 10.1093/cid/ciaa1751 of Candida into a sterile site.

EORTC/MSGERC Definitions of Invasive Fungal Diseases • cid 2021:72 (Suppl 2) • S121

 Candidemia is generally viewed as the most common type of candidemia in ICU patients with signs and symptoms of sys-
IC, and it accounts for the majority of cases included in clinical temic infection is usually made by clinicians by the use of risk-
trials. Candidemia is defined by the isolation of Candida spe- prediction models or non–culture-based diagnostic tests, but is
cies from at least 1 blood culture and is unequivocal. These pa- not standardized [26].
tients are more easily identified than patients with deep-seated The use of risk-prediction models (in this case for diag-
candidiasis, which includes entities such as intra-abdominal nosis and not for prediction) may allow early diagnosis, but
candidiasis (IAC), osteomyelitis, septic arthritis, mediastinitis, they have a low positive-predictive value and their use for uni-
endophthalmitis, endocarditis, urinary tract infections, and versal administration of antifungals remains controversial [27,
meningitis. Most of these foci arise from an earlier episode of 28]. On the other hand, their very high negative-predictive

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candidemia that is often undiagnosed. Conversely, direct in- value allows the diagnosis to be excluded [29]. Of note, some,
troduction of Candida at a sterile site may occur—for example, but not all, models include colonization or colonization of
IAC (abscesses, peritonitis, pancreatitis) following abdominal more than 1 nonsterile site by Candida spp. among the fac-
surgery. Among patients in the ICU with IC, 2 patients will have tors increasing the risk of candidemia (or of IC in general for
isolated candidemia for every 3 patients with deep-seated can- some of the scores) [30–39]. An alternative (or a completion)
didiasis (>20–25% of which can lead to secondary candidemia) to risk-stratification scores is to stratify the risk based on non–
[13]. In the ICU, IAC constitutes the majority of cases with culture-based tests, which, in a way similar to risk scores, is still
deep-seated candidiasis [13–15]. not standardized. They include serological markers (1,3-β-d-
glucan, mannan and anti-mannan, and Candida albicans
germ tube antibody) and molecular methods (including the
Diagnosis
T2Candida test [T2 Biosystems, Lexington, Massachusetts] ,
Three entities must be considered: (1) candidemia in the ab- which combines PCR and magnetic resonance–based detec-
sence of deep-seated candidiasis (including catheter-associated tion of the agglomeration of supermagnetic particles induced
candidemia), (2) candidemia associated with deep-seated can- by the amplicons; the T2Candida test is approved by the Food
didiasis, and (3) deep-seated candidiasis not associated with and Drug Administration for the detection of C. albicans,
candidemia [15]. Candida glabrata, Candida parapsilosis, Candida tropicalis, and
A proven diagnosis of candidemia (either primary or sec- Candida krusei in blood [40, 41]). The main characteristics of
ondary to deep-seated candidemia) relies on the isolation of non–culture-based tests for the diagnosis of candidemia in ICU
Candida spp. from blood cultures. Candidemia is the most fre- patients are summarized in Table 1.
quent diagnosis of proven IFD in the ICU. Two pairs of blood Diagnosis of proven deep-seated candidiasis is much less fre-
culture bottles (10 mL each) should be obtained for aerobic quent than that of proven candidemia, since histopathology is
and anaerobic culture when candidemia is suspected before rarely available and cultures are often obtained from nonsterile
the initiation of antifungal therapy [16]. To potentially increase sites. For example, Candida spp. recovered in peritoneal fluid
the yield of blood cultures above 90%, up to 4 blood culture drawn from intra-abdominal drains may reflect colonization of
pairs should be obtained in 24 hours [17]. Although with the drains from the skin rather than true intra-abdominal candi-
limitation of potential overestimation due to the possible in- diasis [2]. In contrast, samples drawn under sterile conditions
clusion of some cases of catheter colonization, up to 40–50% during surgery or radiology-guided drainage of abscesses are
of all episodes of candidemia may be associated with intrave- indicative of deep-seated Candida infections [72, 73]. Although
nous catheters [18–20]. This is relevant in the ICU since intra- potentially very useful given the frequent absence of proven di-
venous catheters are typically present in this setting [21]. In agnosis, identification of deep-seated candidiasis by means of
patients with central venous lines and suspected candidemia, non–culture-based tests is not standardized, and extrapolation
blood cultures should be obtained via the central line as well of evidence regarding their diagnostic performance is some-
as from a peripheral site [22]. A distinction between catheter- times hampered by the fact that they were usually explored
associated and non–catheter-associated candidemia might be in candidemia or IC in general and not for specific forms of
achieved by comparing the time to positivity or by comparing deep-seated candidiasis. A brief summary of the characteristics
the number of colony-forming units from the blood drawn via of non–culture-based tests for the diagnosis of deep-seated can-
the catheter and the peripheral blood [23, 24]. When cultures didiasis is also shown in Table 1.
of only a catheter tip grow yeasts, while blood cultures remain
sterile, systemic antifungals may not be indicated in every case,
depending on the clinical condition of the patient and the level Defining Proven and Probable Invasive Candidiasis in the Intensive
of contamination of the catheter tip [25]. Candidemia cases Care Unit
may nonetheless remain undetected because of false-negative After several rounds of review and discussion, the proposed
blood cultures [15]. In such a case, presumptive diagnosis of definition for proven IC by the ICU Working Group required

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Table 1.   Characteristics of Non–Culture-Based Tests for the Diagnosis of Candidemia and Deep-Seated Candidiasis in Intensive Care Units

Test Candidemia Deep-Seated Candidemia

Serum BDG • High NPV (frequently 90–95%) [42–45] • Mostly studied in candidemia and IC in general
• Low PPV (possibly 20–40%) [46] • In a prospective study in 89 ICU patients with acute pancreatitis
or who underwent abdominal surgery and at risk of IAC, BDG (2
consecutive measurements) showed 65% and 78% sensitivity
and specificity, respectively [47]
• Inconclusive evidence from RCT regarding the overall impact …
on mortality of candidemia of a BDG-based therapeutic

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strategy, although an improvement in rates of safe antifungal
discontinuation has been described [48, 49]
• Combination with other fungal antigen/antibody-based test of …
inflammatory markers (eg, serum PCT) has been proposed for
improving diagnostic accuracy [50–53] and not for detecting
specific types of IC
Serum Mn/A-Mn • Variable diagnostic performance in different studies [54–57] • Sensitivity of Mn and A-Mn was evaluated separately in 233 ICU
patients with severe abdominal conditions; of them, 20 developed
IAC and 11 candidemia; sensitivity and specificity of Mn were
43% and 67%, respectively; sensitivity and specificity of A-Mn
were 26% and 89%, respectively [50]
• Sensitivity and specificity of 59% and 65%, respectively, …
for candidemia reported in a study of 43 ICU patients with
candidemia and 67 controls [58]
Serum CAGTA • Limited experience compared with BDG and Mn/A-Mn • Sensitivity of CAGTA was 5% and 69% for isolated candidemia
and blood culture–positive deep-seated candidiasis, respectively,
in a study of 50 patients with IC [59]
• Important heterogeneity in specificity has been reported [60] …
• A possible improvement in diagnostic performance when …
used in combination with BDG has been suggested [52]
PCR-based methods • Heterogeneous performance of in-house and commercial • The same considerations expressed for candidemia applied for
methods [61–65] deep-seated candidemia, with the additional note that most
studies refer to candidemia or IC in general and not to specific
forms of IC
• Unable to detect all Candida species …
• Promising results reported for T2Candida panel, which is …
FDA-approved for the detection of C. albicans, C. glabrata,
C. parapsilosis, C. tropicalis, and C. krusei in blood; to be
further evaluated through further real-life experiences [40,
66–71]
Abbreviations: A-Mn, anti-mannan antibodies; BDG, 1,3-β-d-glucan; CAGTA, Candida albicans germ tube antigen; FDA, Food and Drug Administration; IAC, intra-abdominal candidiasis; IC,
invasive candidiasis; ICU, intensive care unit; Mn, mannan antigen; NPV, negative-predictive value; PCR, polymerase chain reaction; PCT, procalcitonin; PPV, positive-predictive value; RCT,
randomized controlled trial.

definitive evidence of the organism in a normally sterile site. It 3. Blood culture yielding Candida species.
should include at least 1 of the following:
The proposed definition of probable IC in the ICU was based
1. Histopathologic, cytopathologic, or direct microscopic ex- on the presence of at least 1 clinical criterion (compatible oc-
amination of material from a normally sterile site, obtained ular findings by fundoscopic examination, hepatosplenic le-
by needle aspiration or biopsy showing budding cells con- sions by computed tomography [CT], clinical or radiological
sistent with Candida species (presence of pseudo-hyphae [nonpulmonary] abnormalities consistent with an infectious-
and/or true hyphae is highly suggestive of Candida species, disease process that are otherwise unexplained) plus at least 1
but these structures are not present in all Candida spe- mycological criterion (positive serum 1,3-β-d-glucan in 2 con-
cies and may also be seen in Trichosporon spp., Geotrichum secutive samples, recovery of Candida in an intra-abdominal
spp., and Magnusiomyces capitatus [previously known as specimen obtained surgically or within 24 hours from external
Geotrichum capitatum], thus confirmation by culture or PCR drainage), plus at least 1 of the following host factors:
is necessary).
2. Recovery of Candida spp. by culture of a specimen obtained 1. Glucocorticoid treatment with prednisone equivalent of
by a sterile procedure (including a freshly placed [<24 hours] 20 mg or more per day
drain) from a normally sterile site showing a clinical or ra- 2. Qualitative or quantitative neutrophil abnormality (inherited
diologic abnormality consistent with an infectious-disease neutrophil deficiency, absolute neutrophil count ≤500 cells/
process. mm3)

EORTC/MSGERC Definitions of Invasive Fungal Diseases • cid 2021:72 (Suppl 2) • S123

3. Impaired gut wall integrity (eg, recent abdominal surgery, performance of the different non–culture-based tests has been
recent chemotherapy, biliary tree abnormality, recurrent in- often evaluated using the IA definition developed for the im-
testinal perforations, ascites, mucositis, severe pancreatitis, munocompromised population with the uncertainty that these
parenteral nutrition) results may not be safely extrapolated to traditional ICU patient
4. Impaired cutaneous barriers to bloodstream infection (eg, populations [1]. Nonetheless, some general patterns can be rec-
presence of central vascular access device, hemodialysis) ognized regarding the performance of non–culture-based tests
5. Candida colonization, defined as recovery of Candida spe- for the diagnosis of IPA in the ICU: (1) the diagnostic perfor-
cies in cultures obtained from 2 or more of the following: res- mance of bronchoalveolar lavage fluid (BALF) galactomannan
piratory tract secretions, stool, skin, wound sites, urine, and is superior to that of serum galactomannan and (2) the use

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drains that have been in place for 24 or more hours of either BALF or serum 1,3-β-d-glucan presents suboptimal
6. Hematopoietic stem cell transplantation (HSCT) specificity [1]. The performance of other non–culture-based
7. Solid-organ transplant (SOT) tests such as the BALF Aspergillus lateral flow device and BALF/
blood Aspergillus PCR is promising, but comparative/combined
experience with other tests and against reliable reference in ICU
INVASIVE ASPERGILLOSIS patients is still limited [1, 83, 85–90].
Over time, different definitions of IA have been proposed
Background
(original or obtained by modifying/adding host factors to the
Invasive aspergillosis is a severe IFD increasingly reported in
2002 and 2008 versions of the EORTC/MSGERC definitions)
patients beyond the traditional risk groups, especially among
and used in different studies evaluating various aspects of the
critically ill patients in the ICU, mostly in the form of invasive
disease (eg, epidemiology, performance of a diagnostic test)
pulmonary aspergillosis (IPA) [74–76]. The prevalence of IA in
in ICU patients [3, 4, 7, 83, 85–87, 91–93]. Although some of
ICU patients varies across hospitals, although important uncer-
them have certainly helped improving recognition of IA, the
tainty surrounds its true value considering the frequent lack of
large number of these proposed definitions testifies to the need
proven diagnosis and the heterogeneity of risk profiles in dif-
for a standard, shared definition in order to optimize reliability
ferent types of ICU patients [1, 76]. Risk factors for IA in the
and comparability of research studies with the ultimate aim of
ICU population include high-dose corticosteroids, chronic ob-
improving diagnosis and management in clinical practice.
structive pulmonary disease, liver disease, malnutrition, burns,
and diabetes [74–76]. In addition, rapid development of IPA has Defining Proven and Probable Invasive Aspergillosis in the Intensive
been reported in ICU patients admitted with respiratory failure Care Unit
secondary to influenza [77, 78]. Recently, the possibility of a After several rounds of review and discussion, the proposed
nonnegligible risk of IPA in ICU patients with severe acute res- definition for proven IA by the ICU Working Group includes
piratory syndrome coronavirus 2 (SARS-CoV-2) infection has definitive evidence of filamentous growth plus associated tissue
also been suggested [79–81]. damage, and should include at least 1 of the following:

Diagnosis 1. Histopathologic, cytopathologic, or direct microscopic ex-

The diagnosis of IA in ICU remains difficult for a number of amination of a specimen obtained by needle aspiration or
reasons [1, 3, 76]. Tissue sampling may be difficult or contraindi- biopsy in which hyphae compatible with Aspergillus spp. are
cated in patients with hemodynamic instability, thrombocyto- seen accompanied by evidence of associated tissue damage
penia, or coagulation disorders. In addition, the yield of cultures (with necessary confirmation by means of culture or PCR)
is frequently suboptimal in terms of sensitivity [82, 83]. Further 2. Recovery of Aspergillus spp. by culture of a specimen
complicating the picture are the following: (1) classic radio- obtained by a sterile procedure from a normally sterile site
graphic signs of IA (such as the halo or air crescent sign) are gen- and clinically or radiologically abnormal site consistent with
erally absent in nonclassical populations [84]; (2) there could be an infectious-disease process
difficulties in obtaining CT scans instead of bedside chest radi-
ography; (3) discrimination of Aspergillus colonization versus in- The proposed definition of probable IA was limited to prob-
fection is problematic [5]; and (4) Aspergillus tracheobronchitis, able IPA in the critical care setting and included mycological
which is rare overall, is rarely considered in the ICU. evidence of Aspergillus spp. [at least 1 of the following: (1) cy-
Against this background, diagnosis of IA is frequently pre- tology, direct microscopy, and/or culture indicating presence
sumptive, with the performance of non–culture-based tests of Aspergillus spp. in a lower respiratory tract specimen; (2)
being of interest for improving accuracy as much as possible. galactomannan antigen index >0.5 in plasma/serum and/or
However, a major problem is that proven diagnosis of IA is also galactomannan antigen >0.8 in BALF], provided that clinical
infrequent in research studies in the ICU. Consequently, the and host factor criteria were met. Specifically, there should be

S124 • cid 2021:72 (Suppl 2) • Bassetti et al

at least 1 clinical/radiological abnormality consistent with an diagnosis of IC and IA in nonneutropenic critically ill patients
otherwise unexplained pulmonary infectious-disease process: was deemed necessary as baseline information on which to base
future discussions and the ultimate development of definitions.
1. Dense, well-circumscribed lesions with or without a halo For this reason, another initiative (FUNDICU project) has been
sign undertaken and is currently completing the first steps (the first
2. Air crescent sign systematic review, focused on the diagnosis of IA in critically
3. Cavity ill patients, has been recently published) [1, 94]. Certainly, the
4. Wedge-shaped and segmental or lobar consolidation systematic literature assessment is only the basis for informing
5. Tracheobronchial ulceration, pseudomembrane, nodule, expert discussions; we also need to consider and accurately

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plaque, or eschar detected by bronchoscopy (for Aspergillus weigh potential solutions from already used/developed defin-
tracheobronchitis) itions (either in specific categories of ICU patients or in non-
ICU patients) [3, 14, 47, 78, 80]. Eventually, we hope this long
Plus at least 1 of the following host factors: process, involving the combination of the proactive discussions
held during the EORTC/MSGERC ICU Working Group meet-
1. Glucocorticoid treatment with prednisone equivalent of ings and the subsequent ongoing work of the FUNDICU ini-
20 mg or more per day tiative, may ultimately result in providing a standardized and
2. Qualitative or quantitative neutrophil abnormality (inherited optimized approach to research and management of IFD in
neutrophil deficiency, absolute neutrophil count of ≤500 nonneutropenic, critically ill patients in the ICU.
cells/mm3)
3. Chronic respiratory airway abnormality (chronic obstructive
lung disease, bronchiectasis) Notes
4. Decompensated cirrhosis Supplement sponsorship. This supplement is sponsored by the
5. Treatment with recognized immunosuppressants (eg, MSGERC/EORTC.
Potential conflicts of interest. Outside the submitted work, M. B. serves
calcineurin or mammalian target of rapamycin [mTOR] in- on scientific advisory boards for Angelini, AstraZeneca, Bayer, Cubist,
hibitors, blockers of tumor necrosis factor [TNF] and similar Pfizer, Menarini, MSD, Nabriva, Paratek, Roche, Shionogi, Tetraphase, The
antifungal immunity pathways, alemtuzumab, ibrutinib, nu- Medicine Company, and Astellas Pharma Inc, and has received funding
for travel or speaker honoraria from Algorithm, Angelini, Astellas Pharma
cleoside analogues) during the past 90 days
Inc, AstraZeneca, Cubist, Pfizer, MSD, Gilead Sciences, Menarini, Novartis,
6. Hematological malignancies/HSCT Ranbaxy, and Teva. Outside the submitted work, B.-J. K. serves on scientific
7. SOT advisory boards for Amplyx, Cidara, and Scynexis. Outside the submitted
8. Human immunodeficiency virus infection work, M. R. reports personal fees from commercial sponsors (Scynexis,
Daiichi Sankyo, Kedplasma GmbH). Outside the submitted work, S. S. re-
9. Severe influenza (or other severe viral pneumonia, such as ports grants from Bloomberg Foundation, grants from Ansun, grants from
coronavirus disease 2019 [COVID-19]) Shire, personal fees from Amplyx, grants from Merck, grants from F2G, per-
sonal fees from Acidophil, personal fees from Janssen, grants from Cidara,
grants from Astellas, and grants and personal fees from ReViral. Outside
CONCLUSIONS the submitted work, E. A. has received fees for lectures from Gilead, Pfizer,
Baxter, and Alexion. His research group has been supported by Ablynx,
With the exception of proven IFD, the ICU Working Group did Fisher & Payckle, Jazz Pharma, and MSD. Outside the submitted work,
not reach a high level of certainty with regard to IFD definitions J. V. reports personal fees from Astellas, Cidara, Amplyx, and F2G. Outside
in ICU patients and the proposed definitions were thus not in- the submitted work, D. R. G. reports personal consultation fees from
Stepstone Pharma GmbH and grants from MSD Italia and Correvio Italia.
cluded in the latest version of the EORTC/MSGERC consensus
Outside the submitted work, T. C. served on advisory boards or consulted
[8]. Several factors hindered reaching a firm definition of prob- for Astellas; Basilea; Cidara; Merck, Sharp & Dohme; Sobi; ThermoFisher;
able disease, including the heterogeneity of predisposing fac- and GE Healthcare and on data safety monitoring boards for Cidara and
tors, but also uncertainty about the true prevalence of IFD in the Novartis. All authors have submitted the ICMJE Form for Disclosure of
Potential Conflicts of Interest. Conflicts that the editors consider relevant to
ICU especially for IA and the unreliability of other definitions the content of the manuscript have been disclosed.
as the reference standard for evaluating tests and radiology per-
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