The 2008 EORTC/MSG
Consensus Definitions:
What’s New? What’s Next?
Nikolaos G. Almyroudis, MD, and Brahm H. Segal, MD
Corresponding author
Brahm H. Segal, MD
State University of New York at Buffalo; Division of Infectious
Diseases, Roswell Park Cancer Institute, Elm and Carlton Streets,
Buffalo, NY 14263, USA.
E-mail: brahm.segal@roswellpark.org
Current Fungal Infection Reports 2009, 3:195–200
Current Medicine Group LLC ISSN 1936-3761
Copyright © 2009 by Current Medicine Group LLC
The defi nitions of invasive fungal diseases are
intended to guide the appropriate use of clini-
cal, radiologic, and various laboratory fi ndings to
increase diagnostic certainty in clinical research. The
need for standardized defi nitions was the result of
highly variable criteria used to diagnose invasive fun-
gal diseases in epidemiologic and therapeutic studies.
We review the original defi nitions published in 2002,
and the need for revision. We also summarize the key
changes in the revised 2008 defi nitions, discuss limi-
tations and pitfalls, and comment on the potential
impact of these changes.
Introduction
In recent years, several diagnostic definitions have appeared
in the literature in various fields of medicine. The need for
diagnostic guidelines usually occurs when diagnostic tests
are insensitive and/or nonspecific and physicians rely on a
combination of clinical, laboratory, or radiologic criteria to
reach a diagnosis. The diagnostic guidelines examine the
accuracy of these criteria and guide their rational use in
clinical practice and in interventional or diagnostic clinical
research. Such examples in the field of infectious diseases
are the Duke criteria for infective endocarditis [1] and
diagnostic guidelines for nontuberculous mycobacteria [2].
Diagnostic criteria are not limited to laboratory tests but
may include clinical signs and symptoms, as well as radio-
logic and bronchoscopic criteria when applicable. Although
both sensitivity and specificity define the clinical use of a
diagnostic test, for diagnostic criteria, positive and negative
predictive values are of major importance. For some infec-
tions, physical examination findings are sufficiently specific
to be diagnostic (eg, mucosal candidiasis, dermatomal zos-
ter). In contrast, the diagnosis of invasive fungal diseases
cannot rely solely on physical examination criteria. When
combined with clinical criteria, radiographic findings can
be suggestive of a diagnosis, but are never pathognomonic.
Indeed, clinical research in mycology requires well-defi ned
mycological criteria that are commonly used in combina-
tion with host factors and clinical and radiological criteria.
Diagnostic criteria for invasive fungal diseases (IFDs)
have a rank order of certainty. Sometimes, fulfilling a
mycological criterion is sufficient for a definitive diagnosis
(eg, invasive mold disease demonstrated by histopathol-
ogy). However, both in clinical research and in practice, we
have to settle for lower levels of evidence (eg, when a tissue
diagnosis is not feasible). Diagnostic criteria for research,
the focus of this article, are intentionally restrictive so as
to target only those patients for inclusion in epidemiologic
or therapeutic research who meet a prespecified threshold
of likelihood of having the fungal disease of interest. These
criteria are distinct from clinical practice, in which anti-
fungal therapy is often and appropriately initiated based on
lower levels of evidence than required for research.
The 2002 Definitions of Invasive
Fungal Infections: The First Attempt
In January of 2002, mycology experts from the Invasive
Fungal Infections Cooperative Group of the European
Organization for Research and Treatment of Cancer, and
the National Institute of Allergy and Infectious Diseases
Mycoses Study Group (EORTC/MSG) published consen-
sus defi nitions on invasive fungal diseases [3]. The aim of
this effort was to provide evidence-based standardized
defi nitions for clinical research, including epidemiologic
studies and antifungal trials. The need for standardized
defi nitions was demonstrated by an analysis of published
clinical trials of IFDs showing poor level of agreement
in diagnostic criteria [4]. The variability in diagnostic
criteria among trials in part reflects the difficulty in diag-
nosing IFDs and the heterogeneity of patient populations
studied. This situation created an obvious need for stan-
dardized defi nitions that would take under consideration
the degree of diagnostic confidence.
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I Advances in Diagnosis and Early Therapy
As a result, the consensus group defi ned three levels
of diagnostic likelihood: proven, probable, and possible
IFDs. The gold standard for the diagnosis of IFDs is the
histologic demonstration of invasive disease or a positive
culture from a normally sterile site (eg, blood, pleural
fluid, or spinal fluid). In patients with hematologic malig-
nancies and stem cell transplant recipients, invasive mold
diseases most commonly manifest as pneumonia; proven
IFD requires demonstration of hyphal invasion into lung.
Because an invasive procedure required to establish proven
IFD may not be feasible in this patient population (based
on overall illness or thrombocytopenia), physicians often
rely on lower levels of diagnostic evidence. Indeed, the
principal challenge for research-based consensus diagnos-
tic criteria is to defi ne the minimum level of evidence of
an IFD required for enrollment in clinical studies.
“Probable” and “possible” fungal infections required
the presence of appropriate host factor, consistent clinical
presentation, and certain microbiologic criteria. Although
at least one appropriate host factor and microbiologic
criteria should be present, one “major” or two “minor”
criteria would advance the diagnostic certainty to “prob-
able.” “Possible” fungal infection required one host factor
and either one microbiological criterion or one “major”
or two “minor” clinical criteria. In summary, “probable”
IFD required criteria from all three categories, whereas
“possible” required criteria from only two. This distinc-
tion is important because antifungal trials typically
restrict enrollment to patients with proven or probable
IFD, but not possible IFD.
The 2002 guidelines focused on patients with hema-
tologic malignancies and stem cell transplant recipients,
and “host factors” were tailored to this patient popula-
tion. Host factor criteria were defi ned as at least one of
the following: neutropenia for more than 10 days, persis-
tent neutropenic fever despite broad-spectrum antibiotics,
neutropenic fever and recent or current use of immuno-
suppressants, graft-versus-host disease, or significant
corticosteroid use. Clinical criteria included symptoms,
physical examination fi ndings, and radiologic data, and
were graded as “major” or “minor” according to their
specificity. For example, CT fi ndings of halo sign, air-
crescent sign, or cavity within an area of consolidation
were major criteria, whereas new infi ltrates not fulfi lling
the above were considered minor criteria.
The Need for Revision
Soon after their publication in 2002, the consensus defi ni-
tions were favorably accepted by the scientific community.
They were applied widely in clinical research and in many
cases in nonhematologic populations, such as solid organ
transplant recipients [5]. In addition, regulatory agencies
such as the US Food and Drug Administration (FDA)
accepted the EORTC/MSG diagnostic criteria when eval-
uating clinical studies used to support an application for
drug approval.
The need for revision was driven by the advances in the
field of diagnosis, the progress in medical therapeutics and
the consequent identification of new risk factors and popu-
lations at risk, and by the experience gained by the clinical
application of the definitions. “Proven” IFD continued to
represent an unambiguous gold standard for diagnosis of
IFD. However, many controversies emerged in the “prob-
able” and “possible” diagnostic categories, leading to
inconsistencies and even creating more ambiguity.
Host factors
Some of the host factors were imprecisely defi ned. High-
risk criteria included prolonged neutropenia in the previous
60 days, immunosuppressive agents within the prior 30
days, fever or hypothermia, a proven or probable IFD dur-
ing the previous episode of neutropenia, or coexistence of
symptomatic AIDS. Prolonged use of corticosteroids, a
significant risk factor for IFD, was classified among host
factors. However, it was not further defi ned in terms of
minimum daily dose. In addition, with advances in anti-
neoplastic therapeutics, new agents were identified as risk
factors for IFDs. Alemtuzumab, a humanized monoclonal
CD52 antibody that is a potent T-cell depleter, has been
widely used in the treatment of B-cell chronic lymphocytic
leukemia, non-Hodgkin’s lymphoma, graft-versus-host
disease, and rejection in solid organ transplant recipients,
and was shown to be associated with IFDs [6,7]. Tumor
necrosis factor (TNF) antagonists (etanercept, infl iximab,
and adalimumab), immunomodulating agents frequently
used in the treatment of rheumatoid arthritis and Crohn’s
disease, have been recognized as risk factors for histo-
plasmosis, and less commonly, other IFDs [8]. Purine
analogues such as fludarabine have also been recognized
as a risk factor for Pneumocystis jiroveci and other IFDs
associated with T-cell impairment [9].
It also became apparent that the defi nitions should
expand to include other patient populations at high risk
to develop IFDs for whom standardized defi nitions would
facilitate clinical trial enrollment. The largest and most
important examples are the recipients of solid organ
transplantation in whom clinical trials on antifungal
agents are frequently conducted and defi nitions published
in 2002 have already been applied. Patients with inherited
immunodeficiency disorders represented another high-risk
population for IFDs in need of standardized defi nitions.
Finally, fever or hypothermia in high-risk patients was
originally included as a host factor. However, an impor-
tant limitation is that fever can occur as a result of many
causes, both infectious and noninfectious. In addition,
fever is more appropriately regarded as a clinical sign
rather than a host factor. Finally, criteria such as “immu-
nosuppressive agents” require a more precise defi nition.
Clinical criteria
Some of the clinical criteria were very broad, thereby
increasing the risk of inclusion of patients who do not
truly have an invasive fungal infection. For example,
 The 2008 EORTC/MSG Consensus Definitions
minor clinical criteria included many nonspecific symp-
toms (ie, cough, dyspnea, nasal discharge, and mental
changes) or fi ndings (ie, pleural effusion, new infi ltrates
not fulfilling major criteria) that are commonly present in
hospitalized patients.
Radiological criteria were grouped with clinical criteria.
Radiological findings suggestive of pulmonary mold infec-
tion include a cavitary lesion, and the presence of a halo
sign or air-crescent sign [10], and these were classified as
major clinical criteria. “New infiltrates not fulfilling major
criteria” were categorized as minor clinical criteria.
Taken together, many immunocompromised patients
with cancer would meet several of the above criteria and
would be classified as having “possible” fungal infection.
This group of patients was very heterogeneous and vague
when compared with those with “probable” and “proven”
IFDs. Moreover, it allowed the inclusion of many immu-
nosuppressed patients who did not truly have an IFD.
Fungal diagnostics
Finally, advances in the field of diagnosis created further
need for revisions. The detection of Aspergillus antigen
(galactomannan) in bronchoalveolar lavage fluid, cerebrospi-
nal fluid, or two or more blood samples was included in the
microbiologic criteria of the 2002 definitions. The galacto-
mannan antigen is a fungal cell wall component that can be
detected by a sandwich enzyme-linked immunosorbent assay
in serum [11], bronchoalveolar lavage [12], and cerebrospinal
fluid [13]. It was approved by the FDA in May 2003 as an
adjunct for the diagnosis of invasive aspergillosis. Its sensitiv-
ity and specificity vary in different studies. A meta-analysis
of 27 reports demonstrated an overall sensitivity of 71%
and specificity of 89% when studied against proven cases
of invasive aspergillosis when used for surveillance [14••].
Cross reactivity can be induced by Histoplasma capsulatum
[15] and Penicillium species. False-positive results have been
associated with concurrent use of piperacillin/tazobactam
[16] and intravenous formulations of amoxicillin/clavulanate
[17], and the sensitivity of the test is affected by simultane-
ous use of mold-active antifungals [18].
The (1 → 3)-β-D-glucan (β-glucan) is another fungal cell
wall component of a variety of fungal pathogens, including
Candida, Aspergillus, Fusarium, Trichosporon, P. jiroveci,
Acremonium, and Saccharomyces [19,20]. The Glucatell
(1 → 3)-β-D-glucan assay (Associates of Cape Cod Inc.,
Falmouth, MA) in serum was approved by the FDA in May
2004 as an aid in the diagnosis of invasive aspergillosis and
other deep mycoses. Among 55 cases of IFDs in patients
with acute myelogenous leukemia and myelodysplastic
syndrome, the sensitivity and specificity of serial β-glucan
measurements were 100% and 90%, respectively, for one
specimen and 65% and 96%, respectively, for two or more
sequential specimens at a cutoff of 60 pg/mL or more [19].
Most IFDs were due to Candida species. As a single-point
assay, β-glucan performed equally well [21]. Based on these
results, the revised guidelines included the β-glucan test as
a diagnostic adjunct.
I Almyroudis and Segal
I 197
The 2008 Revised Definitions
Recognizing the need for revision, the EORTC/MSG
expert panel issued revised defi nitions that were published
in June 2008 [22••]. After several rounds of discussions,
the panelists would either reach a consensus or would
use a majority vote if consensus could not be achieved.
No changes were made regarding the criteria for proven
IFD; documentation of fungal disease by histopathology
or culture from a normally sterile site was required. The
revisions applied to probable and possible fungal disease.
In the following text, we summarize the major changes,
and discuss limitations and potential pitfalls.
“Invasive fungal disease” versus
“invasive fungal infection”
The consensus group recommended the term “invasive fungal
disease” as more appropriate than the older term “invasive
fungal infection.” We believe that this is an appropriate
change because it distinguishes disease from colonization.
Host factors
Host factors were more precisely defined and broadened to
include additional populations at risk for IFDs. Significant
corticosteroid use was defined as a minimum dose of 0.3
mg/kg/day of prednisone or equivalent for at least 3 weeks.
Treatment with T-cell immunosuppressors within the previ-
ous 90 days was added in host factors. Because solid organ
transplant recipients receive T-cell immunosuppressants for
prevention of rejection, they would fall under this host factor.
“Graft-versus-host disease” was changed to “allogeneic stem
cell transplantation” to include all transplant recipients at
any time point after transplant. Patients with severe inherited
immunodeficiency such as chronic granulomatous disease and
severe combined immunodeficiency were included among risk
factors. Fever was eliminated as a host factor.
More precise definitions of host factors are a clear
advantage of the revised guidelines. The expansion of
patient groups from the 2002 guidelines that focused on
patients with cancer to a broader group of immunocom-
promised hosts in the 2008 guidelines has advantages and
potential pitfalls. The advantage is that more patients could
be enrolled in antifungal trials. The major pitfall relates to
enrolling patients who do not have an IFD. For example,
use of a TNF-α antagonist is by itself a sufficient host factor
criterion in the revised criteria. Although allogeneic stem cell
transplant recipients who receive a TNF-α antagonist for
steroid-refractory graft-versus-host disease are at substantial
risk for invasive aspergillosis, patients receiving a TNF-α
antagonist for psoriasis or rheumatoid arthritis are at low
risk. Based on the low prevalence of invasive aspergillosis in
these low-risk patients, the positive predictive value of serum
galactomannan and β-glucan is consequently reduced.
A clear distinction between
“probable” and “possible” IFD
In the revised guidelines, the distinction between “probable”
and “possible” IFD was more clearly defined. “Probable”
198
I Advances in Diagnosis and Early Therapy
and “possible” were defined based on host factors and clini-
cal criteria; clinical criteria required physical examination or
radiological findings that were suggestive of an IFD. A major
revision was the elimination of all “minor” clinical criteria.
These were frequently characterized by nonspecific clinical
manifestations such as cough, dyspnea, or mental status
changes. As a result, “probable” and “possible” categories
require strongly suggestive clinical criteria (eg, a pulmonary
nodule with/without halo sign, air-crescent sign, pulmonary
cavity, or focal lesion in CT of the brain). The distinction
between “probable” and “possible” solely relates to the pres-
ence of mycological criteria in the former.
Diagnostic markers
There were no changes in culture-based diagnostic crite-
ria. The main changes related to the galactomannan and
β-glucan assays. In the 2008 guidelines, only a single
positive serum or plasma galactomannan was required for
a positive result, whereas the 2002 guidelines required at
least two positive results. In addition, the β-glucan assay
was added to the 2008 guidelines as a diagnostic adjunct
for probable IFD. Whereas the serum galactomannan test
can support a diagnosis of probable IFD when combined
with host factors and clinical criteria, interpretation of
a positive β-glucan test is more challenging because it
can detect several fungal diseases, including candidiasis,
aspergillosis, fusariosis, and P. jiroveci. Therefore, a posi-
tive β-glucan test, in combination with host and clinical
criteria, is defi ned as a “probable mycosis other than
cryptococcosis or zygomycosis.” In therapeutic trials of
specific IFDs, the lack of specificity of the β-glucan is a
limitation. Molecular methods of detecting fungi in clini-
cal specimens, such as polymerase chain reaction (PCR),
were not included in the defi nitions because of lack of
standardized and validated methods.
We fully agree with including the β-glucan assay as
a mycological criterion. One pitfall is that with both
galactomannan and β-glucan assays as accepted diagnos-
tic adjuncts, there is, by defi nition, a greater chance of a
false-positive result compared with when only the galacto-
mannan test was available. The requirement that only one
of these tests be positive on a single occasion (as opposed
to requiring positive results on two consecutive occasions)
further increases the likelihood of a false-positive result.
The Effect of the Revised Criteria
on Categories of IFD
As intended, the elimination of the nonspecific “minor”
clinical criteria from the diagnostic guidelines will
decrease the number of patients who would qualify as
“possible” and “probable” IFDs. Besides, the number
of “possible” IFDs will decrease further owing to the
availability of fungal markers that would advance many
previously “possible” cases to “probable.” The fungal
markers will also impact the number of “proven” IFDs.
Because serum galactomannan and β-glucan are nonin-
Figure 1. Expected effects of revised EORTC/MSG guidelines on
proven, probable, and possible invasive fungal disease categories
in clinical research. EORTC/MSG—Invasive Fungal Infections
Cooperative Group of the European Organization for Research
and Treatment of Cancer, and the National Institute of Allergy and
Infectious Diseases Mycoses Study Group.
vasive tests that can be measured in the serum or blood,
they will diminish the need for invasive diagnostic proce-
dures such as biopsy of the affected site, decreasing the
number of histopathology-proven and culture-proven
cases. Therefore, we anticipate a decrease in the number
of “possible” and “proven” IFDs and an increase in the
number of “probable” IFDs in the 2008 versus the 2002
guidelines (Fig. 1). Finally, this shift in the population
from “proven” to “probable” IFDs applies to Aspergillus
species and those fungi detected by β-glucan. They are
not relevant to certain molds, such as zygomycetes, that
are not detectable by the newer fungal markers.
The main concern is that “probable” IFD may be less
stringent in the revised compared with the original guide-
lines. Liberalizing the host factor criteria will result in
including patient populations (eg, those with rheumato-
logic disorders) at lower risk for IFDs than patients with
hematologic malignancies and stem cell transplant recipi-
ents. With regard to invasive mold diseases, the revised
criteria include both galactomannan and β-glucan tests
(as opposed to galactomannan only in the 2002 guide-
lines), and require that either one become positive on a
single occasion to fulfi ll mycological criteria for an IFD.
When either assay is applied to low-risk patient popula-
tions, their positive predictive values are diminished.
Conclusions
PCR-based diagnosis
The need for future revision of the diagnostic guidelines
will be driven by the advances in the field of fungal mark-
ers. These include the better understanding of the available
fungal markers and the development of new diagnostic
tests. Although PCR has been studied for years, the lack
of standardization and clinical validation prevented it from
integration in the revised diagnostic definitions. So far, PCR
 The 2008 EORTC/MSG Consensus Definitions
in lung tissue specimens has correlated well with histopa-
thology [23]. Serial PCR measurements have been studied
prospectively in a small number of patients with hematologic
malignancies against [24] or along with galactomannan
and CT [25•]. These studies were contacted using different
Aspergillus fumigatus–specific probes and demonstrated
acceptable sensitivity and specificity. Quantitative real-time
PCR cross reactive for multiple fungal genera and spe-
cies (pan-fungal PCR) is also undergoing evaluation [26].
Nucleic acid sequence–based amplification is an isothermal
amplification technique for nucleic acids that uses primers
selected from conserved 18S rRNA sequences. It has been
developed for several Aspergillus species [27] and is currently
undergoing clinical evaluation. An additional advantage of
PCR-based techniques is their potential to detect multiple
fungal genera and species at once. This is possible if pan-
fungal primers are used. Genera- or species-specific PCR
analysis can follow to further specify the diagnosis if desir-
able. Although these techniques are not clinically validated
yet, it is likely this will set new standards in the diagnosis of
IFDs. Their specificity will define their significance among
the other diagnostic criteria but most likely will be classified
as criteria for “probable” IFDs.
As both additional host factors and diagnostic tools
(eg, PCR) are incorporated into diagnostic criteria, we
again emphasize concerns about diminished positive
predictive value; this concern is compounded if we only
require any one of a number of diagnostic tests to be posi-
tive on a single occasion to satisfy mycological criteria.
Prophylaxis versus targeted antifungal treatment:
impact on clinical trial enrollment
Strategies for prevention and early treatment of IFDs con-
tinue to evolve and will likely affect how diagnostic tests are
used in clinical research and general practice. For example,
posaconazole prophylaxis was effective in preventing
invasive aspergillosis in patients with acute myelogenous
leukemia and myelodysplastic syndrome receiving induc-
tion chemotherapy [28] and in allogeneic stem cell recipients
with significant graft-versus-host disease [29]. The effect
of mold-active prophylaxis would be to reduce the number
of high-risk patients who develop IFDs and to decrease the
sensitivity of serum galactomannan testing. On the other
hand, several centers use surveillance testing with laboratory
markers as an alternative strategy to mold-active prophy-
laxis or initiating empirical mold-active therapy in patients
with persistent neutropenic fever [30,31]. Active surveillance
testing has the advantages of limiting the number of patients
who receive mold-active agents and detecting IFDs early.
This approach also has the potential to increase the number
of high-risk patients who will meet criteria for probable IFD
required for enrollment in clinical trials.
Host factors revisited
There is a greater appreciation of invasive pulmonary
aspergillosis in critically ill patients without classical risk
factors in whom detection of galactomannan in bron-
I Almyroudis and Segal
I 199
choalveolar fluid may be diagnostically useful [32,33].
The revised EORTC/MSG criteria appropriately excluded
critical illness (eg, requiring intensive care unit admis-
sion) as a host criterion for probable IFD; more research
is required to defi ne the sensitivity, specificity, and predic-
tive value of diagnostic tests in this population.
Finally, we are beginning to learn more about genetic
polymorphisms that predispose to IFDs. For example,
Bochud et al. [34] showed that donor toll-like receptor-4
polymorphisms affected the risk of invasive aspergillosis
in allogeneic hematopoietic stem cell transplant recipients.
Zaas et al. [35] showed in both mouse models of aspergil-
losis and in allogeneic hematopoietic stem cell transplant
recipients that polymorphisms in the plasminogen allele
affected the risk of aspergillosis. Such studies may be
useful to more precisely stratify immunocompromised
patients regarding risk of aspergillosis. In the future,
genetic testing results may be combined with classical risk
factors (eg, neutropenia, immunosuppressive regimens) as
host factors predisposing to IFDs in clinical research.
Disclosure
No potential confl icts of interest relevant to this article
were reported.
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