J. Peter DonnellypersName, Sharon ChenpersName, Carol A. KauffmanpersName, William J. SteinbachpersName, John W. BaddleypersName, Paul E. VerweijpersName, Cornelius J. ClancypersName, John R. WingardpersName, Shawn R. LockhartpersName, Andreas H. GrollpersName, Tania C. SorrellpersName, Matteo BassettipersName, Hamdi AkanpersName, Barbara D. AlexanderpersName, David R. AndespersName, Élie AzoulaypersName, Ralf BialekpersName, Robert W. BradsherpersName, Stéphane BretagnepersName, Thierry CalandrapersName, Angela M. CaliendopersName, Elio CastagnolapersName, Mario CrucianipersName, Manuel Cuenca‐EstrellapersName, Catherine F. DeckerpersName, Sujal R. DesaipersName, Brian T. FisherpersName, Thomas S. HarrisonpersName, Claus Peter HeußelpersName, Henrik Elvang JensenpersName, Christopher C. KibblerpersName, Dimitrios P. KontoyiannispersName, Bart Jan KullbergpersName, Katrien LagroupersName, Frédéric LamothpersName, Thomas LehrnbecherpersName, Jürgen LoefflerpersName, Olivier LortholarypersName, Johan MaertenspersName, Oscar MarchettipersName, Kieren A. MarrpersName, Henry MasurpersName, Jacques F. MeispersName, C Orla MorriseypersName, Márcio NuccipersName, Luis Ostrosky‐ZeichnerpersName, Livio PaganopersName, Thomas F. PattersonpersName, John R. PerfectpersName, Zdeněk RáčilpersName, Emmanuel RoilidespersName, Marcus RuhnkepersName, Cornelia Schaefer ProkoppersName, Shmuel ShohampersName, Monica A. SlavinpersName, David A. StevenspersName, George R. ThompsonpersName, José A. VázquezpersName, Claudio ViscolipersName, Thomas J. WalshpersName, Adilia WarrispersName, L. Joseph WheatpersName, P. Lewis WhitepersName, Theoklis E. ZaoutispersName, Peter G. PappaspersName (2019date). “Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium.” Clinical Infectious Diseasestitle·venue.
Object of study — A CONSENSUS DEFINITION REVISED WHILE ITS THREE CATEGORY NAMES STAY PUT - 'proven', 'probable' andpersName 'possible' invasive fungal disease keep their labels from 2008date while 'probable' is expanded andpersName 'possible' is shrunk, so the same three words now denote different sets of patients
Research question — how to extend research definitions of invasive fungal disease beyond cancer andpersName transplant patients, what to do about tests that did not exist or were unstandardised in 2008date, andpersName where the boundary of each category should now sit
Contribution — revised definitions of proven, probable andpersName possible IFD - new host factorsterm·def, new radiological features, thresholds for galactomannan that replace the manufacturer's, the admission of Aspergillus PCRterm·var, andpersName first definitions for non-HIV pneumocystosis
phenomenon · claim-type · cross-domain-transfer · mechanism · claim-relation · replication-status · limitation — grounded in the full text| phenomenon | a group of diseases that can rarely be proven in life, so that the categories researchers count are degrees of certainty rather than states of the patient — “Tissue diagnosis requires the presence of fungal elements in formalin-fixed paraffin-embedded tissue and signifies proven fungal disease but not the identity of the fungus involved.” | |
| claim-type | method — “Importantly, these definitions are specifically intended for these purposes only and not to direct or guide patient care.” | |
| method — evidence | — “Volunteers from the EORTC Infectious Diseases Group and the MSGERC were assigned according to their expertise to 10 working groups, each charged with appraising a particular topic (see list of contributors in the Notes section). The chairs of the EORTC and MSG (J. P. D. and P. G. P.) selected leaders for each working group, and S. C. served as executive secretary. After completing the first round of working group assignments, leaders presented each group’s initial deliberations and recommendations at the 7th Trends in Medical Mycology Conference in Lisbon, Portugal, October 2015. A slide set was made available until 31 December 2015 online at www.e-materials.com/timm2015/invitation/Member and, on request, for public comment. After several iterations, the final draft of the manuscript was circulated to all members for their approval.” | |
| object of study — evidence | — “There is no change in the classifications of “proven,” “probable,” and “possible” IFD, although the definition of “probable” has been expanded and the scope of the category “possible” has been diminished.” | |
| research question — evidence | — “The 2008 definitions had their shortcomings, including the facts that the definitions were unsuitable for patients with IFD in the setting of intensive care units (ICUs) or in pediatrics, data were insufficient to establish appropriate thresholds for detecting Aspergillus galactomannan (GM), and there was uncertainty about the role of (1,3)-beta-D glucan (BDG). Furthermore, nucleic acid amplification including polymerase chain reaction (PCR)–based tests were excluded because of lack of standardization and validation. Definitions for cryptococcosis and endemic mycoses also needed clarification, and there were no definitions for pneumocystosis.” | |
| contribution — evidence | — “European Organization for Research and Treatment of Cancer and the Mycoses Study Group definitions for probable invasive fungal disease now include solid organ transplant, hematologic malignancy, graft-versus-host disease, the reverse halo sign, revised thresholds for galactomannan, Aspergillus polymerase chain reaction, and definitions for candidiasis, cryptococcosis, non-human immunodeficiency viirus–associated pneumocystosis, and endemic mycoses.” | |
| mechanism | THE LABELS DID NOT CHANGE AND THE CLASSES DID: `There is no change in the classifications of `proven,` `probable,` and `possible` IFD, although the definition of `PROBABLE` has been expanded and the scope of the category `POSSIBLE` has been diminished.` A trial reporting `probable IFD` in 2010 and one reporting it in 2021 are not counting the same patients, and neither label says so. The corpus holds definitions that moved and were renamed; this one moved and kept its name, which is the harder case to detect downstream — “There is no change in the classifications of “proven,” “probable,” and “possible” IFD, although the definition of “probable” has been expanded and the scope of the category “possible” has been diminished.” | mechanisms[0] |
| mechanism | AND THE DEFINITION IS EXPLICITLY NOT FOR TREATING ANYONE: `Importantly, these definitions are specifically intended for these purposes only and not to direct or guide patient care.` Restated at the end: `we have emphasized the need to differentiate between definitions of IFD required for clinical research from those that influence clinical practice. In clinical practice, many would administer an antifungal agent ... without there being sufficient evidence to satisfy the consensus definitions of IFD.` A definition bounded by PURPOSE, not by population or by evidence base - and the authors say plainly that practice does not follow it and should not — “Importantly, these definitions are specifically intended for these purposes only and not to direct or guide patient care.” | mechanisms[1] |
| mechanism | AND FOR ELEVEN YEARS THE THRESHOLD BELONGED TO THE ASSAY MANUFACTURER: `there was no agreement about appropriate thresholds, so the manufacturers' analytical thresholds were adopted.` This revision takes it back - `Revised thresholds for GM now replace those of the manufacturer` - and the replacement still names a brand: `A single threshold (>80 pg/mL) using the Fungitell test ... is recommended; there is insufficient evidence to include assays produced by other manufacturers.` The boundary of a disease category was, and partly still is, a commercial parameter — “In the previous definitions [ 1 ], indirect tests for diagnosing IFD were only included if there was sufficient evidence that they had been standardized and validated. Moreover, commercial tests were included only if criteria for interpretation had been provided. Hence, while tests for GM and BDG were incorporated, tests for detecting fungal nucleic acid were not [ 1 ]. Furthermore, there was no agreement about appropriate thresholds, so the manufacturers’ analytical thresholds were adopted.” | mechanisms[2] |
| mechanism | AND THE THRESHOLD WAS DELIBERATELY INDEXED TO THE SPECIMEN RATHER THAN THE PATIENT: `We adopted different thresholds for different specimens rather than for different host groups.` Two ways to make one test mean the same thing across a population, and the choice is stated. Compare prigerson2009, where items that behaved differently across host groups were DELETED rather than re-thresholded — “We evaluated Aspergillus galactomannan for both adults and children and specific patient groups and its utility and validity for different clinical specimens. We adopted different thresholds for different specimens rather than for different host groups [ 33–35 ] ( Table 2 ).” | mechanisms[3] |
| mechanism | AND A WORKING GROUP FAILED AND SAID SO: `group 10 (IFD definitions in ICU patients) was unable to generate recommendations that preserved A level of certainty consistent with the existing definitions except for proven IFD, and therefore undertook a separate initiative.` One of ten groups reports that its population cannot be brought inside the definition at the certainty the definition requires. The honest outcome of an extension attempt, printed rather than papered over — “However, group 10 (IFD definitions in ICU patients) was unable to generate recommendations that preserved a level of certainty consistent with the existing definitions except for proven IFD ( Table 1 ) and therefore undertook a separate initiative [ 8 ].” | mechanisms[4] |
| mechanism | AND A TERM WAS STRUCK OUT FOR IGNORANCE: `'COLONIZATION' with Cryptococcus spp. is no longer included in the definitions as it is poorly understood and its natural history is unknown.` simonneau2018 KEEPS a whole class - group 5 - for precisely this reason, `the LACK OF ROBUST DATA allowing a definite recognition of predominant pathophysiological mechanisms`. Same criterion, opposite operation: one field files the not-understood into a class of its own, the other deletes the term — ““Colonization” with Cryptococcus spp. is no longer included in the definitions as it is poorly understood and its natural history is unknown.” | mechanisms[5] |
| mechanism | AND ANOTHER TERM WAS ABANDONED FOR A PARTITION: `The term `DISSEMINATED CRYPTOCOCCOSIS` as distinct from CNS cryptococcosis has been abandoned in favor of the terms `PULMONARY,` `CNS` AND `OTHER EXTRAPULMONARY SITES.`` A term whose meaning was `everything beyond one site` replaced by naming the sites. A negative definition traded for an enumeration — “The term “disseminated cryptococcosis” as distinct from CNS cryptococcosis has been abandoned in favor of the terms “pulmonary,” “CNS” and “other extrapulmonary sites.”” | mechanisms[6] |
| mechanism | AND A CLASS WAS EXTENDED TO PEOPLE WITH NO SYMPTOMS: `we also recognize cryptococcal infection among individuals in high-risk host groups who have few, if any, symptoms and only a positive serum cryptococcal antigen test (asymptomatic cryptococcal antigenemia). This condition may be more common than symptomatic disease ... and so are now included in these definitions.` The justification is prognostic - they `may develop clinical cryptococcal disease unless treated` - which is simonneau2018's argument for the 21-24 mmHg band, in a different discipline the same year — “However, we also recognize cryptococcal infection among individuals in high-risk host groups who have few, if any, symptoms and only a positive serum cryptococcal antigen test (asymptomatic cryptococcal antigenemia). This condition may be more common than symptomatic disease, and patients may develop clinical cryptococcal disease unless treated and so are now included in these definitions [ 70 ].” | mechanisms[7] |
| mechanism | AND THE FIELD HAD TO WRITE DOWN THE DIFFERENCE BETWEEN TWO OF ITS OWN WORDS: `There is much confusion about the difference between a host factor and a risk factor. As before, a host factor has been defined as a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD. For example, while impaired gut wall integrity ... may increase the risk of candidiasis, it was not considered specific enough to warrant inclusion as a host factor.` A worked example of the line between a constituent and a correlate - and simonneau2018 demotes splenectomy across the same line in the same year — “While definitions of proven and probable disease have been shown to be reliable in research and attracted little controversy among the group, this cannot be said of the possible IFD category. There is much confusion about the difference between a host factor and a risk factor. As before, a host factor has been defined as a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD [ 1 ]. For example, while impaired gut wall integrity through surgery or illness may increase the risk of candidiasis, it was not considered specific enough to warrant inclusion as a host factor.” | mechanisms[8] |
| mechanism | AND THE UNCERTAIN CATEGORY IS THE CONTESTED ONE: `While definitions of proven and probable disease have been shown to be reliable in research and attracted little controversy among the group, this cannot be said of the possible IFD category.` `Possible` is what remains when a host factor and a clinical feature are present and the mycology is absent - a category defined by a missing measurement, which is why its boundary is the one nobody agrees on — “While definitions of proven and probable disease have been shown to be reliable in research and attracted little controversy among the group, this cannot be said of the possible IFD category. There is much confusion about the difference between a host factor and a risk factor. As before, a host factor has been defined as a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD [ 1 ]. For example, while impaired gut wall integrity through surgery or illness may increase the risk of candidiasis, it was not considered specific enough to warrant inclusion as a host factor.” | mechanisms[9] |
| mechanism | AND THE DIAGNOSTIC TESTS CARRY THEIR OWN SCOPE LIMITS INTO THE DEFINITION: BDG is refused as evidence for a specific disease - `The group did not support the use of serum BDG to rule in patients for clinical trials or for defining IA or IC, as BDG detection is not specific for any one IFD`; tissue histology `signifies proven fungal disease but not the identity of the fungus involved`; and T2Candida's predictive value `increases from 62% ... to 92%` with the population. Each test answers a different question, and the definition has to say which — “The group did not support the use of serum BDG to rule in patients for clinical trials or for defining IA or IC, as BDG detection is not specific for any one IFD.” | mechanisms[10] |
| mechanism | AND A STANDARD WAS SET AS CRITERIA RATHER THAN AS A METHOD: `There are relatively few commercial PCR assays, and most investigators have developed methods in-house. As such, the FPCRI was established to develop criteria for Aspergillus PCR rather than a standardized method per se.` Standardising the output instead of the procedure - the only move available when the procedures are already heterogeneous, and the reason PCR could be admitted in 2019 after exclusion in 2008 — “There are relatively few commercial PCR assays, and most investigators have developed methods in-house. As such, the FPCRI was established to develop criteria for Aspergillus PCR rather than a standardized method per se.” | mechanisms[11] |
| extends | the 2008 EORTC/MSG consensus definitions, whose three category names this revision keeps and whose contents it changes — “There is no change in the classifications of “proven,” “probable,” and “possible” IFD, although the definition of “probable” has been expanded and the scope of the category “possible” has been diminished.” | claim_relations[0] |
| critiques | the 2008 definitions' reliance on the manufacturers' analytical thresholds, their unsuitability for ICU and paediatric patients, and their exclusion of PCR — “The 2008 definitions had their shortcomings, including the facts that the definitions were unsuitable for patients with IFD in the setting of intensive care units (ICUs) or in pediatrics, data were insufficient to establish appropriate thresholds for detecting Aspergillus galactomannan (GM), and there was uncertainty about the role of (1,3)-beta-D glucan (BDG). Furthermore, nucleic acid amplification including polymerase chain reaction (PCR)–based tests were excluded because of lack of standardization and validation. Definitions for cryptococcosis and endemic mycoses also needed clarification, and there were no definitions for pneumocystosis.” | claim_relations[1] |
| extends | the Fungal PCR Initiative's criteria for Aspergillus PCR, which made it possible to admit a test excluded in 2008 for lack of standardisation — “There are relatively few commercial PCR assays, and most investigators have developed methods in-house. As such, the FPCRI was established to develop criteria for Aspergillus PCR rather than a standardized method per se.” | claim_relations[2] |
| critiques | the use of these definitions to guide treatment - 'specifically intended for these purposes only and not to direct or guide patient care' — “Importantly, these definitions are specifically intended for these purposes only and not to direct or guide patient care.” | claim_relations[3] |
| sense | `proven` IFD - histology, culture or a sterile-site specimen. `Can apply to ANY patient, regardless of whether the patient is immunocompromised` - the only one of the three categories that is not restricted by host — “The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses.” | senses[0] |
| sense | `probable` IFD - a host factor AND a clinical feature AND mycological evidence, `proposed for immunocompromised patients only, except for endemic mycoses`. Expanded in this revision without changing the word — “There is no change in the classifications of “proven,” “probable,” and “possible” IFD, although the definition of “probable” has been expanded and the scope of the category “possible” has been diminished.” | senses[1] |
| sense | `possible` IFD - a host factor and a clinical feature with the mycology missing. The category that `attracted controversy` where the other two did not - defined by an absent measurement — “While definitions of proven and probable disease have been shown to be reliable in research and attracted little controversy among the group, this cannot be said of the possible IFD category. There is much confusion about the difference between a host factor and a risk factor. As before, a host factor has been defined as a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD [ 1 ]. For example, while impaired gut wall integrity through surgery or illness may increase the risk of candidiasis, it was not considered specific enough to warrant inclusion as a host factor.” | senses[2] |
| sense | `host factor` - `a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD`. Impaired gut wall integrity raises the risk of candidiasis and is refused as a host factor for not being specific enough — “While definitions of proven and probable disease have been shown to be reliable in research and attracted little controversy among the group, this cannot be said of the possible IFD category. There is much confusion about the difference between a host factor and a risk factor. As before, a host factor has been defined as a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD [ 1 ]. For example, while impaired gut wall integrity through surgery or illness may increase the risk of candidiasis, it was not considered specific enough to warrant inclusion as a host factor.” | senses[3] |
| sense | `exposure` (endemic mycoses) - `a history of residence in an endemic area, no matter how remote, travel to an endemic area, or contact with fomites such as soil or vegetation`. A criterion with no time limit at all — “Exposure to 1 of these fungi is defined as a history of residence in an endemic area, no matter how remote, travel to an endemic area, or contact with fomites such as soil or vegetation that is derived from an endemic area.” | senses[4] |
| control | refusing BDG as evidence for any specific fungal disease, while accepting it for probable IFD in general — held — “A single threshold (>80 pg/mL) using the Fungitell test (Associates of Cape Cod, Falmouth, MA) is recommended; there is insufficient evidence to include assays produced by other manufacturers [ 42 ].” — rules out a non-specific biomarker being used to rule patients into a trial of one particular infection — “The group did not support the use of serum BDG to rule in patients for clinical trials or for defining IA or IC, as BDG detection is not specific for any one IFD.” | controls[0] |
| control | defining a host factor as predisposition rather than raised risk, and testing the rule on impaired gut wall integrity — held — “We also recognize that our definition of a host factor errs on the side of conservatism given the increasing use of drugs such as monoclonal antibodies for treating a variety of conditions.” — rules out a category that would absorb most intensive-care patients — “While definitions of proven and probable disease have been shown to be reliable in research and attracted little controversy among the group, this cannot be said of the possible IFD category. There is much confusion about the difference between a host factor and a risk factor. As before, a host factor has been defined as a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD [ 1 ]. For example, while impaired gut wall integrity through surgery or illness may increase the risk of candidiasis, it was not considered specific enough to warrant inclusion as a host factor.” | controls[1] |
| control | requiring DNA sequencing after PCR, and only in laboratories with a proven record, before tissue findings identify a fungus — held — “There are relatively few commercial PCR assays, and most investigators have developed methods in-house. As such, the FPCRI was established to develop criteria for Aspergillus PCR rather than a standardized method per se.” — rules out an identification from histology alone, which 'signifies proven fungal disease but not the identity of the fungus involved' — “Tissue diagnosis requires the presence of fungal elements in formalin-fixed paraffin-embedded tissue and signifies proven fungal disease but not the identity of the fungus involved.” | controls[2] |
| control | a three-month public comment period after presentation at a conference, before the definitions were finalised — held — “To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups’ findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved.” — rules out a definition known only to the panel that wrote it — “Volunteers from the EORTC Infectious Diseases Group and the MSGERC were assigned according to their expertise to 10 working groups, each charged with appraising a particular topic (see list of contributors in the Notes section). The chairs of the EORTC and MSG (J. P. D. and P. G. P.) selected leaders for each working group, and S. C. served as executive secretary. After completing the first round of working group assignments, leaders presented each group’s initial deliberations and recommendations at the 7th Trends in Medical Mycology Conference in Lisbon, Portugal, October 2015. A slide set was made available until 31 December 2015 online at www.e-materials.com/timm2015/invitation/Member and, on request, for public comment. After several iterations, the final draft of the manuscript was circulated to all members for their approval.” | controls[3] |
| weight | the 2008 EORTC/MSG consensus definitions, whose three category names this revision keeps and whose contents it changes — 0.95 — “There is no change in the classifications of “proven,” “probable,” and “possible” IFD, although the definition of “probable” has been expanded and the scope of the category “possible” has been diminished.” | claim_relations[0] |
| weight | the 2008 definitions' reliance on the manufacturers' analytical thresholds, their unsuitability for ICU and paediatric patients, and their exclusion of PCR — 0.9 — “The 2008 definitions had their shortcomings, including the facts that the definitions were unsuitable for patients with IFD in the setting of intensive care units (ICUs) or in pediatrics, data were insufficient to establish appropriate thresholds for detecting Aspergillus galactomannan (GM), and there was uncertainty about the role of (1,3)-beta-D glucan (BDG). Furthermore, nucleic acid amplification including polymerase chain reaction (PCR)–based tests were excluded because of lack of standardization and validation. Definitions for cryptococcosis and endemic mycoses also needed clarification, and there were no definitions for pneumocystosis.” | claim_relations[1] |
| weight | the Fungal PCR Initiative's criteria for Aspergillus PCR, which made it possible to admit a test excluded in 2008 for lack of standardisation — 0.85 — “There are relatively few commercial PCR assays, and most investigators have developed methods in-house. As such, the FPCRI was established to develop criteria for Aspergillus PCR rather than a standardized method per se.” | claim_relations[2] |
| weight | the use of these definitions to guide treatment - 'specifically intended for these purposes only and not to direct or guide patient care' — 0.85 — “Importantly, these definitions are specifically intended for these purposes only and not to direct or guide patient care.” | claim_relations[3] |
| note | a host factor —distinct-from→ a risk factor — 'There is much confusion about the difference between a host factor and a risk factor. As before, a host factor has been defined as a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD.' The distinction is specificity, not strength - impaired gut wall integrity 'may increase the risk of candidiasis' and is still refused. simonneau2018 moves splenectomy across this same line in the same year, in a different discipline — “While definitions of proven and probable disease have been shown to be reliable in research and attracted little controversy among the group, this cannot be said of the possible IFD category. There is much confusion about the difference between a host factor and a risk factor. As before, a host factor has been defined as a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD [ 1 ]. For example, while impaired gut wall integrity through surgery or illness may increase the risk of candidiasis, it was not considered specific enough to warrant inclusion as a host factor.” | concept_edges[0] |
| relation | a host factor —distinct-from→ a risk factor — a host factor predisposes to the disease; a risk factor merely raises the probability, and the definitions admit only the first — “While definitions of proven and probable disease have been shown to be reliable in research and attracted little controversy among the group, this cannot be said of the possible IFD category. There is much confusion about the difference between a host factor and a risk factor. As before, a host factor has been defined as a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD [ 1 ]. For example, while impaired gut wall integrity through surgery or illness may increase the risk of candidiasis, it was not considered specific enough to warrant inclusion as a host factor.” — “There is much confusion about the difference between a host factor and a risk factor. As before, a host factor has been defined as a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD [ 1 ].” | concept_edges[0] |
| weight | a host factor —distinct-from→ a risk factor — 0.95 — “While definitions of proven and probable disease have been shown to be reliable in research and attracted little controversy among the group, this cannot be said of the possible IFD category. There is much confusion about the difference between a host factor and a risk factor. As before, a host factor has been defined as a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD [ 1 ]. For example, while impaired gut wall integrity through surgery or illness may increase the risk of candidiasis, it was not considered specific enough to warrant inclusion as a host factor.” | concept_edges[0] |
| note | a host factor —operationalised-as→ a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD — 'As before, a host factor has been defined as a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD.' 'As before' matters: this is the one part of the definition the revision left alone, while the list of things that satisfy it grew — “While definitions of proven and probable disease have been shown to be reliable in research and attracted little controversy among the group, this cannot be said of the possible IFD category. There is much confusion about the difference between a host factor and a risk factor. As before, a host factor has been defined as a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD [ 1 ]. For example, while impaired gut wall integrity through surgery or illness may increase the risk of candidiasis, it was not considered specific enough to warrant inclusion as a host factor.” | concept_edges[1] |
| relation | a host factor —operationalised-as→ a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD — the operational test for a host factor is predisposition rather than elevated risk, which is what keeps common ICU exposures out of the category — “While definitions of proven and probable disease have been shown to be reliable in research and attracted little controversy among the group, this cannot be said of the possible IFD category. There is much confusion about the difference between a host factor and a risk factor. As before, a host factor has been defined as a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD [ 1 ]. For example, while impaired gut wall integrity through surgery or illness may increase the risk of candidiasis, it was not considered specific enough to warrant inclusion as a host factor.” — “a host factor has been defined as a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD [ 1 ].” | concept_edges[1] |
| weight | a host factor —operationalised-as→ a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD — 0.95 — “While definitions of proven and probable disease have been shown to be reliable in research and attracted little controversy among the group, this cannot be said of the possible IFD category. There is much confusion about the difference between a host factor and a risk factor. As before, a host factor has been defined as a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD [ 1 ]. For example, while impaired gut wall integrity through surgery or illness may increase the risk of candidiasis, it was not considered specific enough to warrant inclusion as a host factor.” | concept_edges[1] |
| note | definitions of IFD required for clinical research —distinct-from→ those that influence clinical practice — 'Throughout this process, we have emphasized the need to differentiate between definitions of IFD required for clinical research from those that influence clinical practice. In clinical practice, many would administer an antifungal agent to any patient at risk ... without there being sufficient evidence to satisfy the consensus definitions.' A definition restricted by PURPOSE - the first in the corpus; the others are restricted by population or by evidence base — “Throughout this process, we have emphasized the need to differentiate between definitions of IFD required for clinical research from those that influence clinical practice. In clinical practice, many would administer an antifungal agent to any patient at risk of IFD when fungi are detected by biomarkers in serum, plasma, whole blood, or relevant body site fluid without there being sufficient evidence to satisfy the consensus definitions of IFD.” | concept_edges[2] |
| relation | definitions of IFD required for clinical research —distinct-from→ those that influence clinical practice — the research definition is deliberately stricter than clinical behaviour, and the authors say so twice - once at the start and once in the general points — “Throughout this process, we have emphasized the need to differentiate between definitions of IFD required for clinical research from those that influence clinical practice. In clinical practice, many would administer an antifungal agent to any patient at risk of IFD when fungi are detected by biomarkers in serum, plasma, whole blood, or relevant body site fluid without there being sufficient evidence to satisfy the consensus definitions of IFD.” — “we have emphasized the need to differentiate between definitions of IFD required for clinical research from those that influence clinical practice.” | concept_edges[2] |
| weight | definitions of IFD required for clinical research —distinct-from→ those that influence clinical practice — 0.95 — “Throughout this process, we have emphasized the need to differentiate between definitions of IFD required for clinical research from those that influence clinical practice. In clinical practice, many would administer an antifungal agent to any patient at risk of IFD when fungi are detected by biomarkers in serum, plasma, whole blood, or relevant body site fluid without there being sufficient evidence to satisfy the consensus definitions of IFD.” | concept_edges[2] |
| note | Exposure to 1 of these fungi —operationalised-as→ a history of residence in an endemic area — 'Exposure to 1 of these fungi is defined as a history of residence in an endemic area, no matter how remote, travel to an endemic area, or contact with fomites such as soil or vegetation that is derived from an endemic area.' The only criterion in the document with no recency bound at all - and it stands in for the host factor, because endemic mycoses 'affect both healthy and less healthy hosts' — “Exposure to 1 of these fungi is defined as a history of residence in an endemic area, no matter how remote, travel to an endemic area, or contact with fomites such as soil or vegetation that is derived from an endemic area.” | concept_edges[3] |
| relation | Exposure to 1 of these fungi —operationalised-as→ a history of residence in an endemic area — for endemic mycoses, exposure is any residence, travel or fomite contact - 'no matter how remote' - which makes a lifetime of geography a diagnostic criterion — “Exposure to 1 of these fungi is defined as a history of residence in an endemic area, no matter how remote, travel to an endemic area, or contact with fomites such as soil or vegetation that is derived from an endemic area.” | concept_edges[3] |
| weight | Exposure to 1 of these fungi —operationalised-as→ a history of residence in an endemic area — 0.95 — “Exposure to 1 of these fungi is defined as a history of residence in an endemic area, no matter how remote, travel to an endemic area, or contact with fomites such as soil or vegetation that is derived from an endemic area.” | concept_edges[3] |
| audit | Cryptococcus neoformans —distinct-from→ Cryptococcus gattii — Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but reports 'suggest' different presentations and outcomes, and the next sentence says outcomes appear similar; hedged. — “Identification to the species level for Cryptococcus neoformans and Cryptococcus gattii has become increasingly important based on reports that suggest different clinical presentations, outcomes, and responses to antifungal therapy between these 2 species [ 71 , 72 ]. Verification of species that use CGB (L-canavanine, glycine, bromthymol blue) agar or matrix-assisted laser desorption ionization–time of flight mass spectrometry is recommended. Outcomes for HIV-associated cryptococcosis due to C. neoformans and C. gattii appear to be similar, and identification to the species level may be unnecessary [ 73 , 74 ].” | concept_edges[4] |
| note | Cryptococcus neoformans —distinct-from→ Cryptococcus gattii — 'Identification to the species level for Cryptococcus neoformans and Cryptococcus gattii has become increasingly important based on reports that suggest different clinical presentations, outcomes, and responses to antifungal therapy between these 2 species.' Whether the distinction is worth drawing depends on the host, and the paper prints both answers in one paragraph without a rule for choosing — “Identification to the species level for Cryptococcus neoformans and Cryptococcus gattii has become increasingly important based on reports that suggest different clinical presentations, outcomes, and responses to antifungal therapy between these 2 species [ 71 , 72 ]. Verification of species that use CGB (L-canavanine, glycine, bromthymol blue) agar or matrix-assisted laser desorption ionization–time of flight mass spectrometry is recommended. Outcomes for HIV-associated cryptococcosis due to C. neoformans and C. gattii appear to be similar, and identification to the species level may be unnecessary [ 73 , 74 ].” | concept_edges[4] |
| relation | Cryptococcus neoformans —distinct-from→ Cryptococcus gattii — the two species differ in presentation, outcome and antifungal response, so the definitions now ask for identification - except in HIV, where outcomes look the same and identification 'may be unnecessary' — “Identification to the species level for Cryptococcus neoformans and Cryptococcus gattii has become increasingly important based on reports that suggest different clinical presentations, outcomes, and responses to antifungal therapy between these 2 species [ 71 , 72 ]. Verification of species that use CGB (L-canavanine, glycine, bromthymol blue) agar or matrix-assisted laser desorption ionization–time of flight mass spectrometry is recommended. Outcomes for HIV-associated cryptococcosis due to C. neoformans and C. gattii appear to be similar, and identification to the species level may be unnecessary [ 73 , 74 ].” — “Identification to the species level for Cryptococcus neoformans and Cryptococcus gattii has become increasingly important based on reports that suggest different clinical presentations, outcomes, and responses to antifungal therapy between these 2 species” | concept_edges[4] |
| weight | Cryptococcus neoformans —distinct-from→ Cryptococcus gattii — 0.9 — “Identification to the species level for Cryptococcus neoformans and Cryptococcus gattii has become increasingly important based on reports that suggest different clinical presentations, outcomes, and responses to antifungal therapy between these 2 species [ 71 , 72 ]. Verification of species that use CGB (L-canavanine, glycine, bromthymol blue) agar or matrix-assisted laser desorption ionization–time of flight mass spectrometry is recommended. Outcomes for HIV-associated cryptococcosis due to C. neoformans and C. gattii appear to be similar, and identification to the species level may be unnecessary [ 73 , 74 ].” | concept_edges[4] |
| effect direction | Exposure to mold-active antifungals —causes→ the utility of the GM test — reduces — “Exposure to mold-active antifungals compromises the utility of the GM test for IA [ 38 ] by reducing its sensitivity [ 39 ]. Therefore, caution should be exercised when GM is found to be absent from serum or plasma in patients receiving mold-active antifungals.” — “compromises the utility of the GM test for IA [ 38 ] by reducing its sensitivity” | concept_edges[5] |
| note | Exposure to mold-active antifungals —causes→ the utility of the GM test — 'Exposure to mold-active antifungals compromises the utility of the GM test for IA by reducing its sensitivity. Therefore, caution should be exercised when GM is found to be absent from serum or plasma in patients receiving mold-active antifungals.' The definition depends on a measurement that the standard of care degrades - the high-risk patients on prophylaxis are the ones whose negative result is least informative — “Exposure to mold-active antifungals compromises the utility of the GM test for IA [ 38 ] by reducing its sensitivity [ 39 ]. Therefore, caution should be exercised when GM is found to be absent from serum or plasma in patients receiving mold-active antifungals.” | concept_edges[5] |
| relation | Exposure to mold-active antifungals —causes→ the utility of the GM test — antifungal prophylaxis lowers the sensitivity of galactomannan, so a negative test means less in exactly the patients most likely to be tested — “Exposure to mold-active antifungals compromises the utility of the GM test for IA [ 38 ] by reducing its sensitivity [ 39 ]. Therefore, caution should be exercised when GM is found to be absent from serum or plasma in patients receiving mold-active antifungals.” — “Exposure to mold-active antifungals compromises the utility of the GM test for IA [ 38 ] by reducing its sensitivity” | concept_edges[5] |
| weight | Exposure to mold-active antifungals —causes→ the utility of the GM test — 0.9 — “Exposure to mold-active antifungals compromises the utility of the GM test for IA [ 38 ] by reducing its sensitivity [ 39 ]. Therefore, caution should be exercised when GM is found to be absent from serum or plasma in patients receiving mold-active antifungals.” | concept_edges[5] |
| note | revised thresholds for galactomannan —part-of→ definitions for probable invasive fungal disease — 'EORTC and MSG DEFINITIONS FOR PROBABLE INVASIVE FUNGAL DISEASE NOW INCLUDE solid organ transplant, hematologic malignancy, graft-versus-host disease, the reverse halo sign, revised thresholds for galactomannan, Aspergillus polymerase chain reaction, and definitions for candidiasis, cryptococcosis, ... and endemic mycoses.' This list is what 'no change in the classifications' conceals - the word 'probable' is the same and its contents are not — “European Organization for Research and Treatment of Cancer and the Mycoses Study Group definitions for probable invasive fungal disease now include solid organ transplant, hematologic malignancy, graft-versus-host disease, the reverse halo sign, revised thresholds for galactomannan, Aspergillus polymerase chain reaction, and definitions for candidiasis, cryptococcosis, non-human immunodeficiency viirus–associated pneumocystosis, and endemic mycoses.” | concept_edges[6] |
| relation | revised thresholds for galactomannan —part-of→ definitions for probable invasive fungal disease — the probable category now contains new host factors, a new radiological sign, GM thresholds that replace the manufacturer's, and Aspergillus PCR — “European Organization for Research and Treatment of Cancer and the Mycoses Study Group definitions for probable invasive fungal disease now include solid organ transplant, hematologic malignancy, graft-versus-host disease, the reverse halo sign, revised thresholds for galactomannan, Aspergillus polymerase chain reaction, and definitions for candidiasis, cryptococcosis, non-human immunodeficiency viirus–associated pneumocystosis, and endemic mycoses.” — “definitions for probable invasive fungal disease now include solid organ transplant, hematologic malignancy, graft-versus-host disease, the reverse halo sign, revised thresholds for galactomannan” | concept_edges[6] |
| weight | revised thresholds for galactomannan —part-of→ definitions for probable invasive fungal disease — 0.9 — “European Organization for Research and Treatment of Cancer and the Mycoses Study Group definitions for probable invasive fungal disease now include solid organ transplant, hematologic malignancy, graft-versus-host disease, the reverse halo sign, revised thresholds for galactomannan, Aspergillus polymerase chain reaction, and definitions for candidiasis, cryptococcosis, non-human immunodeficiency viirus–associated pneumocystosis, and endemic mycoses.” | concept_edges[6] |
| note | disseminated cryptococcosis —contrasted-with→ CNS cryptococcosis — `The term `DISSEMINATED CRYPTOCOCCOSIS` as distinct from CNS cryptococcosis has been abandoned in favor of the terms `PULMONARY,` `CNS` AND `OTHER EXTRAPULMONARY SITES.`` Typed `contrasted-with`: the paper reports the distinction in order to retire it. A term defined as the complement of another is exactly the kind that gets replaced by an enumeration — “The term “disseminated cryptococcosis” as distinct from CNS cryptococcosis has been abandoned in favor of the terms “pulmonary,” “CNS” and “other extrapulmonary sites.”” | concept_edges[7] |
| relation | disseminated cryptococcosis —contrasted-with→ CNS cryptococcosis — 'disseminated' existed only as the complement of CNS disease and has been replaced by naming the sites - pulmonary, CNS, other extrapulmonary — “The term “disseminated cryptococcosis” as distinct from CNS cryptococcosis has been abandoned in favor of the terms “pulmonary,” “CNS” and “other extrapulmonary sites.”” | concept_edges[7] |
| weight | disseminated cryptococcosis —contrasted-with→ CNS cryptococcosis — 0.95 — “The term “disseminated cryptococcosis” as distinct from CNS cryptococcosis has been abandoned in favor of the terms “pulmonary,” “CNS” and “other extrapulmonary sites.”” | concept_edges[7] |
| outcome | control — held — “The group did not support the use of serum BDG to rule in patients for clinical trials or for defining IA or IC, as BDG detection is not specific for any one IFD.” — “A single threshold (>80 pg/mL) using the Fungitell test (Associates of Cape Cod, Falmouth, MA) is recommended; there is insufficient evidence to include assays produced by other manufacturers [ 42 ].” | controls[0] |
| outcome | control — held — “While definitions of proven and probable disease have been shown to be reliable in research and attracted little controversy among the group, this cannot be said of the possible IFD category. There is much confusion about the difference between a host factor and a risk factor. As before, a host factor has been defined as a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD [ 1 ]. For example, while impaired gut wall integrity through surgery or illness may increase the risk of candidiasis, it was not considered specific enough to warrant inclusion as a host factor.” — “We also recognize that our definition of a host factor errs on the side of conservatism given the increasing use of drugs such as monoclonal antibodies for treating a variety of conditions.” | controls[1] |
| outcome | control — held — “Tissue diagnosis requires the presence of fungal elements in formalin-fixed paraffin-embedded tissue and signifies proven fungal disease but not the identity of the fungus involved.” — “There are relatively few commercial PCR assays, and most investigators have developed methods in-house. As such, the FPCRI was established to develop criteria for Aspergillus PCR rather than a standardized method per se.” | controls[2] |
| outcome | control — held — “Volunteers from the EORTC Infectious Diseases Group and the MSGERC were assigned according to their expertise to 10 working groups, each charged with appraising a particular topic (see list of contributors in the Notes section). The chairs of the EORTC and MSG (J. P. D. and P. G. P.) selected leaders for each working group, and S. C. served as executive secretary. After completing the first round of working group assignments, leaders presented each group’s initial deliberations and recommendations at the 7th Trends in Medical Mycology Conference in Lisbon, Portugal, October 2015. A slide set was made available until 31 December 2015 online at www.e-materials.com/timm2015/invitation/Member and, on request, for public comment. After several iterations, the final draft of the manuscript was circulated to all members for their approval.” — “To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups’ findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved.” | controls[3] |
| limitation | THE PAPER SAYS ITS OWN CATEGORIES EXCLUDE REAL DISEASE: `We acknowledge the limitations of these definitions, including the exclusion of certain cases of IFD. However, the reliance on host factors, clinical features, and mycologic evidence to define IFD in selected populations has proven its value for clinical trials.` A research definition is allowed to be narrower than the disease; what it is not allowed to do is be read as a prevalence — “In summary, these revised definitions represent consensus expert opinion based on the best available evidence. As such, they will need to be reviewed regularly for their utility and relevance and, where possible, extended to other populations affected by IFDs. We acknowledge the limitations of these definitions, including the exclusion of certain cases of IFD.” | limitations[0] |
| limitation | AND THE HOST-FACTOR LIST IS CONSERVATIVE BY ADMISSION, IN A CHANGING POPULATION: `We also recognize that our definition of a host factor errs on the side of conservatism given the increasing use of drugs such as monoclonal antibodies for treating a variety of conditions.` The denominator of at-risk patients is growing faster than the list that defines it, and the definition will therefore miss more cases over time by construction — “We also recognize that our definition of a host factor errs on the side of conservatism given the increasing use of drugs such as monoclonal antibodies for treating a variety of conditions.” | limitations[1] |
| limitation | AND THE 2008 VERSION'S FAILURES ARE THE MAP OF THIS ONE'S EXPOSURE: `the definitions were UNSUITABLE FOR PATIENTS ... IN INTENSIVE CARE UNITS OR IN PEDIATRICS, DATA WERE INSUFFICIENT to establish appropriate thresholds ..., and there was uncertainty about the role of (1,3)-beta-D glucan. Furthermore, ... PCR-BASED TESTS WERE EXCLUDED BECAUSE OF LACK OF STANDARDIZATION.` Eleven years of studies used a definition its own successors call unsuitable for two whole populations — “The 2008 definitions had their shortcomings, including the facts that the definitions were unsuitable for patients with IFD in the setting of intensive care units (ICUs) or in pediatrics, data were insufficient to establish appropriate thresholds for detecting Aspergillus galactomannan (GM), and there was uncertainty about the role of (1,3)-beta-D glucan (BDG). Furthermore, nucleic acid amplification including polymerase chain reaction (PCR)–based tests were excluded because of lack of standardization and validation. Definitions for cryptococcosis and endemic mycoses also needed clarification, and there were no definitions for pneumocystosis.” | limitations[2] |
| limitation | AND ONE OF THE TEN WORKING GROUPS COULD NOT DO ITS JOB: `group 10 (IFD definitions in ICU patients) was unable to generate recommendations that preserved a level of certainty consistent with the existing definitions except for proven IFD.` The ICU population named as a gap in 2008 is still outside the definitions in 2019, and the reason is that the certainty the categories require cannot be reached there — “However, group 10 (IFD definitions in ICU patients) was unable to generate recommendations that preserved a level of certainty consistent with the existing definitions except for proven IFD ( Table 1 ) and therefore undertook a separate initiative [ 8 ].” | limitations[3] |
| limitation | AND THE SAME SPECIES QUESTION IS ANSWERED BOTH WAYS ON ONE PAGE: `Identification to the species level for Cryptococcus neoformans and Cryptococcus gattii has become increasingly important based on reports that suggest different clinical presentations, outcomes, and responses to antifungal therapy` - and then `Outcomes for HIV-associated cryptococcosis due to C. neoformans and C. gattii appear to be similar, and identification to the species level may be unnecessary.` Whether a distinction matters depends on the host, and both halves are printed without a rule for choosing between them — “Identification to the species level for Cryptococcus neoformans and Cryptococcus gattii has become increasingly important based on reports that suggest different clinical presentations, outcomes, and responses to antifungal therapy between these 2 species [ 71 , 72 ]. Verification of species that use CGB (L-canavanine, glycine, bromthymol blue) agar or matrix-assisted laser desorption ionization–time of flight mass spectrometry is recommended. Outcomes for HIV-associated cryptococcosis due to C. neoformans and C. gattii appear to be similar, and identification to the species level may be unnecessary [ 73 , 74 ].” | limitations[4] |
| limitation | AND THE DISCLOSURES ARE EXTENSIVE AND UNIFORM ACROSS 62 AUTHORS: `J. P. Donnelly reports personal fees from F2G Ltd, Gilead Sciences, and Pfizer outside the submitted work.` Comparable statements follow for most of the author list, naming the manufacturers of antifungals and of the diagnostic assays whose thresholds this document sets. All declared, none hidden - and the panel that fixes an assay's cutoff is advised by people paid by the companies selling the assays, which is a fact about how this field is organised — “J. P. Donnelly reports personal fees from F2G Ltd, Gilead Sciences, and Pfizer outside the submitted work.” | limitations[5] |
finding · quantity · variable · definition · key-term — grounded in the full text| finding | — “There is no change in the classifications of “proven,” “probable,” and “possible” IFD, although the definition of “probable” has been expanded and the scope of the category “possible” has been diminished.” | content_tags.findings[0] |
| finding | — “Importantly, these definitions are specifically intended for these purposes only and not to direct or guide patient care.” | content_tags.findings[1] |
| finding | — “In the previous definitions [ 1 ], indirect tests for diagnosing IFD were only included if there was sufficient evidence that they had been standardized and validated. Moreover, commercial tests were included only if criteria for interpretation had been provided. Hence, while tests for GM and BDG were incorporated, tests for detecting fungal nucleic acid were not [ 1 ]. Furthermore, there was no agreement about appropriate thresholds, so the manufacturers’ analytical thresholds were adopted.” | content_tags.findings[2] |
| finding | — ““Colonization” with Cryptococcus spp. is no longer included in the definitions as it is poorly understood and its natural history is unknown.” | content_tags.findings[3] |
| finding | — “The term “disseminated cryptococcosis” as distinct from CNS cryptococcosis has been abandoned in favor of the terms “pulmonary,” “CNS” and “other extrapulmonary sites.”” | content_tags.findings[4] |
| finding | — “While definitions of proven and probable disease have been shown to be reliable in research and attracted little controversy among the group, this cannot be said of the possible IFD category. There is much confusion about the difference between a host factor and a risk factor. As before, a host factor has been defined as a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD [ 1 ]. For example, while impaired gut wall integrity through surgery or illness may increase the risk of candidiasis, it was not considered specific enough to warrant inclusion as a host factor.” | content_tags.findings[5] |
| finding | — “However, group 10 (IFD definitions in ICU patients) was unable to generate recommendations that preserved a level of certainty consistent with the existing definitions except for proven IFD ( Table 1 ) and therefore undertook a separate initiative [ 8 ].” | content_tags.findings[6] |
| finding | — “However, we also recognize cryptococcal infection among individuals in high-risk host groups who have few, if any, symptoms and only a positive serum cryptococcal antigen test (asymptomatic cryptococcal antigenemia). This condition may be more common than symptomatic disease, and patients may develop clinical cryptococcal disease unless treated and so are now included in these definitions [ 70 ].” | content_tags.findings[7] |
| finding | — “There are relatively few commercial PCR assays, and most investigators have developed methods in-house. As such, the FPCRI was established to develop criteria for Aspergillus PCR rather than a standardized method per se.” | content_tags.findings[8] |
| finding | — “In summary, these revised definitions represent consensus expert opinion based on the best available evidence. As such, they will need to be reviewed regularly for their utility and relevance and, where possible, extended to other populations affected by IFDs. We acknowledge the limitations of these definitions, including the exclusion of certain cases of IFD.” | content_tags.findings[9] |
| quantity | 3 names unchanged; `probable` expanded, `possible` diminished, `proven` extended to any patient — — “The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses.” | content_tags.quantities[0] |
| quantity | 10 working groups, 1 conference, a 3-month public comment period, several rounds — — “To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups’ findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved.” | content_tags.quantities[1] |
| quantity | 80 pg/mL, on the Fungitell test only — — “A single threshold (>80 pg/mL) using the Fungitell test (Associates of Cape Cod, Falmouth, MA) is recommended; there is insufficient evidence to include assays produced by other manufacturers [ 42 ].” | content_tags.quantities[2] |
| quantity | 62% in ICU sepsis, 92% in neutropenic transplant and leukaemia patients — — “The PPV increases from 62% among patients with sepsis, shock, or lengths of stay greater than 3–7 days in an ICU to 92% for bone marrow transplant recipients and patients with leukemia who are neutropenic but not receiving any antifungal prophylaxis.” | content_tags.quantities[3] |
| variable | galactomannan (GM) — “We evaluated Aspergillus galactomannan for both adults and children and specific patient groups and its utility and validity for different clinical specimens. We adopted different thresholds for different specimens rather than for different host groups [ 33–35 ] ( Table 2 ).” | content_tags.variables[0] |
| variable | (1,3)-beta-D glucan (BDG) — “The group did not support the use of serum BDG to rule in patients for clinical trials or for defining IA or IC, as BDG detection is not specific for any one IFD.” | content_tags.variables[1] |
| variable | Aspergillus PCR — “There are relatively few commercial PCR assays, and most investigators have developed methods in-house. As such, the FPCRI was established to develop criteria for Aspergillus PCR rather than a standardized method per se.” | content_tags.variables[2] |
| definition | host factor — “While definitions of proven and probable disease have been shown to be reliable in research and attracted little controversy among the group, this cannot be said of the possible IFD category. There is much confusion about the difference between a host factor and a risk factor. As before, a host factor has been defined as a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD [ 1 ]. For example, while impaired gut wall integrity through surgery or illness may increase the risk of candidiasis, it was not considered specific enough to warrant inclusion as a host factor.” | content_tags.definitions[1] |
| definition | exposure — “Exposure to 1 of these fungi is defined as a history of residence in an endemic area, no matter how remote, travel to an endemic area, or contact with fomites such as soil or vegetation that is derived from an endemic area.” | content_tags.definitions[2] |
| definition | tissue diagnosis — “Tissue diagnosis requires the presence of fungal elements in formalin-fixed paraffin-embedded tissue and signifies proven fungal disease but not the identity of the fungus involved.” | content_tags.definitions[4] |
| concept | a host factor — not defined in this paper's own words; a characteristic that predisposes to IFD, as against one that merely raises risk — “While definitions of proven and probable disease have been shown to be reliable in research and attracted little controversy among the group, this cannot be said of the possible IFD category. There is much confusion about the difference between a host factor and a risk factor. As before, a host factor has been defined as a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD [ 1 ]. For example, while impaired gut wall integrity through surgery or illness may increase the risk of candidiasis, it was not considered specific enough to warrant inclusion as a host factor.” | concepts[0] |
| concept | a risk factor — not defined in this paper's own words; the neighbouring term the definition has to be separated from — “While definitions of proven and probable disease have been shown to be reliable in research and attracted little controversy among the group, this cannot be said of the possible IFD category. There is much confusion about the difference between a host factor and a risk factor. As before, a host factor has been defined as a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD [ 1 ]. For example, while impaired gut wall integrity through surgery or illness may increase the risk of candidiasis, it was not considered specific enough to warrant inclusion as a host factor.” | concepts[1] |
| concept | a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD — not defined in this paper's own words; the definition of a host factor, unchanged since 2008 — “While definitions of proven and probable disease have been shown to be reliable in research and attracted little controversy among the group, this cannot be said of the possible IFD category. There is much confusion about the difference between a host factor and a risk factor. As before, a host factor has been defined as a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFD [ 1 ]. For example, while impaired gut wall integrity through surgery or illness may increase the risk of candidiasis, it was not considered specific enough to warrant inclusion as a host factor.” | concepts[2] |
| concept | definitions of IFD required for clinical research — not defined in this paper's own words; what this document is - and the only thing it claims to be — “Throughout this process, we have emphasized the need to differentiate between definitions of IFD required for clinical research from those that influence clinical practice. In clinical practice, many would administer an antifungal agent to any patient at risk of IFD when fungi are detected by biomarkers in serum, plasma, whole blood, or relevant body site fluid without there being sufficient evidence to satisfy the consensus definitions of IFD.” | concepts[3] |
| concept | those that influence clinical practice — not defined in this paper's own words; the other kind of definition, which the authors deliberately do not write — “Throughout this process, we have emphasized the need to differentiate between definitions of IFD required for clinical research from those that influence clinical practice. In clinical practice, many would administer an antifungal agent to any patient at risk of IFD when fungi are detected by biomarkers in serum, plasma, whole blood, or relevant body site fluid without there being sufficient evidence to satisfy the consensus definitions of IFD.” | concepts[4] |
| concept | Exposure to 1 of these fungi — not defined in this paper's own words; the endemic-mycoses criterion that stands in for a host factor — “Exposure to 1 of these fungi is defined as a history of residence in an endemic area, no matter how remote, travel to an endemic area, or contact with fomites such as soil or vegetation that is derived from an endemic area.” | concepts[5] |
| concept | a history of residence in an endemic area — not defined in this paper's own words; what exposure is operationalised as - with no recency requirement — “Exposure to 1 of these fungi is defined as a history of residence in an endemic area, no matter how remote, travel to an endemic area, or contact with fomites such as soil or vegetation that is derived from an endemic area.” | concepts[6] |
| concept | Cryptococcus neoformans — not defined in this paper's own words; one of the two cryptococcal species the definitions now ask to be told apart — “Identification to the species level for Cryptococcus neoformans and Cryptococcus gattii has become increasingly important based on reports that suggest different clinical presentations, outcomes, and responses to antifungal therapy between these 2 species [ 71 , 72 ]. Verification of species that use CGB (L-canavanine, glycine, bromthymol blue) agar or matrix-assisted laser desorption ionization–time of flight mass spectrometry is recommended. Outcomes for HIV-associated cryptococcosis due to C. neoformans and C. gattii appear to be similar, and identification to the species level may be unnecessary [ 73 , 74 ].” | concepts[7] |
| concept | Cryptococcus gattii — not defined in this paper's own words; the other - differing in presentation and treatment response, except in HIV — “Identification to the species level for Cryptococcus neoformans and Cryptococcus gattii has become increasingly important based on reports that suggest different clinical presentations, outcomes, and responses to antifungal therapy between these 2 species [ 71 , 72 ]. Verification of species that use CGB (L-canavanine, glycine, bromthymol blue) agar or matrix-assisted laser desorption ionization–time of flight mass spectrometry is recommended. Outcomes for HIV-associated cryptococcosis due to C. neoformans and C. gattii appear to be similar, and identification to the species level may be unnecessary [ 73 , 74 ].” | concepts[8] |
| concept | Exposure to mold-active antifungals — not defined in this paper's own words; prophylaxis or treatment already given when the test is run — “Exposure to mold-active antifungals compromises the utility of the GM test for IA [ 38 ] by reducing its sensitivity [ 39 ]. Therefore, caution should be exercised when GM is found to be absent from serum or plasma in patients receiving mold-active antifungals.” | concepts[9] |
| concept | the utility of the GM test — not defined in this paper's own words; what that exposure degrades, by lowering sensitivity — “Exposure to mold-active antifungals compromises the utility of the GM test for IA [ 38 ] by reducing its sensitivity [ 39 ]. Therefore, caution should be exercised when GM is found to be absent from serum or plasma in patients receiving mold-active antifungals.” | concepts[10] |
| concept | definitions for probable invasive fungal disease — not defined in this paper's own words; the category this revision expanded — “European Organization for Research and Treatment of Cancer and the Mycoses Study Group definitions for probable invasive fungal disease now include solid organ transplant, hematologic malignancy, graft-versus-host disease, the reverse halo sign, revised thresholds for galactomannan, Aspergillus polymerase chain reaction, and definitions for candidiasis, cryptococcosis, non-human immunodeficiency viirus–associated pneumocystosis, and endemic mycoses.” | concepts[11] |
| concept | revised thresholds for galactomannan — not defined in this paper's own words; one of the new components - and the one that displaces the manufacturer's cutoff — “European Organization for Research and Treatment of Cancer and the Mycoses Study Group definitions for probable invasive fungal disease now include solid organ transplant, hematologic malignancy, graft-versus-host disease, the reverse halo sign, revised thresholds for galactomannan, Aspergillus polymerase chain reaction, and definitions for candidiasis, cryptococcosis, non-human immunodeficiency viirus–associated pneumocystosis, and endemic mycoses.” | concepts[12] |
| concept | disseminated cryptococcosis — not defined in this paper's own words; the abandoned term, whose meaning was 'beyond the CNS' — “The term “disseminated cryptococcosis” as distinct from CNS cryptococcosis has been abandoned in favor of the terms “pulmonary,” “CNS” and “other extrapulmonary sites.”” | concepts[13] |
| concept | CNS cryptococcosis — not defined in this paper's own words; the term it was defined against — “The term “disseminated cryptococcosis” as distinct from CNS cryptococcosis has been abandoned in favor of the terms “pulmonary,” “CNS” and “other extrapulmonary sites.”” | concepts[14] |
| a positive predictive value that moves 30 points with the population | — “The PPV increases from 62% among patients with sepsis, shock, or lengths of stay greater than 3–7 days in an ICU to 92% for bone marrow transplant recipients and patients with leukemia who are neutropenic but not receiving any antifungal prophylaxis.” | content_tags.statistics[0] |
| a diagnostic threshold that was a commercial parameter | — “In the previous definitions [ 1 ], indirect tests for diagnosing IFD were only included if there was sufficient evidence that they had been standardized and validated. Moreover, commercial tests were included only if criteria for interpretation had been provided. Hence, while tests for GM and BDG were incorporated, tests for detecting fungal nucleic acid were not [ 1 ]. Furthermore, there was no agreement about appropriate thresholds, so the manufacturers’ analytical thresholds were adopted.” | content_tags.statistics[1] |
| sensitivity degraded by the standard of care | — “Exposure to mold-active antifungals compromises the utility of the GM test for IA [ 38 ] by reducing its sensitivity [ 39 ]. Therefore, caution should be exercised when GM is found to be absent from serum or plasma in patients receiving mold-active antifungals.” | content_tags.statistics[2] |
| claim type | method — a second reading reaching the same value; recorded: method — “These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.” | alternatives.claim_type |
| method | expert-consensus — a second reading DIFFERING from the recorded value; recorded: expert-consensus — “To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD.” | alternatives.method |
| phenomenon | the consensus definitions of proven, probable and possible invasive fungal disease — a second reading DIFFERING from the recorded value; recorded: a group of diseases that can rarely be proven in life, so that the categories researchers count are degrees of certainty — “The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies.” | alternatives.phenomenon |
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1409 cid Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America Clin Infect Dis Oxford University Press PMC7486838 7486838 7486838 31802125 10.1093/cid/ciz1008 Revision andpersName Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research andpersName Treatment of Cancer andpersName the Mycoses Study Group Education andpersName Research Consortium DonnellypersName J Peter 1 ✉ ChenpersName Sharon C 2 KauffmanpersName Carol A 3 SteinbachpersName William J 4 BaddleypersName John W 5 VerweijpersName Paul E 6 ClancypersName Cornelius J 7 WingardpersName John R 8 LockhartpersName Shawn R 9 GrollpersName Andreas H 10 SorrellpersName Tania C 11 BassettipersName Matteo 12 AkanpersName Hamdi 13 AlexanderpersName Barbara D 14 AndespersName David 15 AzoulaypersName Elie 16 BialekpersName Ralf 17 BradsherpersName Robert W Jr 18 BretagnepersName Stephane 19 CalandrapersName Thierry 20 CaliendopersName Angela M 21 CastagnolapersName Elio 22 CrucianipersName Mario 23 Cuenca-EstrellapersName Manuel 24 DeckerpersName Catherine F 25 DesaipersName Sujal R 26 FisherpersName Brian 27 HarrisonpersName Thomas 28 Heussel Claus Peter 29 JensenpersName Henrik E 30 KibblerpersName Christopher C 31 KontoyiannispersName Dimitrios P 32 KullbergpersName Bart-Jan 33 LagroupersName Katrien 34 LamothpersName Frédéric 35 LehrnbecherpersName Thomas 36 LoefflerpersName Jurgen 37 LortholarypersName Olivier 38 MaertenspersName Johan 39 62 MarchettipersName Oscar 20 MarrpersName Kieren A 40 MasurpersName Henry 41 MeispersName Jacques F 42 MorriseypersName C Orla 43 NuccipersName Marcio 44 Ostrosky-ZeichnerpersName Luis 45 PaganopersName Livio 46 PattersonpersName Thomas F 47 PerfectpersName John R 14 Racil Zdenek 48 RoilidespersName Emmanuel 49 RuhnkepersName Marcus 50 ProkoppersName Cornelia Schaefer 51 ShohampersName Shmuel 40 SlavinpersName Monica A 52 StevenspersName David A 53 64 ThompsonpersName George R III 54 Vazquez Jose A 55 ViscolipersName Claudio 56 WalshpersName Thomas J 57 WarrispersName Adilia 58 WheatpersName L Joseph 59 WhitepersName P Lewis 60 ZaoutispersName Theoklis E 61 PappaspersName Peter G 5 1 Department of Hematology, Radboudumc, Nijmegen, The Netherlands 2 Centre for Infectious Diseases andpersName Microbiology, Laboratory Services, Institute of Clinical Pathology andpersName Medical Research, Westmead Hospital, University of Sydney, Sydney, Australia 3 Division of Infectious Diseases, University of Michigan, VA Ann Arbor Healthcare System, Ann Arbor, Michigan, USA 4 Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA 5 Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA 6 Center of Expertise in Mycology Radboudumc/CWZ, Nijmegen, The Netherlands 7 University of Pittsburgh, Pittsburg, Pennsylvania, USA 8 Department of Medicine, University of Florida College of Medicine, Gainesville, Florida, USA 9 Mycotic Diseases Branch, Centers for Disease Control andpersName Prevention, Atlanta, Georgia, USA 10 Infectious Disease Research Program, Center for Bone Marrow Transplantation andpersName Department of Pediatric Hematology andpersName Oncology University Children’s Hospital, Münster, Germany 11 University of Sydney, Marie Bashir Institute for Infectious Diseases & Biosecurity, University of Sydney School of Medicine Faculty of Medicine andpersName Health, Westmead Institute for Centre for Infectious Diseases andpersName Microbiology, Western Sydney Local Health District, Sydney, Australia 12 Infectious Disease Clinic, Department of Medicine University of Udine andpersName Department of Health Sciences, DISSAL, University of Genoa, Genoa, Italy 13 Ankara University, Faculty of Medicine, Cebeci Campus, Hematology Clinical Research Unit, Ankara, Turkey 14 Department of Medicine andpersName Division of Infectious Diseases, Duke University Medical Center, Durham, North Carolina, USA 15 Division of Infectious Diseases, Departments of Medicine, Microbiology andpersName Immunology School of Medicine andpersName Public Health andpersName School of Pharmacy, University of Wisconsin, Madison, Wisconsin, USA 16 Médicine Intensive et Réanimation Hôpital Saint-Louis, APHP, Université Paris Diderot, Paris, France 17 Molecular Diagnostics of Infectious Diseases, Microbiology, LADR Zentrallabor Dr. Kramer & Kollegen, Geesthacht, Germany 18 Division of Infectious Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA 19 Institut Pasteur, Molecular Mycology Unit, CNRS UMR2000, Mycology Laboratory, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France 20 Infectious Diseases Service, Department of Medicine, Lausanne University Hospital andpersName University of Lausanne, Lausanne, Switzerland 21 Department of Medicine, Alpert Warren Medical School of Brown University, Providence, Rhode Island, USA 22 Infectious Diseases Unit, IRCCS Istituto Giannina Gaslini, Genova, Italy 23 Infectious Diseases Unit, G. Fracastoro Hospital, San Bonifacio, Verona, Italy 24 Spanish National Centre for Microbiology, Instituto de Salud Carlos III, Madrid, Spain 25 Infectious Diseases Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA 26 National Heart & Lung Institute, Imperial College London, the Royal Brompton & Harefield NHS Foundation Trust, London, UK 27 Pediatric Infectious Diseases Division at the Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA 28 Centre for Global Health, Institute for Infection andpersName Immunity, St Georges University of London, London, UK 29 Diagnostic andpersName Interventional Radiology, University Hospital Heidelberg, Translational Lung Research Center andpersName Diagnostic andpersName Interventional Radiology with Nuclear Medicine, Thoraxklinik Heidelberg, Heidelberg, Germany 30 Faculty of Health andpersName Medical Sciences, University of Copenhagen, Copenhagen, Denmark 31 Centre for Medical Microbiology, University College London, London, UK 32 UT MD Anderson Cancer Center, Houston, Texas, USA 33 Radboud Center for Infectious Diseases andpersName Department of Medicine, Radboudumc, Nijmegen, The Netherlands 34 Department of Microbiology, Immunology andpersName Transplantation andpersName Department of Laboratory Medicine andpersName National Reference Centre for Mycosis, University Hospitals Leuven, Leuven, Belgium 35 Infectious Diseases Service, Department of Medicine andpersName Institute of Microbiology, Lausanne University Hospital andpersName University of Lausanne, Lausanne, Switzerland 36 Pediatric Hematology andpersName Oncology, Hospital for Children andpersName Adolescents, University of Frankfurt, Frankfurt, Germany 37 Molecular Biology andpersName Infection, Medical Hospital II, WÜ4i, University Hospital Würzburg, Würzburg, Germany 38 Paris University, Necker Pasteur Center for Infectious Diseases andpersName Tropical Medicine, IHU Imagine & Institut Pasteur, Molecular Mycology Unit, CNRS UMR 2000, Paris, France 39 Department of Hematology, University Hospitals Leuven, Leuven, Belgium 62 Department of Microbiology, Immunology andpersName Transplantation, K.U. Leuven, Leuven, Belgium 40 Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School 41 Critical Care Medicine Department NIH-Clinical Center, Bethesda, Maryland, USA 42 Department of Medical Microbiology andpersName Infectious Diseases andpersName Centre of Expertise in Mycology Radboudumc/Canisius Wilhelmina Hospital, Nijmegen, The Netherlands 43 Alfred Health andpersName Monash University, Melbourne, Australia 44 Department of Internal Medicine, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil 45 Division of Infectious Diseases, McGovern Medical School, Houston, Texas, USA 46 Istituto di Ematologia, Università Cattolica S. Cuore, Rome, Italy 47 UT Health San Antonio andpersName South Texas Veterans Health Care System, San Antonio, Texas, USA 48 Department of Internal Medicine–Hematology andpersName Oncology, Masaryk University andpersName University Hospital Brno, Brno, Czech Republic 49 Infectious Diseases Unit, 3rd Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration General Hospital, Thessaloniki, Greece 50 Department of Hematology & Oncology, Lukas Hospital, Buende, Germany 51 Meander Medical Center Amersfoort andpersName Radiology, Radboud University Medical Center, Nijmegen, The Netherlands 52 Department of Infectious Diseases, Peter MacCallum Cancer Center andpersName the National Centre for Infections in Cancer, The University of Melbourne, Melbourne, Victoria, Australia 53 Division of Infectious Diseases andpersName Geographic Medicine, Stanford University Medical School, Stanford, California 64 California Institute for Medical Research, San Jose, California, USA 54 Department of Internal Medicine, Division of Infectious Diseases, University of California Davis Medical Center, Sacramento, California, USA 55 Division of Infectious Diseases, Medical College of Georgia/Augusta University, Augusta, Georgia, USA 56 Division of Infectious Disease, University of Genova andpersName San Martino University Hospital, Genova, Italy 57 Weill Cornell Medicine of Cornell University, Departments of Medicine, Pediatrics, Microbiology & Immunology, New York, New York, USA 58 MRC Centre for Medical Mycology at the University of Aberdeen, Aberdeen, UK 59 MiraVista Diagnostics, Indianapolis, Indiana, USA 60 Public Health Wales Mycology Reference Laboratory, University Hospital of Wales, Heath Park, Cardiff, UK 61 Perelman School of Medicine at the University of Pennsylvania, Children’s Hospital of Philadelphia andpersName Roberts Center for Pediatric Research, Philadelphia, Pennsylvania, USA ✉ Correspondence: J. P. DonnellypersName, De Hoefkamp 1096, 6545 MD Nijmegen, The Netherlands ( p.donnellypersName@usa.net ).
5 12 2019 71 6 1367 1367–1376 15 9 2020 © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted reuse, distribution, andpersName reproduction in any medium, provided the original work is properly cited. See " Defining Invasive Fungal Diseases for Clinical Research: A Work in Progress. " with doi: 10.1093/cid/ciz1013. Abstract Background Invasive fungal diseases (IFDs) remain important causes of morbidity andpersName mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research andpersName Treatment of Cancer andpersName the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, andpersName undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential.
Methods To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, andpersName special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups’ findings were presented at a scientific symposium andpersName after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved.
Results There is no change in the classifications of “proven,” “probable,” andpersName “possible” IFD, although the definition of “probable” has been expanded andpersName the scope of the category “possible” has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable andpersName possible categories are proposed for immunocompromised patients only, except for endemic mycoses.
Conclusions These updated definitions of IFDs should prove applicable in clinical, diagnostic, andpersName epidemiologic research of a broader range of patients at high-risk.
Keywords: consensus, definitions, invasive fungal diseases, diagnosis, research European Organization for Research andpersName Treatment of Cancer andpersName the Mycoses Study Group definitions for probable invasive fungal diseaseterm now include solid organ transplant, hematologic malignancy, graft-versus-host disease, the reverse halo sign, revised thresholds for galactomannanterm, Aspergillus polymerase chain reaction, andpersName definitions for candidiasis, cryptococcosis, non-human immunodeficiency viirus–associated pneumocystosis, andpersName endemic mycoses.
status released display-pdf yes is-olf no is-manuscript no is-preprint no is-journal-matter no is-scanned no is-retracted no Received 2019 May 27; Accepted 2019 Oct 8; Collection date 2020 Sep 15.
( See the Editorial Commentary by Rogers on pages 1377–8 .) The European Organization for Research andpersName Treatment of Cancer andpersName the Mycoses Study Group Education andpersName Research Consortium (EORTC/MSGERC) consensus definitions of invasive fungal diseases (IFDs) were last updated in 2008date [ 1 ]. These definitions achieved their original aim in fostering communication andpersName enabling comparison of study findings among those engaged in research into IFD of patients with cancer andpersName recipients of hematopoietic stem cell transplants (HSCTs) or solid organ transplants (SOTs) [ 2 , 3 ]. Moreover, they have been adopted by regulatory agencies for evaluation of antifungals andpersName have been used to evaluate diagnostic tests andpersName to conduct epidemiologic studies [ 4–7 ]. Importantly, these definitions are specifically intended for these purposes only andpersName not to direct or guide patient care.
The 2008date definitions had their shortcomings, including the facts that the definitions were unsuitable for patients with IFD in the setting of intensive care units (ICUs) or in pediatrics, data were insufficient to establish appropriate thresholds for detecting Aspergillus galactomannan (GM)term·var, andpersName there was uncertainty about the role of (1,3)-beta-D glucan (BDG)term·var. Furthermore, nucleic acid amplification including polymerase chain reaction (PCR)–based tests were excluded because of lack of standardization andpersName validation. Definitions for cryptococcosis andpersName endemic mycoses also needed clarification, andpersName there were no definitions for pneumocystosis.
PROCESS Volunteers from the EORTC Infectious Diseases Group andpersName the MSGERC were assigned according to their expertise to 10 working groups, each charged with appraising a particular topic (see list of contributors in the Notes section). The chairs of the EORTC andpersName MSG (J. P. D. andpersName P. G. P.) selected leaders for each working group, andpersName S. C. served as executive secretary. After completing the first round of working group assignments, leaders presented each group’s initial deliberations andpersName recommendations at the 7th Trends in Medical Mycology Conference in Lisbon, Portugal, October 2015. A slide set was made available until 31 December 2015 online at www.e-materials.com/timm2015/invitation/Member andpersName, on request, for public comment. After several iterations, the final draft of the manuscript was circulated to all members for their approval.
REVISIONS ANDpersName UPDATES Special Populations Pediatrics andpersName patients in the ICU were considered as special populations. However, group 10 (IFD definitions in ICU patients) was unable to generate recommendations that preserved a level of certainty consistent with the existing definitions except for proven IFD ( Table 1 ) andpersName therefore undertook a separate initiative [ 8 ].
Table 1. Criteria for Proven Invasive Fungal Disease Fungus Microscopic Analysis: Sterile Material Culture: Sterile Material Blood Serology Tissue Nucleic Acid Diagnosis Molds a Histopathologic, cytopathologic, or direct microscopic examination b of a specimen obtained by needle aspiration or biopsy in which hyphae or melanized yeast-like forms are seen accompanied by evidence of associated tissue damage Recovery of a hyaline or pigmented mold by culture of a specimen obtained by a sterile procedure from a normally sterile andpersName clinically or radiologically abnormal site consistent with an infectious disease process, excluding BAL fluid, a paranasal or mastoid sinus cavity specimen, andpersName urine Blood culture that yields a mold c (eg, Fusarium species) in the context of a compatible infectious disease process Not applicable Amplification of fungal DNA by PCR combined with DNA sequencing when molds are seen in formalin-fixed paraffin-embedded tissue Yeasts a Histopathologic, cytopathologic, or direct microscopic examination of a specimen obtained by needle aspiration or biopsy from a normally sterile site (other than mucous membranes) showing yeast cells, for example, Cryptococcus species indicating encapsulated budding yeasts or Candida species showing pseudohyphae or true hyphae d Recovery of a yeast by culture of a sample obtained by a sterile procedure (including a freshly placed [<24 hours ago] drain) from a normally sterile site showing a clinical or radiological abnormality consistent with an infectious disease process Blood culture that yields yeast (eg, Cryptococcus or Candida species) or yeast-like fungi (eg, Trichosporon species) Cryptococcal antigen in cerebrospinal fluid or blood confirms cryptococcosis Amplification of fungal DNA by PCR combined with DNA sequencing when yeasts are seen in formalin-fixed paraffin-embedded tissue Pneumocystis Detection of the organism microscopically in tissue, BAL fluid, expectorated sputum using conventional or immunofluorescence staining Not applicable Not applicable Not applicable Not applicable Endemic mycoses Histopathology or direct microscopy of specimens obtained from an affected site showing the distinctive form of the fungus Recovery by culture of the fungus from specimens from an affected site Blood culture that yields the fungus Not applicable Not applicable Abbreviations: BAL, bronchoalveolar lavage; PCR, polymerase chain reaction.
a If culture is available, append the identification at the genus or species level from the culture results.
b Tissue andpersName cells submitted for histopathologic or cytopathologic studies should be stained using Grocott-Gomori methenamine silver stain or periodic acid Schiff stain to facilitate inspection of fungal structures. Whenever possible, wet mounts of specimens from foci related to invasive fungal disease should be stained with a fluorescent dye (eg, calcofluor or blankophor).
c Recovery of Aspergillus species from blood cultures rarely indicates endovascular disease andpersName almost always represents contamination.
d Trichosporon andpersName yeast-like Geotrichum species andpersName Blastoschizomyces capitatus may also form pseudohyphae or true hyphae.
Pediatrics: Group 1 There was a clear need to establish pediatric-specific IFD definitions as the clinical andpersName radiologic manifestations of IFD in children, that is, patients aged <18 years, may differ significantly from those in adults. Most importantly, the incidence of invasive candidiasis (IC) is higher in neonates than in other age groups [ 9–11 ]. The degree of prematurity, based on gestational age andpersName birth weight, is a unique risk factor among neonates; hematogenous Candida meningoencephalitis affects premature infants disproportionately andpersName has serious consequences including seizures, intraventricular hemorrhage, andpersName developmental delay [ 12 , 13 ]. With respect to IC due to non- Candida albicans species, Candida glabrata is the most common pathogen in adults, whereas Candida parapsilosis predominates in children andpersName neonates [ 14 ]. Risk factors for invasive mold diseases include innate immunologic defects, with Aspergillus nidulans being associated with chronic granulomatous disease, while Aspergillus fumigatus is seen more often in other patient groups [ 15 ].
Neonates with IC often present with subtle clinical findings, andpersName cultures are frequently sterile, including cerebrospinal fluid (CSF) samples from neonates with candidemia andpersName concurrent Candida meningitis. Diagnosis is often inferred from insensitive andpersName nonspecific surrogate tests, such as increased C-reactive protein or thrombocytopenia, which has been shown to be a predictor of candidemia in infants [ 16 , 17 ]. In neonates, a positive urine culture has a significance similar to that of a positive blood culture as an indicator of IC [ 16 ]. Radiographic findings are less specific in children than those reported in adults [ 18 ]. Chest computerized tomography (CT) scans in children with proven invasive pulmonary aspergillosis (IPA) commonly show nonspecific changes andpersName not the halo sign, air crescent formation, or cavitation seen in adults [ 19 ].
There are also far fewer data to support the clinical use of nonculture-based fungal biomarkers in neonates andpersName children [ 20 ], although the GM assay performs similarly in children andpersName adults when used as an adjunctive tool to diagnose invasive aspergillosis (IA) [ 20 , 21 ]. Likewise, there are few data regarding the use of BDG, Candida mannan antigen, andpersName anti-mannan antibody biomarkers in pediatrics [ 22 ]. Recent data support the utility of BDG in CSF for the diagnosis andpersName therapeutic monitoring of children with Candida meningoencephalitis [ 23 ], but the data are sparse regarding the utility of PCR assays andpersName the T2Candida assay for diagnosis [ 24 ].
Diagnostic Tests andpersName Imaging In the previous definitions [ 1 ], indirect tests for diagnosing IFD were only included if there was sufficient evidence that they had been standardized andpersName validated. Moreover, commercial tests were included only if criteria for interpretation had been provided. Hence, while tests for GM andpersName BDG were incorporated, tests for detecting fungal nucleic acid were not [ 1 ]. Furthermore, there was no agreement about appropriate thresholds, so the manufacturers’ analytical thresholds were adopted. The evidence for using GM to diagnose IA has grown considerably since then, andpersName testing for BDG has been extended to a wide range of patients. With respect to Aspergillus PCRterm·var, the International Society of Human andpersName Animal Mycology working group Fungal PCR Initiative (FPCRI; www.fpcri.eu ) has made significant progress toward setting a standard for the technique after vigorous validation [ 25 ].
Imaging: Group 2 There is mounting evidence that the radiologic manifestations of invasive mold disease are more varied than previously recognized. The increased sensitivity of newer imaging techniques enables a greater number andpersName depth of abnormalities to be seen in different anatomic regions. Recent data relating to the role of imaging in the diagnosis of IPA andpersName pulmonary mucormycosis (PM) in adults suggest that a high-resolution CT scan (HRCT) is preferred to chest radiographs, magnetic resonance imaging (MRI), andpersName positron emission tomography (PET), likely reflecting that HRCT is more sensitive than a chest radiograph, more widely available than MRI, andpersName the experience with HRCT is much larger than with PET [ 26 , 27 ]. Among patients with IPA, nodules or infiltrates with a halo sign remain useful among neutropenic patients but they are nonspecific for IPA in other groups [ 28 ]. Furthermore, the air crescent sign is a late andpersName nonspecific sign. Among nonneutropenic patients, multiple pulmonary nodules andpersName various nonspecific findings including bronchopneumonia, consolidation, cavitation, pleural effusions, ground glass opacities, tree-in-bud opacities, andpersName atelectasis are found [ 29 ]. Overall, consolidation is the most frequent presentation of PM, followed by mass lesions, nodules, andpersName cavitation [ 30 ]. Multiple nodules (more than10) andpersName pleural effusions appear to be more frequent in PM than in IPA [ 31 ]. Moreover, the reverse halo sign is more specific for PM than IPA, although the differential diagnosis also includes other diseases including tuberculosis [ 32 ].
Aspergillus Galactomannan: Group 3 We evaluated Aspergillus galactomannan for both adults andpersName children andpersName specific patient groups andpersName its utility andpersName validity for different clinical specimens. We adopted different thresholds for different specimens rather than for different host groups [ 33–35 ] ( Table 2 ). These differ from those recommended by the manufacturer of the GM assay (Platelia Aspergillus (Bio-Rad, CA), validated only for use in serum andpersName bronchoalveolar lavage (BAL) fluid; however, detection of GM in plasma andpersName CSF should support a diagnosis of IA [ 36 , 37 ]. Exposure to mold-active antifungalsterm compromises the utility of the GM testterm for IA [ 38 ] by reducing its sensitivity [ 39 ]. Therefore, caution should be exercised when GM is found to be absent from serum or plasma in patients receiving mold-active antifungals. There was consensus that similar GM thresholds are appropriate for adults andpersName children.
Table 2. Probable Invasive Pulmonary Mold Diseases Host factorsterm·def Recent history of neutropenia (<0.5 × 10 9 neutrophils/L [<500 neutrophils/mm 3 ] for >10 days) temporally related to the onset of invasive fungal disease Hematologic malignancy a Receipt of an allogeneic stem cell transplant Receipt of a solid organ transplant Prolonged use of corticosteroids (excluding among patients with allergic bronchopulmonary aspergillosis) at a therapeutic dose of ≥0.3 mg/kg corticosteroids for ≥3 weeks in the past 60 days Treatment with other recognized T-cell immunosuppressants, such as calcineurin inhibitors, tumor necrosis factor-a blockers, lymphocyte-specific monoclonal antibodies, immunosuppressive nucleoside analogues during the past 90 days Treatment with recognized B-cell immunosuppressants, such as Bruton’s tyrosine kinase inhibitors, eg, ibrutinib Inherited severe immunodeficiency (such as chronic granulomatous disease, STAT 3 deficiency, or severe combined immunodeficiency) Acute graft-versus-host disease grade III or IV involving the gut, lungs, or liver that is refractory to first-line treatment with steroids Clinical features Pulmonary aspergillosis The presence of 1 of the following 4 patterns on CT: Dense, well-circumscribed lesions(s) with or without a halo sign Air crescent sign Cavity Wedge-shaped andpersName segmental or lobar consolidation Other pulmonary mold diseases As for pulmonary aspergillosis but also including a reverse halo sign Tracheobronchitis Tracheobronchial ulceration, nodule, pseudomembrane, plaque, or eschar seen on bronchoscopic analysis Sino-nasal diseases Acute localized pain (including pain radiating to the eye) Nasal ulcer with black eschar Extension from the paranasal sinus across bony barriers, including into the orbit Central nervous system infection 1 of the following 2 signs: Focal lesions on imaging Meningeal enhancement on magnetic resonance imaging or CT Mycological evidence Any mold, for example, Aspergillus , Fusarium , Scedosporium species or Mucorales recovered by culture from sputum, BAL, bronchial brush, or aspirate Microscopical detection of fungal elements in sputum, BAL, bronchial brush, or aspirate indicating a mold Tracheobronchitis Aspergillus recovered by culture of BAL or bronchial brush Microscopic detection of fungal elements in BAL or bronchial brush indicating a mold Sino-nasal diseases Mold recovered by culture of sinus aspirate samples Microscopic detection of fungal elements in sinus aspirate samples indicating a mold Aspergillosis only Galactomannan antigen Antigen detected in plasma, serum, BAL, or CSF Any 1 of the following: Single serum or plasma: ≥1.0 BAL fluid: ≥1.0 Single serum or plasma: ≥0.7 andpersName BAL fluid ≥0.8 CSF: ≥1.0 Aspergillus PCRterm·var Any 1 of the following: Plasma, serum, or whole blood 2 or more consecutive PCR tests positive BAL fluid 2 or more duplicate PCR tests positive At least 1 PCR test positive in plasma, serum, or whole blood andpersName 1 PCR test positive in BAL fluid Aspergillus species recovered by culture from sputum, BAL, bronchial brush, or aspirate Probable invasive fungal diseases (IFD) requires the presence of at least 1 host factorterm·def, a clinical feature andpersName mycologic evidence andpersName is proposed for immunocompromised patients only, whereas proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. Probable IFD requires the presence of a host factorterm, a clinical feature, andpersName mycologic evidence. Cases that meet the criteria for a host factorterm andpersName a clinical feature but for which mycological evidence has not been found are considered possible IFD. (1,3)-beta-D glucan was not considered to provide mycological evidence of any invasive mold disease.
Abbreviations: BAL, bronchoalveolar lavage; CSF, cerebrospinal fluid; CT, computed tomography; PCR, polymerase chain reaction.
a Hematologic malignancy refers to active malignancy, in receipt of treatment for this malignancy, andpersName those in remission in the recent past. These patients would comprise largely acute leukemias andpersName lymphomas, as well as multiple myeloma, whereas patients with aplastic anemia represent a more heterogeneous group of individuals andpersName are not included.
BDG andpersName T2Candida Assays: Group 4 The group considers detection of BDG to be suitable for diagnosing probable IFD in the appropriate clinical setting. This includes patients with hematologic malignancies with andpersName without neutropenia, neutropenia following HSCT, andpersName certain patients in the ICU who are at higher risk (>10%) for IC as a result of gastrointestinal surgery with recurrent anastomotic leaks, perforations of the upper gastrointestinal tract, or necrotizing pancreatitis when there is clinical suspicion of infection [ 40 , 41 ]. A single threshold (>80 pg/mL) using the Fungitell test (Associates of Cape Cod, Falmouth, MA) is recommended; there is insufficient evidence to include assays produced by other manufacturers [ 42 ]. Confidence for true positive results increases with repeated positive tests andpersName for values that greatly exceed the positivity threshold [ 43 ]. There may be variability in positive predictive value (PPV) andpersName negative predictive value (NPV) based on patient population, but a single threshold is favored at this time. The group did not support the use of serum BDG to rule in patients for clinical trials or for defining IA or IC, as BDG detection is not specific for any one IFD. It was agreed that this test should only be used on serum samples, although the test has been used for CSF samples with some success to support a diagnosis of central nervous system (CNS) IFD in certain circumstances when other diagnostic tests are negative or inconclusive [ 44 ].
The T2Candida panel has been cleared by the US Food andpersName Drug Administration for the detection of common Candida species from whole blood specimens. The test has a very high NPV but, as with all such tests, the PPV is variable andpersName depends upon disease prevalence in a given patient population [ 45 , 46 ]. The PPV increases from 62% among patients with sepsis, shock, or lengths of stay greater than 3–7 days in an ICU to 92% for bone marrow transplant recipients andpersName patients with leukemia who are neutropenic but not receiving any antifungal prophylaxis. The test has been included as mycologic evidence to support a diagnosis of candidemia in selected clinical trials [ 47 ].
Aspergillus PCRterm·var: Group 5 In considering Aspergillus PCRterm·var, target species, patient populations, appropriate specimens for testing, technical issues, comparison with other biomarker assays, andpersName unique attributes of PCR assays were reviewed. The data were sufficiently robust for performing Aspergillus PCRterm·var on serum, plasma, whole blood, andpersName BAL fluid in adults. The group acknowledged that Aspergillus PCRterm·var data have been evaluated most extensively for adults with hematologic malignancies andpersName HSCT. Systematic reviews of Aspergillus PCRterm·var methods on blood andpersName BAL fluid conclude that PCR provides a robust diagnostic test for screening andpersName confirming the diagnosis of Aspergillus infection [ 22 , 48–53 ].
There are relatively few commercial PCR assays, andpersName most investigators have developed methods in-house. As such, the FPCRI was established to develop criteria for Aspergillus PCRterm·var rather than a standardized method per se. Despite technologic variability, PCR performance was comparable with that for detecting GM andpersName BDG [ 54 ]. Moreover, commercial PCR tests performed using methodology in line with the FPCRI recommendations provide a standardized approach that has been independently associated with improved performance. A unique feature of PCR is its ability to detect both genus andpersName species of Aspergillus . PCR is also capable of identifying certain mutations associated with triazole resistance directly from clinical specimens [ 55–57 ].
Tissue Diagnosisterm·def: Group 6 Tissue diagnosisterm·def requires the presence of fungal elements in formalin-fixed paraffin-embedded tissue andpersName signifies proven fungal disease but not the identity of the fungus involved. To achieve this, we recommend amplification of fungal DNA by PCR combined with DNA sequencing, but only when fungal elements are seen by histopathology. PCR would add value by allowing identification of the fungus to genus andpersName possibly species levels. Because the technique used should be rigorously quality controlled, only laboratories with a proven record in performing DNA extraction from formalin-fixed tissue should undertake this. The identity of the fungus should be consistent with the histopathologic findings [ 58–60 ].
Other Disease Entities Pneumocystosis: Group 7 The inclusion of Pneumocystis jirovecii pneumonia (PCP) diagnosis in the updated definitions was limited to patients not living with human immunodeficiency virus (HIV). Diagnosing PCP has been more difficult among these patients possibly due to a more focal pulmonary involvement, lower suspicion of disease, andpersName lower sensitivity of traditional histologic andpersName microscopy diagnostic tests [ 61 ]. As such, it is important to more fully define host factorsterm·def for patients at increased risk for PCP. We selected receipt of therapeutic doses of corticosteroids for at least 2 weeks within the past 60 days; antineoplastic, antiinflammatory, or immunosuppressive treatment; andpersName low CD4 lymphocyte counts due to a medical condition. This includes, but is not limited to, patients with primary immunodeficiencies, hematologic malignancies, SOTs, andpersName allogeneic HSCT recipients [ 62 , 63 ]. Clinical criteria in this population tend to be nonspecific andpersName include cough, dyspnea, andpersName hypoxemia. Radiographic abnormalities include bilateral ground-glass opacities andpersName, less frequently, consolidation, small nodules, unilateral infiltrates, pleural effusions, andpersName cystic lesions [ 61 , 64 , 65 ]. Amplification of P. jirovecii DNA by quantitative real-time PCR on BAL fluid, expectorated sputum, or oral wash specimens is preferred to qualitative PCR andpersName is helpful to establish probable disease. However, further studies are needed to validate thresholds for positivity [ 66 , 67 ]. Similarly, 2 or more serum BDG levels of ≥80 ng/L are useful for diagnosing probable disease in appropriate clinical context provided other IFDs have been excluded [ 68 , 69 ].
Cryptococcosis: Group 8 A broader understanding of the natural history andpersName host factorsterm·def associated with cryptococcal disease warrants updating these definitions. We support the previous definitions of proven andpersName probable cryptococcal disease in any host. However, we also recognize cryptococcal infection among individuals in high-risk host groups who have few, if any, symptoms andpersName only a positive serum cryptococcal antigen test (asymptomatic cryptococcal antigenemia). This condition may be more common than symptomatic disease, andpersName patients may develop clinical cryptococcal disease unless treated andpersName so are now included in these definitions [ 70 ]. The term “disseminated cryptococcosisterm” as distinct from CNS cryptococcosisterm has been abandoned in favor of the terms “pulmonary,” “CNS” andpersName “other extrapulmonary sites.” “Colonization” with Cryptococcus spp. is no longer included in the definitions as it is poorly understood andpersName its natural history is unknown.
Identification to the species level for Cryptococcus neoformansterm andpersName Cryptococcus gattiiterm has become increasingly important based on reports that suggest different clinical presentations, outcomes, andpersName responses to antifungal therapy between these 2 species [ 71 , 72 ]. Verification of species that use CGB (L-canavanine, glycine, bromthymol blue) agar or matrix-assisted laser desorption ionization–time of flight mass spectrometry is recommended. Outcomes for HIV-associated cryptococcosis due to C. neoformans andpersName C. gattii appear to be similar, andpersName identification to the species level may be unnecessary [ 73 , 74 ].
Endemic Mycoses: Group 9 The endemic mycoses are caused by environmental fungi that are usually restricted geographically andpersName cause disease in immunocompetent andpersName immunocompromised hosts. Causative agents include Histoplasma capsulatum var. capsulatum andpersName H. capsulatum var. duboisii , Blastomyces species complex (eg, B. dermatitidis , B. gilchristii , B. helicus , B. silverae , andpersName B. parvus ), Coccidioides immitis/Coccidioides posadasii , Paracoccidioides brasiliensis/Paracoccidioides lutzii, Sporothrix species complex ( S. brasiliensis , S. schenckii sensu stricto , S. globosa , andpersName S. luriei ), Talaromyces (formerly Penicillium ) marneffei , andpersName Emergomyces species ( E. pasteurianus , E. africanus , E. orientalis , E. canadensis , andpersName E. europaeus ) [ 75–80 ]. Probable endemic mycoses are defined by evidence of environmental exposureterm·def to the fungus, a compatible clinical illness, andpersName the presence of either Histoplasma or Blastomyces antigen in any body fluid or antibody to Coccidioides species in serum or CSF as recovery by culture andpersName histopathologic evidence of infection is generally lacking. There are no approved serologic tests for T. marneffei , S. schenckii species complex, or P. brasiliensis . Exposure to 1 of these fungiterm is defined as a history of residence in an endemic areaterm, no matter how remote, travel to an endemic area, or contact with fomites such as soil or vegetation that is derived from an endemic area.
Proven Invasive Fungal Disease The revised definitions of proven IFD are shown in Table 1 .
Probable Invasive Fungal Disease Several changes were made to the definitions of probable IFD ( Tables 2 andpersName 3 ). For example, host factorsterm·def were expanded to include inherited severe immunodeficiency andpersName low CD4 lymphocyte counts. Radiographic features were expanded to include wedge-shaped andpersName segmental or lobar consolidation andpersName a reverse halo sign to indicate mold disease of the lower respiratory tract. Revised thresholds for GM now replace those of the manufacturer. Aspergillus PCRterm·var is now included, andpersName there are mycologic criteria for non-HIV–associated pneumocystosis.
Table 3. Other Probable Invasive Diseases Candidiasis Host factorsterm·def Recent history of neutropenia <0.5 × 10 9 neutrophils/L (<500 neutrophils/mm 3 for >10 days) temporally related to the onset of invasive fungal disease Hematologic malignancy Receipt of an allogeneic stem cell transplant Solid organ transplant recipient Prolonged use of corticosteroids (excluding among patients with allergic bronchopulmonary aspergillosis) at a therapeutic dose of ≥0.3 mg/kg corticosteroids for ≥3 weeks in the past 60 days Treatment with other recognized T-cell immunosuppressants, such as calcineurin inhibitors, tumor necrosis factor-a blockers, lymphocyte-specific monoclonal antibodies, immunosuppressive nucleoside analogues during the past 90 days Inherited severe immunodeficiency (such as chronic granulomatous disease, STAT 3 deficiency, CARD9 deficiency, STAT-1 gain of function, or severe combined immunodeficiency) Acute graft-versus-host disease grade III or IV involving the gut, lungs, or liver that is refractory to first-line treatment with steroids Clinical features At least 1 of the following 2 entities after an episode of candidemia within the previous 2 weeks: Small, target-like abscesses in liver or spleen (bull’s-eye lesions) or in the brain, or, meningeal enhancement Progressive retinal exudates or vitreal opacities on ophthalmologic examination Mycological evidence ß-D-glucan (Fungitell) ≥80 ng/L (pg/mL) detected in at least 2 consecutive serum samples provided that other etiologies have been excluded Positive T2Candida a Cryptococcosis Host factorsterm·def b Human immunodeficiency virus infection Solid organ or stem cell transplant recipient Hematologic malignancy Antibody deficiency (eg, common variable immunoglobulin deficiency) Immunosuppressive therapy (including monoclonal antibodies) End-stage liver or renal disease Idiopathic CD4 lymphocytopenia Clinical features Meningeal inflammation Radiological lesion consistent with cryptococcal disease Mycological evidence Recovery of Cryptococcus from a specimen obtained from any nonsterile site Pneumocystosis c Host factorsterm·def Low CD4 lymphocyte counts <200 cells/mm 3 (200 × 10 6 cells/L) for any reason Exposureterm·def to medication (antineoplastic therapy, antiinflammatory, or immunosuppressive treatment) associated with T-cell dysfunction Use of therapeutic doses of ≥0.3 mg/kg prednisone equivalent for ≥2 weeks in the past 60 days Solid organ transplant Clinical features Any consistent radiographic features particularly bilateral ground glass opacities, consolidations, small nodules or unilateral infiltrates lobar infiltrate, nodular infiltrate with or without cavitation, multifocal infiltrates, miliary pattern d Respiratory symptoms with cough, dyspnea, andpersName hypoxemia accompanying radiographic abnormalities including consolidations, small nodules, unilateral infiltrates, pleural effusions, or cystic lesions on chest X-ray or computed tomography scan Mycological evidence ß-D-glucan (Fungitell) ≥80 ng/L (pg/mL) detection in ≥2 consecutive serum samples provided other etiologies have been excluded Detection of Pneumocystis jirovecii DNA by quantitative real-time polymerase chain reaction in a respiratory tract specimen Endemic mycoses Host factorsterm·def Not applicable as these diseases affect both healthy andpersName less healthy hosts Clinical features Evidence for geographical or occupational exposureterm·def (including remote) to the fungus andpersName compatible clinical illness Mycological evidence Histoplasma or Blastomyces antigen in urine, serum, or body fluid Antibody to Coccidioides in cerebrospinal fluid or 2-fold rise in 2 consecutive serum samples Probable invasive fungal diseases (IFD)requires the presence of at least 1 host factorterm·def, a clinical feature andpersName mycologic evidence andpersName is proposed for immunocompromised patients only, whereas proven invasive fungal disease can apply to any patient, regardless of whether the patient is immunocompromised. Except for endemic mycoses, probable IFD requires the presence of a host factorterm, a clinical feature, andpersName mycologic evidence, whereas cases that meet the criteria for a host factorterm andpersName a clinical feature but for which mycological evidence has not been found are considered possible IFD.
a T2Candida is US Food andpersName Drug Administration approved for the detection of Candida albicans , Candida parapsilosis , Candida tropicalis , Candida krusei, andpersName Candida glabrata in blood.
b Cryptococcosis also occurs in phenotypically normal hosts.
c Definitions for human immunodeficiency virus–associated pneumocystosis are not included here.
d Bilateral, diffuse ground glass opacities with interstitial infiltrates are more common than other features such as consolidations, small nodules, thin-walled cavities, andpersName unilateral infiltrates.
Possible Invasive Fungal Disease While definitions of proven andpersName probable disease have been shown to be reliable in research andpersName attracted little controversy among the group, this cannot be said of the possible IFD category. There is much confusion about the difference between a host factorterm andpersName a risk factorterm. As before, a host factorterm has been defined as a characteristic of individuals clearly predisposed to, and not simply at risk of, an IFDterm [ 1 ]. For example, while impaired gut wall integrity through surgery or illness may increase the risk of candidiasis, it was not considered specific enough to warrant inclusion as a host factorterm. Pulmonary abnormalities such as tree-in-bud opacities andpersName interstitial abnormalities were excluded from the clinical features as they can be due to a wide range of pathologies in addition to IFD.
GENERAL POINTS Throughout this process, we have emphasized the need to differentiate between definitions of IFD required for clinical researchterm from those that influence clinical practiceterm. In clinical practice, many would administer an antifungal agent to any patient at risk of IFD when fungi are detected by biomarkers in serum, plasma, whole blood, or relevant body site fluid without there being sufficient evidence to satisfy the consensus definitions of IFD. We also recognize that our definition of a host factorterm errs on the side of conservatism given the increasing use of drugs such as monoclonal antibodies for treating a variety of conditions.
Other controversial issues included distinguishing between the performance characteristics of tests for screening andpersName confirmation, the impact of exposureterm·def to antifungal agents used for prophylaxis or treatment on imaging andpersName diagnostic tests, andpersName the use of biomarkers to monitor therapeutic outcome. We agree that further research will be required to evaluate the evidence for each of these assays. Finally, there was consensus that diagnostic strategies to determine the relative efficiency of an available test, alone or in combination with other diagnostic tests, should be considered further.
CONCLUSIONS In summary, these revised definitions represent consensus expert opinion based on the best available evidence. As such, they will need to be reviewed regularly for their utility andpersName relevance andpersName, where possible, extended to other populations affected by IFDs. We acknowledge the limitations of these definitions, including the exclusion of certain cases of IFD. However, the reliance on host factorsterm·def, clinical features, andpersName mycologic evidence to define IFD in selected populations has proven its value for clinical trials, epidemiologic studies, andpersName the evaluation of diagnostic tests.
Notes Author contributions. Pediatrics: William SteinbachpersName (Chair, Mycoses Study Group [MSG]), Brian FisherpersName (MSG), Andreas GrollpersName (European Organization for Research andpersName Treatment of Cancer [EORTC]) Thomas LehrnbecherpersName (EORTC), Emmanuel RoilidespersName (EORTC), Thomas J WalshpersName (MSG), Adilia WarrispersName (EORTC), Theo ZaoutispersName (MSG). Guidance on imaging: John W. BaddleypersName (Chair, MSG), Barbara AlexanderpersName (MSG), Sujal DesaipersName (EORTC), Klaus Peter Heussel (EORTC), Frédéric LamothpersName (EORTC), Orla MorriseypersName (MSG), Cornelia Schaefer ProkoppersName (EORTC). Update of galactomannan: Paul VerweijpersName (Chair, EORTC), Elio CastagnolapersName (EORTC), Johan MaertenspersName (EORTC), Kieren MarrpersName (MSG), Joseph WheatpersName (MSG). Update on beta-D-glucan, T2Candida: Cornelius J. ClancypersName (Chair, MSG), Hamdi AkanpersName (EORTC), David AndespersName (MSG), Mario CrucianipersName (EORTC), Frédéric LamothpersName (EORTC), Oscar MarchettipersName (EORTC), Luis Ostrosky- Zeichner (MSG), Zdenek Racil (EORTC). Update of polymerase chain reaction: John R. WingardpersName (Chair, MSG), Stephane BretagnepersName (EORTC), Angela CaliendopersName (MSG), Jurgen LoefflerpersName (EORTC), Tom PattersonpersName (MSG), Monica SlavinpersName (MSG), P Lewis WhitepersName (EORTC). Tissue diagnosisterm·def: Shawn LockhartpersName (Chair, MSG), Ralf BialekpersName (EORTC), Manuel Cuenca (EORTC), Henrik JensenpersName (EORTC), Chris KibblerpersName (EORTC), Dimitrios KontoyiannispersName (MSG). Pneumocystosis: Andreas GrollpersName (Chair, EORTC), Sharon ChenpersName (MSG), Catherine DeckerpersName (MSG), Katrien LagroupersName (EORTC), Henry MasurpersName (MSG), Livio PaganopersName (EORTC), Claudio ViscolipersName (EORTC). Cryptococcosis: Tania SorrellpersName (Chair, MSG), Peter PappaspersName (MSG), Tom HarrisonpersName (EORTC), Olivier LortholarypersName (EORTC), John PerfectpersName (MSG). Endemic mycosis: Carol A. KauffmanpersName (Chair, MSG), Robert W. BradsherpersName (MSG), Jacques F. MeispersName (EORTC), Marcio NuccipersName (MSG), David StevenspersName (MSG), George R ThompsonpersName (MSG). Inclusion of patients in the intensive care unit: Matteo BassettipersName (Chair, EORTC), Elie AzoulaypersName (EORTC), Thierry CalandrapersName (EORTC), Bart-Jan KullbergpersName (EORTC), Frédéric LamothpersName (EORTC), Marcus RuhnkepersName (EORTC), Shmuel ShohampersName (MSG), Jose Vazquez (MSG).
Disclaimer . The findings andpersName conclusions in this report are those of the authors andpersName do not necessarily represent the official position of the Centers for Disease Control andpersName Prevention.
Potential conflicts of interest. H. AkanpersName reports being a primary investigator in a clinical trial for MSD. B. D. AlexanderpersName reports grants from Astellas, Cidara, Scynexis, F2G, andpersName Viamet andpersName personal fees from Astellas, Scynexis, andpersName UpToDate outside the submitted work. D. AndespersName reports grants andpersName consulting fees from Amplyx, Matinas, Cidara, andpersName Merck outside the submitted work. E. AzoulaypersName reports personal fees from Gilead, Pfizer, Ablynx, Alexion, andpersName Baxter; grants andpersName personal fees from MSD; andpersName conference invitation from Gilead outside the submitted work. M. BassettipersName reports grants from Pfizer, MSD, andpersName Cidara andpersName personal fees from Pfizer, MSD, Astellas, ThermoFisher, Gilead, Cidara, Biomerieux, andpersName Menarini outside the submitted work. S. BretagnepersName reports grants from MSD andpersName Pfizer andpersName personal fees from Gilead outside the submitted work. T. CalandrapersName reports advisory board membership from Astellas, Basilea, Cidara, MSD, Sobi, ThermoFisher, andpersName GE Healthcare andpersName data monitoring board membership from Novartis. A. M. CaliendopersName reports grants from T2 Biosystems outside the submitted work. E. CastagnolapersName reports personal fees from Gilead outside the submitted work. S. C. ChenpersName reports grants from MSD Australia outside the submitted work. C. J. ClancypersName reports consultancy fees from Merck, Cidara, Astellas, The Medicine Company, Scynexis, andpersName T2Biosystems; grants/pending grants from T2Biosystems, Merck, Cidara, andpersName Astellas; andpersName personal fees from Merck andpersName T2 Biosystems outside the submitted work. M. Cuenca-EstrellapersName reports grants andpersName personal fees from Gilead Sciences andpersName grants from F2G, Scynexis, Cidara, andpersName Amplyx outside the submitted work. S. R. DesaipersName reports paid honorarium andpersName travel expenses from Interstitial Lung Disease MDT—Boehringer-Ingelheim. J. P. DonnellypersName reports personal fees from F2G Ltd, Gilead Sciences, andpersName Pfizer outside the submitted work. B. FisherpersName reports grants from Pfizer, Merck, andpersName the National Institutes of Health andpersName personal fees from Astellas outside the submitted work. T. HarrisonpersName reports grants from Gilead Sciences andpersName personal fees from Gilead Sciences, Pfizer, andpersName Viamet outside the submitted work. C. P. Heussel reports personal fees from Basilea, Bayer, Boehringer-Ingelheim, Gilead, Interimmune, MSD, Novartis, andpersName Pfizer; grants from the German Center for Lung Research, MeVis, Pfizer, andpersName Siemens; andpersName consultancy fees from Fresenius outside the submitted work. C. A. Kaufmann reports data safety monitoring board membership for Cidara Therapeudics outside the submitted work. D. P. KontoyiannispersName reports personal fees from Merck & Co, Gilead Sciences, United Medical, Astellas Pharma, Pharma, Cidara Therapeutics, Amplyx Pharmaceuticals, andpersName Mayne Pharma outside the submitted work. B.-J. KullbergpersName reports personal fees from Amplyx, Astellas, Cidara, Pfizer, andpersName Scynexis outside the submitted work. K. LagroupersName reports personal fees andpersName travel support from Pfizer andpersName MSD andpersName personal fees from Abbott, SMB Laboratoires Brussels, Gilead, andpersName Roche outside the submitted work. F. LamothpersName reports personal fees from MSD andpersName Basilea outside the submitted work. T. LehrnbecherpersName reports grants, personal fees, andpersName nonfinancial support from Gilead Sciences; personal fees andpersName nonfinancial support from MSD/Merck andpersName Astellas; andpersName personal fees from Basilea outside the submitted work. J. MaertenspersName reports personal fees andpersName nonfinancial support from Basilea Pharmaceuticals, Bio-Rad Laboratories, Cidara, F2G Ltd, Gilead Sciences, Merck, andpersName Pfizer Inc andpersName grants from Gilead Sciences outside the submitted work. K. A. MarrpersName reports personal fees from Amplyx, Cidara, andpersName Merck; licensing royalties from MycoMed Technologies; andpersName patents from MycoMed outside the submitted work. J. F. MeispersName reports grants from F2G Ltd, personal fees from Gilead Sciences, other from Pulmocide, grants andpersName personal fees from Scynexis, personal fees andpersName other from TEVA, andpersName personal fees andpersName other from United Medical outside the submitted work. C. O. Morrissey reports grants from Gilead Sciences, Merck, Sharp andpersName Dohme andpersName advisory board membership from Merck, Sharp, andpersName Dohme outside the submitted work. M. NuccipersName reports personal fees from Pfizer, MSD, Basilea, Gilead, Biotoscana, Teva, Abbvie, Astellas, andpersName Janssen outside the submitted work. L. Ostrosky-ZeichnerpersName reports personal fees from Merck, F2G, Mayne, Viracor, andpersName Gilead; grants andpersName personal fees from Pfizer, Astellas, Scynexis, andpersName Cidara; grants from Amplyx; andpersName personal fees from Realtime outside the submitted work. L. PaganopersName reports personal fees from MSD andpersName Pfizer andpersName grants andpersName personal fees from Gilead outside the submitted work. T. F. PattersonpersName reports personal fees from Basilea; grants from Cidara; andpersName personal fees from Gilead, Merck, Scynexis, Toyama, andpersName Pfizer outside the submitted work. J. R. PerfectpersName reports grants from Pfizer andpersName Mayne; grants andpersName other from Merck, Minnetronix, andpersName Amplyx andpersName other from Viamet, F2G, Vical, Matinas, Cidara during the conduct of the study. E. RoilidespersName reports grants from Astellas Pharma, Gilead Sciences, MSD Sharp & Dohme, Pfizer outside the submitted work. M. RuhnkepersName reports personal fees from SCYNEXIS, Basilea, Kedplasma, andpersName Daiichi outside the submitted work. S. ShohampersName reports grants from Merck, Astellas, Shionogi, Cidara, Scynexis, Shire, T2 Microsystems, Ansun, Emergent, andpersName Gilead andpersName personal fees from Merck outside the submitted work. M.A. SlavinpersName reports grants from Merck; personal fees from Merck; andpersName other from Pfizer andpersName Gilead outside the submitted work. D. A. StevenspersName reports grants from Astellas andpersName Riptide andpersName consulting fees from Pulmatrix, the US Department of Justice, andpersName Fresenius outside the submitted work. G. R. ThompsonpersName reports grants andpersName other from Astellas, Cidara, Vical, Scynexis, F2G, andpersName Mayne andpersName grants from RealTime Labs outside the submitted work. J. A. Vazquez reports personal fees from Astellas, Cidara, Amplyx, andpersName F2G outside the submitted work. C. ViscolipersName reports personal fees from MSD Int, Gilead, Pfizer, Angelini, Astellas, andpersName Basilea outside the submitted work. P. E.VerweijpersName reports grants from Gilead Sciences, MSD, Pfizer, andpersName F2G andpersName nonfinancial support from OLM andpersName IMMY outside the submitted work. T. J. WalshpersName has received grants for experimental andpersName clinical antifungal pharmacology andpersName molecular diagnostics to his institution from Amplyx, Astellas, Lediant, Merck, Scynexis, andpersName T2 Biosystems andpersName has served as a consultant to Amplyx, Astellas, Gilead, Lediant, Merck, andpersName Scynexis. A. WarrispersName reports grants andpersName personal fees from Gilead outside the submitted work. P. L. WhitepersName reports nonfinancial support from Bruker, Dynamiker, andpersName Launch; personal fees andpersName nonfinancial support from Gilead; andpersName personal fees from MSD outside the submitted work. J. R. WingardpersName reports personal fees from Ansun, Astellas, Behring, Celgene, Cidara, Merck, andpersName Shire outside the submitted work. T. E. ZaoutispersName reports personal fees from Pfizer outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.