Update: New EORTC /MSG Update: New EORTC /MSG criteria for clinical trialscriteria for clinical trials
J Peter Donnelly BSc FIBMS J Peter Donnelly BSc FIBMS MIBiol MIBiol PhDPhDDepartment of HaematologyDepartment of Haematology
Nijmegen University Centre for Infectious DiseasesNijmegen University Centre for Infectious DiseasesUniversity Hospital St RadboudUniversity Hospital St RadboudRadboud University NijmegenRadboud University Nijmegen
The NetherlandsThe Netherlands
Defining invasive fungal diseaseDefining invasive fungal disease
EORTCEORTC--IFICG & NIAIDIFICG & NIAID--MSGMSG
200220022002
Original aims Original aims
To improve the ability for both clinicians and To improve the ability for both clinicians and researchers:researchers:
•• in comparing protocols and outcome of trials in comparing protocols and outcome of trials
•• In assessing reports on therapeutic and diagnostic In assessing reports on therapeutic and diagnostic interventions interventions
•• in eliminating subjective classificationin eliminating subjective classification
StrengthsStrengths
Who uses the EORTC/MSG definitions?Who uses the EORTC/MSG definitions?
Clinical trialsClinical trialsClinical trials
Diagnostic testsDiagnostic testsDiagnostic tests
How valuable do you consider the How valuable do you consider the EORTC/MSG definitions?EORTC/MSG definitions?
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
very usefulquite usefuldon't knownot very usefulquite useless
Better communicationBetter communication
Strengths Strengths
EORTC/MSG definitionsEORTC/MSG definitions•• havehave fostered better fostered better communicationcommunication•• have been accepted by major journalshave been accepted by major journals•• are being applied by registration authoritiesare being applied by registration authorities•• have been adopted for therapeutic trialshave been adopted for therapeutic trials•• are used for approving diagnostic testsare used for approving diagnostic tests
•• Why revise?Why revise?•• The processThe process•• DefinitionsDefinitions IIII
•• Why revise?Why revise?•• The processThe process•• DefinitionsDefinitions IIII
LimitationsLimitations
ProblemsProblems
INAPPROPRIATE USEINAPPROPRIATE USE
•• applied for clinical usesapplied for clinical uses
•• patients without cancerpatients without cancer
ProblemsProblems
INAPPROPRIATE USEINAPPROPRIATE USE
•• applied for clinical usesapplied for clinical uses
•• patients without cancerpatients without cancer
APPROPRIATE USEAPPROPRIATE USE
•• no criteria for endemicno criteria for endemic mycoses, mycoses, fusariosis fusariosis
•• host factors too vaguehost factors too vague
•• clinical features given equal weightclinical features given equal weight
•• insecurity about insecurity about AspergillusAspergillus antigenantigen
•• PCR not includedPCR not included
Invasive fungal disease
Haematological malignancyHaematological malignancy
Allogeneic HSCTAllogeneic HSCT
Patient groups at risk of developing Patient groups at risk of developing IFDIFD
Goal of adapting definitionsGoal of adapting definitions
provenproven
probableprobable
possiblepossible
presentpresent
Goal of adapting definitionsGoal of adapting definitions
provenproven
probableprobable
possiblepossible
presentpresent
provenproven
probableprobable
possiblepossible
futurefuture
Question Question
Host factor
Mycology
++
++
Clinical features
neutropenicneutropenic
Halo sign onHalo sign on pulmonary CTpulmonary CT
Blood & BAL: Galactomannan Blood & BAL: Galactomannan --veve
Blood: PCR positiveBlood: PCR positive
Diagnosis?Diagnosis?Diagnosis?
1.possible invasive aspergillosis.
2.probable invasive aspergillosis.
3.proven invasive aspergillosis.
4.possible invasive fungal infection
1.1.possible invasive aspergillosis.possible invasive aspergillosis.
2.2.probable invasive aspergillosis.probable invasive aspergillosis.
3.3.proven invasive aspergillosis.proven invasive aspergillosis.
4.4.possible invasive fungal infectionpossible invasive fungal infection
Answer Answer
Host factor
Mycology
++
++
Clinical features
neutropenicneutropenic
Halo sign onHalo sign on pulmonary CTpulmonary CT
Blood & BAL: Galactomannan Blood & BAL: Galactomannan --veve
Blood: PCR positiveBlood: PCR positive
DiagnosisDiagnosisDiagnosis
1.possible invasive aspergillosis.
2.probable invasive aspergillosis.
3.proven invasive aspergillosis.
4.possible invasive fungal infection
1.1.possible invasive aspergillosis.possible invasive aspergillosis.
2.2.probable invasive aspergillosis.probable invasive aspergillosis.
3.3.proven invasive aspergillosis.proven invasive aspergillosis.
4.4.possible invasive fungal infectionpossible invasive fungal infection
•• Why revise?Why revise?•• The processThe process•• DefinitionsDefinitions IIII
ICAAC 43 Chicago 2003ICAAC 43 Chicago 2003
a)a) the need for the rules for defining IFI to be clear and the need for the rules for defining IFI to be clear and consistent was of paramount importanceconsistent was of paramount importance
b)b) proven invasive fungal infection (IFI) does not proven invasive fungal infection (IFI) does not require the presence of a host factor as suchrequire the presence of a host factor as such
c)c) for probable IFI the host factors should be expanded for probable IFI the host factors should be expanded to includeto include•• solid organ transplantssolid organ transplants•• HIV infectionHIV infection•• hereditary immunodeficiencieshereditary immunodeficiencies•• connective tissue disordersconnective tissue disorders•• low birthlow birth--weight (<1500 g) infantsweight (<1500 g) infants•• diabetes mellitusdiabetes mellitus•• immunopharmacological treatments e.g. infliximab,immunopharmacological treatments e.g. infliximab,
dicluzimab, fludarabinedicluzimab, fludarabine
ICAAC 43 Chicago 2003ICAAC 43 Chicago 2003
e)e) PROVEN, PROBABLE and POSSIBLE should remain as PROVEN, PROBABLE and POSSIBLE should remain as categories for IFIcategories for IFI
f)f) probable IFI will continue to require that all three probable IFI will continue to require that all three elements should be present and therefore is defined elements should be present and therefore is defined as host factors AND clinical features AND mycological as host factors AND clinical features AND mycological evidenceevidence
g)g) the definitions for proven IFI will remain unchanged. the definitions for proven IFI will remain unchanged. The principle is that the criteria for proven or The principle is that the criteria for proven or probable IFI have to be met in full in order to assign probable IFI have to be met in full in order to assign a level of certainty.a level of certainty.
ICAAC 43 Chicago 2003 ICAAC 43 Chicago 2003 -- working partiesworking parties
Task Task GroupGroup
to review the criteriato review the criteriaEndemic mycosesEndemic mycoses
to review the criteriato review the criteriaCryptococcosisCryptococcosis
ImagingImaging, , galactomannan, BALgalactomannan, BALAspergillosis and Aspergillosis and infections due to infections due to other mouldsother moulds
new criteria for candidaemianew criteria for candidaemiaCandidiasisCandidiasis
Working parties Working parties -- 1 year later1 year later
Task Task GroupGroup
completedcompletedEndemic mycosesEndemic mycoses
--CryptococcosisCryptococcosis
--Aspergillosis and Aspergillosis and infections due to infections due to other mouldsother moulds
--CandidiasisCandidiasis
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The best laid schemes o' Mice an' Men, The best laid schemes o' Mice an' Men, Gang aft agley, Gang aft agley, An' lea'e us nought but grief an' pain, An' lea'e us nought but grief an' pain, For promis'd joy!For promis'd joy!
(The best laid schemes of Mice and Men(The best laid schemes of Mice and Menoften go awry,often go awry,And leave us nothing but grief and pain,And leave us nothing but grief and pain,For promised joy!)For promised joy!)
Robert Burns (1759 Robert Burns (1759 -- 1796)1796)Q u i c k T i m e ™ a n d aT I F F ( U n c o m p r e s s e d ) d e c o m p r e s s o r
a r e n e e d e d t o s e e t h i s p i c t u r e .
Head to headHead to head
Plan BPlan B
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Proven IFI.docProven IFI.doc Host factors.docHost factors.doc
Microbiological Criteria.docMicrobiological Criteria.doc
Three wise men?Three wise men?
Consensus groupConsensus group
Consensus GroupConsensus Group
Round 1Round 1
EE--mailmail
EE--mailmailEE--mailmail
EE--mailmail
EE--mailmail
Round 2Round 2
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Definitions II processDefinitions II process
Round 1Round 1Round 1
Kieren Kieren Marr Marr
Jack Edwards Jack Edwards
Bill Dismukes Bill Dismukes
Jack Bennett Jack Bennett
Claudio Viscoli Claudio Viscoli
Marcus Marcus RuhnkeRuhnke
Johan Maertens Johan Maertens
Olivier Lortholary Olivier Lortholary
Bartjan Kullberg Bartjan Kullberg
Raoul Herbrecht Raoul Herbrecht
Jacques Bille Jacques Bille
Sibel Ascioglu Sibel Ascioglu
J Peter Donnelly J Peter Donnelly
Tom Walsh Tom Walsh
Ben De Pauw Ben De Pauw
Chris Chris KibblerKibbler
Patricia Munoz Patricia Munoz
Angela Restrepo Angela Restrepo
Theo Zaoutis Theo Zaoutis
Brahm Segal Brahm Segal
Georg Georg Masschmeyer Masschmeyer
Frank Odds Frank Odds
David Denning David Denning
Carol Kauffman Carol Kauffman
John John Wingard Wingard
David Stevens David Stevens
Jack Sobel Jack Sobel
John Perfect John Perfect
Tom Patterson Tom Patterson
Pete Pappas Pete Pappas
Round 5Round 5Round 5
Round 6Round 6Round 6Round 2Round 2Round 2
Round 3Round 3Round 3
Round 4Round 4Round 4
Round ‘em upRound ‘em up
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•• Why revise?Why revise?•• The processThe process•• DefinitionsDefinitions IIII
No changeNo change
Proven invasive fungal infective Proven invasive fungal infective diseasedisease
TissueTissue Blood cultureBlood culture
histologyhistologyhistology
culturecultureculture
MycologyMycology
Defining invasive fungal diseaseDefining invasive fungal disease
Host factor
Clinical feature
Mycology
EORTC/MSGDefinitions for invasive fungal disease
EORTC/MSGEORTC/MSGDefinitions for invasive fungal disease Definitions for invasive fungal disease
2002 - 20072002 2002 -- 20072007
First changeFirst change
What’s in a name?What’s in a name?
IInvasive nvasive FFungal ungal IInfectionnfection
200220022002
What’s in a name?What’s in a name?
IInvasive nvasive FFungal ungal IInfectionnfection
IInvasive nvasive FFungal ungal DDiseaseisease
200720072007
Second changeSecond change
Definitions I Definitions I -- Possible invasive Possible invasive fungal diseasefungal disease
Host factor
Clinical features
++
Mycology
OROR
200220022002
ProbableProbable=
Invasive fungal disease Invasive fungal disease --Definitions IIDefinitions II
PossiblePossible=
= Not classifiedNot classified
=
=
MycologyClinical
featuresHost
factors + +
Clinical features+Host
factors
Negativeor
Not done
Host factors
Negativeor
Not done
Clinical features+Host
factors
Negativeor
Not done
+Host factors Mycology
none
none
microscopy = Proven Proven tissue culture
ProbableProbable=
Invasive fungal disease Invasive fungal disease --Definitions IIDefinitions II
PossiblePossible=
=Not classifiedNot classified
=
=
MycologyClinical
featuresHost
factors + +
Clinical features+Host
factors
Negativeor
Not done
Host factors
Negativeor
Not done
Clinical features+Host
factors
Negativeor
Not done
+Host factors Mycology
none
none
microscopy = Proven Proven tissue culture
ProbableProbable=
Invasive fungal disease Invasive fungal disease --Definitions IIDefinitions II
PossiblePossible
=
=
Not classifiedNot classified
=
=
MycologyClinical
featuresHost
factors + +
Clinical features+Host
factors
Negativeor
Not done
Host factors
Negativeor
Not done
Clinical features+Host
factors
Negativeor
Not done
+Host factors Mycology
none
none
microscopy = Proven Proven tissue culture
Definitions II Definitions II -- Possible invasive Possible invasive fungal diseasefungal disease
Host factor
Clinical features++
Characteristic of invasive fungal disease
BUT no mycological evidence
200720072007
Third changeThird change
Definitions Definitions -- Host factorsHost factors
Host factor
neutropenianeutropenianeutropenia
> 4 days unexplained fever despite broad spectrum antibiotics
> 4 days unexplained > 4 days unexplained fever despite broad fever despite broad spectrum antibioticsspectrum antibiotics
Graft versus Host DiseaseGraft versus Host DiseaseGraft versus Host Disease
> 3 weeks corticosteroids> 3 weeks corticosteroids> 3 weeks corticosteroids
<36°C or > 38°C and • prior mycosis• AIDS• Immunosuppressive drugs• > 10 days neutropenia
<36°C or > 38°C and <36°C or > 38°C and •• prior mycosisprior mycosis•• AIDSAIDS•• Immunosuppressive drugsImmunosuppressive drugs•• > 10 days neutropenia> 10 days neutropenia
200220022002
Definitions Definitions -- Host factorsHost factors
Host factor
200720072007
neutropenianeutropenianeutropenia
> 4 days unexplained fever despite broad spectrum antibiotics
> 4 days unexplained > 4 days unexplained fever despite broad fever despite broad spectrum antibioticsspectrum antibiotics
Graft versus Host DiseaseGraft versus Host DiseaseGraft versus Host Disease
> 3 weeks corticosteroids> 3 weeks corticosteroids> 3 weeks corticosteroids
<36°C or > 38°C and • prior mycosis• AIDS• Immunosuppressive drugs• > 10 days neutropenia
<36°C or > 38°C and <36°C or > 38°C and •• prior mycosisprior mycosis•• AIDSAIDS•• Immunosuppressive drugsImmunosuppressive drugs•• > 10 days neutropenia> 10 days neutropenia
Definitions Definitions -- Host factorsHost factors
Host factor
200720072007
> 4 days unexplained fever despite broad spectrum antibiotics
> 4 days unexplained > 4 days unexplained fever despite broad fever despite broad spectrum antibioticsspectrum antibiotics
Graft versus Host DiseaseGraft versus Host DiseaseGraft versus Host Disease
<36°C or > 38°C and • prior mycosis• AIDS• Immunosuppressive drugs• > 10 days neutropenia
<36°C or > 38°C and <36°C or > 38°C and •• prior mycosisprior mycosis•• AIDSAIDS•• Immunosuppressive drugsImmunosuppressive drugs•• > 10 days neutropenia> 10 days neutropenia
neutropenianeutropenianeutropenia
> 3 weeks corticosteroids> 3 weeks corticosteroids> 3 weeks corticosteroids
Definitions Definitions -- Host factorsHost factors
Host factor
200720072007
neutropenianeutropenianeutropenia
> 3 weeks corticosteroids> 3 weeks corticosteroids> 3 weeks corticosteroids
Treatment with other recognizedT-cell immune suppressants
Treatment with other recognizedTreatment with other recognizedTT--cell immune suppressants cell immune suppressants
Inherited severe immunodeficiencyInherited severe immunodeficiencyInherited severe immunodeficiency
Allogeneic HSCT recipientAllogeneic HSCT recipientAllogeneic HSCT recipient
Invasive fungal disease
Haematological malignancyHaematological malignancy
Allogeneic HSCTAllogeneic HSCT
Patients at risk of developing IFDPatients at risk of developing IFD
200220022002
Invasive fungal disease
Haematological malignancyHaematological malignancy
AllogeneicAllogeneic HSCTHSCT
CGDCGD
Steroids Steroids
LiverLiver
HeartHeart
TransplantTransplant
RenalRenal
LungLung
Patients at risk of developing IFDPatients at risk of developing IFD
ICUICU
200720072007
Fourth changeFourth change
Definitions Definitions -- Clinical featuresClinical features
Clinical feature
Halo signHalo signAirAir--crescent signcrescent signcavitycavity
Lower respiratory tract infectionLower respiratory tract infectionLower respiratory tract infection
Sinonasal infectionSinonasal infectionSinonasal infection
CNS infectionCNS infectionCNS infection Disseminated fungal infectionDisseminated fungal infectionDisseminated fungal infection
Chronic disseminated candidiasisChronic disseminated candidiasisChronic disseminated candidiasis
Radiological evidenceRadiological evidence
Radiological evidenceRadiological evidence Unexplained papular or nodular skin lesionsUnexplained papular or nodular skin lesionsChorioretinitisChorioretinitisendophthalmitisendophthalmitis
Bull’s eye lesions in liver or spleenBull’s eye lesions in liver or spleen
MAJORMAJOR
= 1= 1
200220022002
Definitions Definitions -- Clinical featuresClinical features
Clinical feature
Cough, chest pain, haemoptysis, dyspnoeaCough, chest pain, haemoptysis, dyspnoeaPhysical finding of pleural rubPhysical finding of pleural rubAny new infiltrate not fulfilling major criterion Any new infiltrate not fulfilling major criterion
Lower respiratory tract infectionLower respiratory tract infectionLower respiratory tract infection
Sinonasal infectionSinonasal infectionSinonasal infection
CNS infectionCNS infectionCNS infection
Nasal discharge. stuffinessNasal discharge. stuffinessNose ulceration. eschar orNose ulceration. eschar or epistaxisepistaxisPeriorbital swellingPeriorbital swellingMaxillary tendernessMaxillary tendernessBlack necrotic lesions or perforation of the hardBlack necrotic lesions or perforation of the hard--palatepalate
CSFCSF No pathogensNo pathogensno malignant cellsno malignant cellsabnormal biochemistryabnormal biochemistryabnormal cell countabnormal cell count
Focal neurological Focal neurological seizuresseizureshemiparesishemiparesiscranial nerve palsycranial nerve palsy
Mental changesMental changesMeningeal irritationMeningeal irritation
MINORMINOR
= 2= 2
200220022002
Definitions Definitions -- Clinical featuresClinical features
Clinical feature
Lower respiratory tract IFDLower respiratory tract IFDLower respiratory tract IFD
Sinonasal IFDSinonasal IFDSinonasal IFD
CNS IFDCNS IFDCNS IFD
Chronic disseminated candidiasisChronic disseminated candidiasisChronic disseminated candidiasis
No more major and no more minorNo more major and no more minor
200720072007
Definitions Definitions -- Clinical featuresClinical features
Clinical feature
Lower respiratory tract IFDLower respiratory tract IFDLower respiratory tract IFD
Sinonasal IFDSinonasal IFDSinonasal IFD
CNS IFDCNS IFDCNS IFD
No more major and no more minorNo more major and no more minor
200720072007
Chronic disseminated candidiasisChronic disseminated candidiasisChronic disseminated candidiasis
Definitions Definitions -- Clinical featuresClinical features
Lower respiratory tract IFDLower respiratory tract IFDLower respiratory tract IFD
A) the presence of one of the following A) the presence of one of the following ““specificspecific””imaging signs on CT:imaging signs on CT:--
•• Well defined nodule(s) with a halo signWell defined nodule(s) with a halo sign
•• Well defined nodule(s) without a halo signWell defined nodule(s) without a halo sign
•• WedgeWedge--shaped infiltrateshaped infiltrate
•• Air crescent signAir crescent sign
•• CavityCavity
200720072007
halo signhalo signnodulesnodules
Specific pulmonary infiltrates on CT scanSpecific pulmonary infiltrates on CT scan
air crescent signair crescent signcavitycavity
Definitions Definitions -- Clinical featuresClinical features
Lower respiratory tract IFDLower respiratory tract IFDLower respiratory tract IFD
B) the presence of a new nonB) the presence of a new non--specific focal infiltrate specific focal infiltrate
PLUS at least one of the following:PLUS at least one of the following:--
•• Pleural rubPleural rub
•• Pleural painPleural pain
•• HemoptysisHemoptysis
200720072007
Fifth changeFifth change
Definitions Definitions -- MycologyMycology
Mycology
Culture of mould from tissue. aspirate BAL or sputum Culture of mould from tissue. aspirate BAL or sputum
mould seen in sinus aspiratemould seen in sinus aspirate
Fungi seen in tissue or sterile body fluidsFungi seen in tissue or sterile body fluids
antigen in blood, BAL, CSFantigen in blood, BAL, CSF
200220022002
Definitions Definitions -- MycologyMycology
Culture of mould from tissue. aspirate BAL or sputum Culture of mould from tissue. aspirate BAL or sputum
mould seen in sinus aspiratemould seen in sinus aspirate
Fungi seen in tissue or sterile body fluidsFungi seen in tissue or sterile body fluids
BetaBeta--DD--glucan in BAL, CSF or bloodglucan in BAL, CSF or blood
200720072007
antigen in blood, BAL, CSFantigen in blood, BAL, CSF
Mycology
Definitions Definitions -- MycologyMycology
Culture of mould from tissue. aspirate BAL or sputum Culture of mould from tissue. aspirate BAL or sputum
mould seen in sinus aspiratemould seen in sinus aspirate
Fungi seen in tissue or sterile body fluidsFungi seen in tissue or sterile body fluids
200720072007
BetaBeta--DD--glucan in BAL, CSF or bloodglucan in BAL, CSF or blood
antigen in blood, BAL, CSFantigen in blood, BAL, CSF
Mycology
Definitions Definitions -- MycologyMycology
Culture of mould from tissue. aspirate BAL or sputum Culture of mould from tissue. aspirate BAL or sputum
mould seen in sinus aspiratemould seen in sinus aspirate
Fungi seen in tissue or sterile body fluidsFungi seen in tissue or sterile body fluids PCR to detect nucleic acidPCR to detect nucleic acid
Not until a PCR system is Not until a PCR system is developed that has been developed that has been externally validated for blood, externally validated for blood, tissue, or BAL fluidtissue, or BAL fluid
200720072007
BetaBeta--DD--glucan in BAL, CSF or bloodglucan in BAL, CSF or blood
antigen in blood, BAL, CSFantigen in blood, BAL, CSF
Mycology
Towards a European standard for Towards a European standard for Aspergillus PCRAspergillus PCR
SteeringcommitteeSteeringSteering
committeecommittee
J Peter DonnellyJ Peter Donnelly
LaboratoryWorking partyLaboratoryLaboratoryWorking partyWorking party
ClinicalWorking party
ClinicalClinicalWorking partyWorking party
Jurgen LoefflerJurgen Loeffler
Stephane Stephane BretagneBretagne
Lewis WhiteLewis White
Rosemary BarnesRosemary Barnes
Werner HeinzWerner Heinz
Willem Willem MelchersMelchers
Niklas FinnstrNiklas Finnströömm
Lena Lena KlingsporKlingspor
Johan MaertensJohan Maertens
Catherine Catherine CordonnierCordonnier
Slicing the cakeSlicing the cake
Separating the chaff from the wheatSeparating the chaff from the wheat
proven/probable IFDproven/probable IFDproven/probable IFD
patients at risk
Separating the chaff from the wheatSeparating the chaff from the wheat
Host factors
proven/probable IFDproven/probable IFDproven/probable IFD
patients at risk
Separating the chaff from the wheatSeparating the chaff from the wheat
Host factors
clinical
proven/probable IFDproven/probable IFDproven/probable IFD
patients at risk
Separating the chaff from the wheatSeparating the chaff from the wheat
Host factors
proven/probable IFDproven/probable IFDproven/probable IFD
mycology clinical
patients at risk
Screening test for a potentially fatal Screening test for a potentially fatal disease with a low prevalencedisease with a low prevalence
+-
Controls Tests
- -+±
not ruled outnot ruled outstart treatmentstart treatment
ruled outruled outwithhold treatmentwithhold treatment
Do you apply EORTC/MSG definitions in Do you apply EORTC/MSG definitions in daily practice?daily practice?
0%
10%
20%
30%
40%
50%
60%
70%
all the timemost of the timeoccasionally seldom never
PatientPatient
Scheme for managing highScheme for managing high--risk patientsrisk patients
yesyes
Clinical evidence of IFDClinical evidence of IFD
PatientPatient
Scheme for managing highScheme for managing high--risk patientsrisk patients
nono
yesyes
Clinical evidence of IFDClinical evidence of IFD
PatientPatient
Scheme for managing highScheme for managing high--risk patientsrisk patients
nono
Microbiological evidence of IFDMicrobiological evidence of IFDCultureCultureCulture ++ GalactomannanGalactomannanGalactomannan ++
yesyes
yesyes
“Probable”“Probable”IFDIFD
Clinical evidence of IFDClinical evidence of IFD
PatientPatient
Scheme for managing highScheme for managing high--risk patientsrisk patients
nono
Microbiological evidence of IFDMicrobiological evidence of IFDCultureCultureCulture ++ GalactomannanGalactomannanGalactomannan ++
yesyes
yesyes
“Probable”“Probable”IFDIFD
Clinical evidence of IFDClinical evidence of IFD
PatientPatient
Scheme for managing highScheme for managing high--risk patientsrisk patients
nono
nono
“Possible”“Possible”IFDIFD
Microbiological evidence of IFDMicrobiological evidence of IFDCultureCultureCulture ++ GalactomannanGalactomannanGalactomannan ++
yesyes
yesyes
“Probable”“Probable”IFDIFD
Clinical evidence of IFDClinical evidence of IFD
PatientPatient
Scheme for managing highScheme for managing high--risk patientsrisk patients
nono
nono
“Possible”“Possible”IFDIFD
CultureCultureCulture ++ GalactomannanGalactomannanGalactomannan ++
“Unlikely” IFD“Unlikely” IFD
yesyes nono
Microbiological evidence of IFDMicrobiological evidence of IFD
EORTC/MSG definitions EORTC/MSG definitions -- aspergillosisaspergillosis
Host factor
HSCT HSCT
Mycology
antigenaemiaantigenaemia++++
Clinical features
Halo sign on CT scanHalo sign on CT scan
ProbableProbable
EORTC/MSG definitions EORTC/MSG definitions -- aspergillosisaspergillosis
Host factor
HSCT HSCT nonenone++++
Clinical features
Halo sign on CT scanHalo sign on CT scan
ProbableProbable(modified criteria)(modified criteria)
Mycology
EORTC/MSG definitions EORTC/MSG definitions -- aspergillosisaspergillosis
Host factor
HSCT HSCT nonenone++++
Clinical features
Halo sign on CT scanHalo sign on CT scan
possiblepossible
Mycology
For example..For example..
CID 2007:44 (15 May) • Cornely et al.CID 2007:44 (15 May) • Cornely et al.
3 3033Extrapulmonary infection 34851Pulmonary infection
105767No 14243Yes
Neutropenia at baseline44448Uncontrolled15453Controlled
Hematological malignancy54550No 35047Yes
Allogeneic stem cell transplantation
84856Patients with aspergillosis diagnosed by presence of halo sign only
34239Patients with microbiologically confirmed aspergillosis
44650All patients with aspergillosis 44650All patientsa
Difference, %10 mg/kg per day
3 mg/kg per day
Patient group or characteristic
Percentage of patients with favorable overall response by liposomal amphotericin B dosage
Table 2. Favorable overall responses among all Table 2. Favorable overall responses among all patients and subsets of patients.patients and subsets of patients.
CID 2007:44 (15 May) • Cornely et al.CID 2007:44 (15 May) • Cornely et al.
84856Patients with aspergillosis diagnosed by presence of halo sign only
34239Patients with microbiologically confirmed aspergillosis
44650All patients with aspergillosis
44650All patientsa
Difference, %
10 mg/kg
per day
3 mg/kg
per day
Patient group or characteristic
Percentage of patients with favorable overall response by liposomal amphotericin B dosage
Table 2. Favorable overall responses among all Table 2. Favorable overall responses among all patients and subsets of patients.patients and subsets of patients.
probableprobable
CID 2007:44 (15 May) • Cornely et al.CID 2007:44 (15 May) • Cornely et al.
84856Patients with aspergillosis diagnosed by presence of halo sign only
34239Patients with microbiologically confirmed aspergillosis
44650All patients with aspergillosis
44650All patientsa
Difference, %
10 mg/kg
per day
3 mg/kg
per day
Patient group or characteristic
Percentage of patients with favorable overall response by liposomal amphotericin B dosage
Table 2. Favorable overall responses among all Table 2. Favorable overall responses among all patients and subsets of patients.patients and subsets of patients.
possiblepossible
CID 2007:44 (15 May) • Cornely et al.CID 2007:44 (15 May) • Cornely et al.
At risk populationAt risk populationprovenproven
probableprobable
possiblepossible
unclassifiedunclassified
Currently eligibleCurrently eligibleprovenproven
probableprobable
Eligible for future studiesEligible for future studiesprovenproven
probableprobable
possiblepossible
Conclusion Conclusion
•• The revised definitions should make trials The revised definitions should make trials simpler and more represenatativesimpler and more represenatative
•• Much still needs to be done in the ICUMuch still needs to be done in the ICU
•• PCR needs to come into linePCR needs to come into lineFailure to Failure to meet the definitions does NOT mean there meet the definitions does NOT mean there is no IFD ….is no IFD ….
only that the criteria for only that the criteria for defining IFD have not been metdefining IFD have not been met
•• Valid until 2009?Valid until 2009?