Update: New EORTC /MSG Update: New EORTC /MSG criteria for clinical trials criteria for clinical trials J Peter Donnelly BSc FIBMS J Peter Donnelly BSc FIBMS MIBiol MIBiol PhD PhD Department of Haematology Department of Haematology Nijmegen University Centre for Infectious Diseases Nijmegen University Centre for Infectious Diseases University Hospital St Radboud University Hospital St Radboud Radboud University Nijmegen Radboud University Nijmegen The Netherlands The Netherlands
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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
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
•• 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
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
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 .
<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
<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
> 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
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
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
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
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