Update: New EORTC /MSG criteria for clinical trials - PEG · Update: New EORTC /MSG criteria for clinical trials ... • connective tissue disorders ... Physical finding of pleural

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


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


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 .

Head to headHead to head

Plan BPlan B



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





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 6Round 6Round 6Round 2Round 2Round 2



Round ‘em upRound ‘em up




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


factors

Negativeor

Not done

+Host factors Mycology

none

none

microscopy = Proven Proven tissue culture

ProbableProbable=


PossiblePossible=

=Not classifiedNot classified

=

=

MycologyClinical

featuresHost

factors + +


factors

Negativeor

Not done

Host factors

Negativeor

Not done


factors

Negativeor

Not done


none

none


ProbableProbable=


PossiblePossible

=

=

Not classifiedNot classified

=

=

MycologyClinical

featuresHost

factors + +


factors

Negativeor

Not done

Host factors

Negativeor

Not done


factors

Negativeor

Not done


none

none


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


Host factor

200720072007









Host factor

200720072007









Host factor

200720072007



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



Allogeneic HSCTAllogeneic HSCT

Patients at risk of developing IFDPatients at risk of developing IFD

200220022002



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


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


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


Clinical feature


Sinonasal IFDSinonasal IFDSinonasal IFD

CNS IFDCNS IFDCNS IFD

No more major and no more minorNo more major and no more minor

200720072007




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



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





BetaBeta--DD--glucan in BAL, CSF or bloodglucan in BAL, CSF or blood

200720072007


Mycology





200720072007



Mycology




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



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


Host factors


patients at risk


Host factors

clinical


patients at risk


Host factors


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


nono

yesyes


PatientPatient


nono

Microbiological evidence of IFDMicrobiological evidence of IFDCultureCultureCulture ++ GalactomannanGalactomannanGalactomannan ++

yesyes

yesyes

“Probable”“Probable”IFDIFD


PatientPatient


nono


yesyes

yesyes



PatientPatient


nono

nono

“Possible”“Possible”IFDIFD


yesyes

yesyes



PatientPatient


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


Host factor

HSCT HSCT nonenone++++

Clinical features


ProbableProbable(modified criteria)(modified criteria)

Mycology


Host factor

HSCT HSCT nonenone++++

Clinical features


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.




44650All patients with aspergillosis

44650All patientsa

Difference, %

10 mg/kg

per day

3 mg/kg

per day




probableprobable




44650All patients with aspergillosis

44650All patientsa

Difference, %

10 mg/kg

per day

3 mg/kg

per day




possiblepossible


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?

Documents

Update: New EORTC /MSG criteria for clinical trials - PEG · Update: New EORTC /MSG criteria for clinical trials ... • connective tissue disorders ... Physical finding of pleural