the importance of epidemiology in the diagnosis of invasive fungal infections j peter donnelly bsc...

The importance of epidemiology The importance of epidemiology in the diagnosis of invasive in the diagnosis of invasive

fungal infectionsfungal infections

J Peter Donnelly BSc PhDJ Peter Donnelly BSc PhD

Department of HaematologyDepartment of HaematologyUniversity Medical Centre St RadboudUniversity Medical Centre St Radboud

Nijmegen, The NetherlandsNijmegen, The Netherlands

Some issuesSome issues

Microscopy and culture are essentially unavailable to microbiologists Microscopy and culture are essentially unavailable to microbiologists with respect to invasive fungal infections (IFI)with respect to invasive fungal infections (IFI)

BecauseBecause

• IFI commonly affects the lungs initially but cases can easily go IFI commonly affects the lungs initially but cases can easily go unnoticedunnoticed

• Even when recognized early, suitable specimens can be difficult Even when recognized early, suitable specimens can be difficult to obtain to obtain

• Tests for detecting fungal pathogens in clinical material Tests for detecting fungal pathogens in clinical material (particularly blood) are available, but there is no consensus (particularly blood) are available, but there is no consensus about their clinical utilityabout their clinical utility

HenceHence

many expect nothing from diagnosis and do not even attempt to make many expect nothing from diagnosis and do not even attempt to make one. The resulting lack of adequate diagnoses makes estimating the one. The resulting lack of adequate diagnoses makes estimating the prevalence and incidence of IFI unreliable.prevalence and incidence of IFI unreliable.

EpidemiologyEpidemiology

This dismal state of affairs serves only to This dismal state of affairs serves only to emphasize the importance of epidemiology emphasize the importance of epidemiology since, in order to determine the value of any since, in order to determine the value of any diagnostic test or battery of tests, one has to diagnostic test or battery of tests, one has to know the underlying prevalence of the disease, know the underlying prevalence of the disease, particularly when this is low.particularly when this is low.

The first questions are:-The first questions are:-

• Who gets IFI? Who gets IFI?

• What do they get and how?What do they get and how?

• When do they get?When do they get?

Who gets IFI?Who gets IFI?

Candidaemia in French hospitalsCandidaemia in French hospitals

originorigin central linecentral line 26%26% digestive tractdigestive tract 11%11% unknownunknown 43%43%

Incidence/ 1000 admissionsIncidence/ 1000 admissionsTotal Total 0.290.29General hospitalGeneral hospital 0.170.17Teaching hospitalTeaching hospital 0.380.38Cancer centerCancer center 0.710.71

Andremont et al, ICAAC 1998, San Diego

parapsilosisparapsilosis

glabrataglabratatropicalistropicalis

albicansalbicans

kruseikrusei

Risk factorRisk factor CancerCancer ICUICU

Neutropenia, HSCT, chemotherapy,Neutropenia, HSCT, chemotherapy,

GvHD, mucosal barrier injuryGvHD, mucosal barrier injury

Candida colonisationCandida colonisation

Broad-spectrum antibioticsBroad-spectrum antibiotics

Haemodialysis, azotemiaHaemodialysis, azotemia

Central venous catheterCentral venous catheter

Severity of illnessSeverity of illness

HyperalimentationHyperalimentation

Recurrent/persistent GI tract perforation Recurrent/persistent GI tract perforation

Prior surgeryPrior surgery

Neonatal ICU (age, low APGAR,Neonatal ICU (age, low APGAR,

LOS, shock, H2 blockers, intubation)LOS, shock, H2 blockers, intubation)

Rex & Sobel Clin Infect Dis 2001 32;1191

Risk factors for invasive candidosisRisk factors for invasive candidosis

Incidence of invasive fungal infections among Incidence of invasive fungal infections among solid organ transplant recipientssolid organ transplant recipients

TransplantTransplant IFIIFI

RenalRenal 1.4 - 141.4 - 14

HeartHeart 5 - 215 - 21

LiverLiver 7 - 427 - 42

Lung & heart/lungLung & heart/lung 15 - 3515 - 35

Small bowelSmall bowel 40 - 5940 - 59

Pancreas Pancreas 18 - 3818 - 38

AspergillusAspergillus CandidaCandida

Singh Clin Infect Dis. 2001 31: 545

Timing of fungal infections after solid organ transplantTiming of fungal infections after solid organ transplant

11 22 33 44 55 66 77 88

CMVCMV

CandidaCandida

AspergillusAspergillus

CryptococcusCryptococcus

Endemic fungiEndemic fungi

PneumocystisPneumocystis

Snydman Clin Infect Dis. 2001 33: S5

00

Incidence of fatal fungal infections amongst Incidence of fatal fungal infections amongst patients other than those with HIV in the USApatients other than those with HIV in the USA

Mc Neil et al 2001 Clin Infect Dis 33;641

Candidiasis

AspergillosisAspergillosis

0%0% 53%53%

Acute InvasiveAcute Invasive

CandidiasisCandidiasis

Acute InvasiveAcute Invasive

CandidiasisCandidiasis

81 patients81 patients

4646

NO YES

BacteraemiaBacteraemia

++++++++ColonisationColonisationColonisationColonisation

Guiot et al, Clin Infect Dis 1994; 18:525-32 641

Invasive candidiasis, colonisation and bacteraemiaInvasive candidiasis, colonisation and bacteraemia

1414 2424 88 77 1313 1515

3535

11 00 00 00 11 88

- - - - ++++ ++++++++ - - - - ++++

Risk groupRisk group ColonisationColonisation Mucosal barrier injuryMucosal barrier injury TreatmentTreatment

LowLow nono nono nono

Intermediate Intermediate nono yesyes nono

yesyes nono yes or no*yes or no*

High riskHigh risk yesyes yesyes yesyes

MBI and invasive MBI and invasive CandidaCandida infections infections

* depending on other predisposing factors* depending on other predisposing factors

Invasive aspergillosis and underlying diseaseInvasive aspergillosis and underlying disease

ConditionCondition range (%)range (%)

Chronic granulomatous diseaseChronic granulomatous disease 25-4025-40

Lung ± heart transplantLung ± heart transplant 19-2619-26

Liver transplantLiver transplant 1.5-101.5-10

Heart & renal transplantHeart & renal transplant 0.5-100.5-10

AIDSAIDS 0-120-12

SCIDSCID 3.53.5

BurnsBurns 1-71-7

SLESLE 11

Acute leukaemiaAcute leukaemia 5-245-24

Allogeneic HSCTAllogeneic HSCT 4-94-9

Autologous HSCT (no growth factors)Autologous HSCT (no growth factors) 0.5-60.5-6

Autologous HSCT (with growth factors)Autologous HSCT (with growth factors) <1<1

Denning Clin Infect Dis 2001 26 pp781-805

0 10 20 30 40%0 10 20 30 40%

haematopoietic haematopoietic stem cell stem cell

transplanttransplant

Denning. Clin Inf Dis 1998

autologousautologous

Incidence of invasive aspergillosis under Incidence of invasive aspergillosis under various conditionsvarious conditions

heartheart/heart-lung transplant/heart-lung transplant

chronic granulomatous diseasechronic granulomatous disease

acute leukemiaacute leukemia

allogeneicallogeneic

solid organ transplantsolid organ transplant

AIDSAIDS

+ growth factor+ growth factor

Transplant typeTransplant type incidence (%)incidence (%)

LungLung 8.4 8.4

Haematopoietic stem cellHaematopoietic stem cell 6.4 6.4AutologousAutologous 2.6 2.6AllogeneicAllogeneic

Related donorRelated donor 6.7 6.7Unrelated donor Unrelated donor 10.310.3

HeartHeart 6.2 6.2

LiverLiver 1.7 1.7

PancreasPancreas 1.3 1.3

KidneyKidney 0.7 0.7

Transplant typeTransplant type incidence (%)incidence (%)

LungLung 8.4 8.4

Haematopoietic stem cellHaematopoietic stem cell 6.4 6.4AutologousAutologous 2.6 2.6AllogeneicAllogeneic

Related donorRelated donor 6.7 6.7Unrelated donor Unrelated donor 10.310.3

HeartHeart 6.2 6.2

LiverLiver 1.7 1.7

PancreasPancreas 1.3 1.3

KidneyKidney 0.7 0.7

Paterson et al. Medicine 1999;78:123-38.

Incidence of invasive aspergillosis in transplant Incidence of invasive aspergillosis in transplant recipientsrecipients

Aspergillosis at autopsy - sites of infectionAspergillosis at autopsy - sites of infection

aspergillosiaspergillosiss

Lungs onlyLungs only

CNS onlyCNS onlyDisseminatedDisseminated(not lungs) (not lungs)

Disseminated Disseminated

Vogeser et al Eur J Clin Microbiol Infect Dis 1999;18; 42-45

1187 autopsies 1993 - 19961187 autopsies 1993 - 199648 (4%) aspergillosis48 (4%) aspergillosis

Explaining the current trends in opportunistic Explaining the current trends in opportunistic fungal infectionsfungal infections

Singh Clin Infect Dis 2001 33;1692

Increase in number of susceptible hostsIncrease in number of susceptible hosts

New medical methods New medical methods

• HSCT - CD 34HSCT - CD 34++ selection selection

• Advances in surgical techniques for solid transplantAdvances in surgical techniques for solid transplant

• immunesuppressive regimens for solid transplantimmunesuppressive regimens for solid transplant

• More conservative approach More conservative approach • Less use of corticosteroidsLess use of corticosteroids• Use of novel agentsUse of novel agents

Antimicrobial prophylaxisAntimicrobial prophylaxis

• Fluoroquinolones for Gram negative bacilliFluoroquinolones for Gram negative bacilli• Fluconazole for Fluconazole for CandidaCandida• Ganciclovir for CMVGanciclovir for CMV

Improved laboratory expertiseImproved laboratory expertise

• detection detection • identificationidentification

Invasive fungal infections

Haematological malignancyHaematological malignancy

Allogeneic HSCTAllogeneic HSCT

ICUICU

CGDCGD

BurnsBurns

LiverLiver

HeartHeart

TransplantTransplant

RenalRenal

LungLung

Who gets IFI?Who gets IFI?

HIVHIV

What do they get and how?What do they get and how?

The main playersThe main players

Hi Bud!

Hi pal!

Huh. You guys get all

the attention

How do they get it?How do they get it?

Candida - colonisationCandida - colonisation

Candida parapsilosisCandida parapsilosisCandida albicansCandida albicans

Candida parapsilosisCandida parapsilosisCandida albicansCandida albicans

Candida albicansCandida albicansCandida tropicalisCandida tropicalis

Candida albicansCandida albicansCandida tropicalisCandida tropicalis

Candida albicansCandida albicansCandida glabrataCandida glabrata

Candida kruseiCandida krusei

Candida albicansCandida albicansCandida glabrataCandida glabrata


GI tractGI tract

antibioticsinsult

injury selection

translocationtranslocation

infectioninfection CandidaCandida species species

Normal Normal commensal commensal floraflora

DiseaseDisease

Model for invasive candidiasisModel for invasive candidiasis

AspergillosisAspergillosis

Aspergillus from the breeze or the bucketAspergillus from the breeze or the bucket

Graybill Clin Infect Dis 2001 26 pp781-805

What do they get and how ?What do they get and how ?

• MainlyMainly Candida albicans Candida albicans oror Aspergillus Aspergillus fumigatusfumigatus

• prior colonisation with Candida species is a prior colonisation with Candida species is a prerequisite for infectionprerequisite for infection

• Spores of Spores of AspergillusAspergillus and other moulds are and other moulds are inhaled directly through the air or indirectly inhaled directly through the air or indirectly from aerosols of contaminated waterfrom aerosols of contaminated water

When do they get it?When do they get it?

days after transplantdays after transplant

1010 2020 3030 4040 5050 6060 7070 8080 9090 100100 110110 120120 130130 140140 150150 160160 170170 180180 >180>180

Cas

esC

ases

2020

1818

1616

1414

1212

1010

88

66

44

22

00

Wald et al J Infect Dis 1997:175;1459

Time to diagnosis of aspergillosis after BMTTime to diagnosis of aspergillosis after BMT

Aspergillosis following HSC transplantAspergillosis following HSC transplantG

ran

ulo

cyte

s (lo

gG

ran

ulo

cyte

s (lo

g 1010

1x

10

1x

1066 /

L)

/L)

0.10.1

11

1010

3636

3737

3838

3939

4040

4141

Te

mp

era

ture

°C

Te

mp

era

ture

°C

DaysDays MonthsMonths

-7-7 00 77 1414 2121 1212 66 99 1212-14-14 662828 88 1010

WeeksWeeksTransplantTransplant

ENGRAFTMENTENGRAFTMENTENGRAFTMENTENGRAFTMENTPRE-PRE-TRANSPLANTTRANSPLANTPRE-PRE-TRANSPLANTTRANSPLANT

EARLY POST-ENGRAFTMENTEARLY POST-ENGRAFTMENTEARLY POST-ENGRAFTMENTEARLY POST-ENGRAFTMENT LATE POST-ENGRAFTMENTLATE POST-ENGRAFTMENTLATE POST-ENGRAFTMENTLATE POST-ENGRAFTMENT

Stem cellsStem cells acute GvHDacute GvHD low IgGlow IgGchronic GvHDchronic GvHD

neutropenianeutropenia corticosteroidscorticosteroids

Source of stem cells and GVHDSource of stem cells and GVHD

Cutler et al 2002 J Clin Oncol 19:3685-3691

FEVERFEVER

ALKALINE PHOSPHATASEALKALINE PHOSPHATASE

NEUTROPHILSNEUTROPHILS

DISSEMINATIONDISSEMINATION MICROCOLONIESMICROCOLONIES "BULLS EYE""BULLS EYE"

HEPATOSPLENIC CANDIDIASISHEPATOSPLENIC CANDIDIASIS

when do they get? when do they get?

• Both candidiasis and aspergillosis occur during Both candidiasis and aspergillosis occur during neutropenia but also manifest themselves later neutropenia but also manifest themselves later after bone marrow recovery.after bone marrow recovery.

• Patients are at risk of aspergillosis for as long Patients are at risk of aspergillosis for as long as they have active GvHD or are receiving high as they have active GvHD or are receiving high dose corticosteroidsdose corticosteroids

DiagnosisDiagnosis

Sites of infectionSites of infection

Candida albicansCandida albicans

Candida glabrataCandida glabrata



Candida glabrataCandida glabrata


Candida parapsilosisCandida parapsilosis


Candida parapsilosisCandida parapsilosis



Candida tropicalisCandida tropicalis


Candida tropicalisCandida tropicalis

MouldsMouldsMouldsMouldsYeastYeastYeastYeast

Aspergillus fumigatusAspergillus fumigatusAspergillus fumigatusAspergillus fumigatus

MucorMucorMucorMucor

Fusarium speciesFusarium speciesFusarium speciesFusarium species

Defining invasive fungal infectionDefining invasive fungal infection

Host factor

Clinical feature

Mycology

Invasive Fungal Infections Cooperative Group

MycosesMycosesStudyStudyGroupGroup


Ascioglu et al 2002Clin Infect Dis 34:7-14

Defining infection - Host factorsDefining infection - Host factors

Host factor

neutropenianeutropenianeutropenianeutropenia

> 4 days unexplained > 4 days unexplained fever despite broad fever despite broad spectrum antibioticsspectrum 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 DiseaseGraft versus Host Disease

> 3 weeks corticosteroids> 3 weeks corticosteroids> 3 weeks corticosteroids> 3 weeks corticosteroids

<36°C or > 38°C and <36°C or > 38°C and • prior mycosisprior mycosis• AIDSAIDS• ImmunosuppressivesImmunosuppressives• > 10 days neutropenia> 10 days neutropenia

<36°C or > 38°C and <36°C or > 38°C and • prior mycosisprior mycosis• AIDSAIDS• ImmunosuppressivesImmunosuppressives• > 10 days neutropenia> 10 days neutropenia





Defining infection - Clinical featuresDefining infection - Clinical features

Clinical feature




Halo signHalo signAir-crescent signAir-crescent signcavitycavity

Lower respiratory tract infectionLower respiratory tract infectionLower respiratory tract infectionLower respiratory tract infection

Sinonasal infectionSinonasal infectionSinonasal infectionSinonasal infection

CNS infectionCNS infectionCNS infectionCNS infection Disseminated fungal infectionDisseminated fungal infectionDisseminated fungal infectionDisseminated fungal infection

Chronic disseminated candidiasisChronic 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


Defining infection - Clinical featuresDefining infection - Clinical 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 infectionLower respiratory tract infection

Sinonasal infectionSinonasal infectionSinonasal infectionSinonasal infection

CNS infectionCNS infectionCNS infectionCNS infection

Nasal discharge, stuffinessNasal discharge, stuffinessNose ulceration, eschar or epistaxisNose ulceration, eschar or epistaxisPeriorbital swellingPeriorbital swellingMaxillary tendernessMaxillary tendernessBlack necrotic lesions or perforation of the hard-palateBlack necrotic lesions or perforation of the hard-palate

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


Defining infection - MycologyDefining infection - Mycology

Mycology

antigen in BAL, CSF or bloodantigen in BAL, CSF or blood

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





Proven invasive fungal infective diseaseProven invasive fungal infective disease

Host factor

Clinical features++ Tissue++ Mycology++





Host factor

Probable invasive fungal infective diseaseProbable invasive fungal infective disease

Clinical features++ Mycology++





Possible invasive fungal infective diseasePossible invasive fungal infective disease

Host factor

Clinical features

++

Mycology

OROR





Mycology

EORTC/MSG definitions of fungal infections -EORTC/MSG definitions of fungal infections -aspergillosisaspergillosis

Host factor

Clinical features

Halo sign on chest CT scanHalo sign on chest CT scan

coughcough

pleural rubpleural rub

antigenaemiaantigenaemiaGVHD GVHD

OR

++

++ ++

Probable disease

Probable disease

EORTC/MSG definitions of fungal infections -EORTC/MSG definitions of fungal infections -candidosiscandidosis

elevated alkaline phosphataseelevated alkaline phosphatase

Small, peripheral, target-like abscesses Small, peripheral, target-like abscesses (Bull’s eye) in liver and/or spleen (Bull’s eye) in liver and/or spleen demonstrated by CT, MRI or ultra demonstrated by CT, MRI or ultra sonogram.sonogram.

NeutropeniaNeutropenia ++

+/-+/-

Host factor

Clinical features Mycology

Probable disease

Probable disease

Strategy Strategy

includeinclude all patients likely to have aspergillosis and all patients likely to have aspergillosis and treat them treat them pre-emptivelypre-emptively with the safest with the safest and most effective drugand most effective drug

Aim of the strategyAim of the strategy

ANDAND

excludeexclude all patients unlikely to have the disease all patients unlikely to have the disease and adopt aand adopt a WAIT-and-SEE WAIT-and-SEE policypolicy

By using techniques that offer a By using techniques that offer a high negativehigh negative predictive value predictive value i.e.i.e. a low false-negative rate a low false-negative rate

AMLAML

HSC transplantHSC transplant

Risk factor selectionRisk factor selection

Risk factors diagnosis

HSC transplantHSC transplant

febrilefebrile

RadiologyRadiology

MycologyMycology

febrilefebrile

PulmonaryPulmonaryInfiltrateInfiltrate

AntigenAntigen

++

Screening test for a potentially fatal disease Screening test for a potentially fatal disease with a low prevalencewith a low prevalence

+

-

Controls Tests

- -

+±

not ruled outnot ruled outstart treatmentstart treatment

not ruled outnot ruled outstart treatmentstart treatment

ruled outruled outwithhold treatmentwithhold treatment

ruled outruled outwithhold treatmentwithhold treatment

CT scanCT scan

At riskAt risk

3 x weekly GM-ELISA3 x weekly GM-ELISA

yes no

ELISA GM positive

OROROROR

> 5 d unexplained fever

OROROROR

abnormal chest X-ray

EORTC/MSG criteriaEORTC/MSG criteria

A strategy for managing pulmonary aspergillosisA strategy for managing pulmonary aspergillosis

therapytherapy wait-and-seewait-and-see

yesyes

yesyes

probable

no

unlikely

yesyesno

possible

Clinical features

Prevalence ≥ 10%

yesyes no

no

Microbiological evidence

A strategyA strategy

At riskAt risk

Pre-emptive therapyPre-emptive therapy

eg. CT scan halo-eg. CT scan halo-signsign

or air-crescent signor air-crescent sign

Obtaining a specimen - tools of the tradeObtaining a specimen - tools of the trade

BronchoscopyBronchoscopyBronchoscopyBronchoscopy

BrushBrush

BiopsyBiopsy

Bronchoalveolar Bronchoalveolar lavagelavage

Lung biopsyLung biopsyLung biopsyLung biopsy

Sputum Sputum Sputum Sputum

Fine needle aspirateFine needle aspirateFine needle aspirateFine needle aspirate

Bronchoscopy specimen - processingBronchoscopy specimen - processing

BALBALBALBAL Culture Culture Culture Culture

cytologycytologycytologycytology

CentrifugeCentrifuge500 g 5 min500 g 5 min

Martin et al 1987 Mayo Clin Proc 62:549-557

Aerobic bacteriaAerobic bacteria S. pneumoniae, Ps aeruginosaS. pneumoniae, Ps aeruginosaEnterobacteriaEnterobacteria KlesiellaKlesiella spp sppLegionellaLegionella spp sppMycobacteriaMycobacteria M. tuberculosisM. tuberculosisNocardiaNocardia spp sppMycoplasmaMycoplasma spp sppYeastsYeasts Candida Candida sppsppMouldsMoulds A. fumigatusA. fumigatusVirusVirus CMV, HSV, RSVCMV, HSV, RSV

GramGramGiemsaGiemsaSilverSilverAcid-fast stainAcid-fast stainIFAIFA --LegionellaLegionella

10-20 mL10-20 mL10-20 mL10-20 mL

10-20 mL10-20 mL10-20 mL10-20 mL CytospinCytospinCytospinCytospin

Shell vialShell vialcultureculture

Shell vialShell vialcultureculture

IFAIFA -CMV-CMV-HSV-HSV

-- RSVRSVinfluenza A & Binfluenza A & B

Mycology

Clinical features

Host factors + + ProbableProbable=

= Proven Proven Mycology

Clinical features

Host factors + +

tissue

Mycology+Host

factors

Negativeor

Not done

Clinical features+Host

factors

Negativeor

Not done=

=PossiblePossible

Invasive Fungal InfectionInvasive Fungal Infection

Conclusions Conclusions

• Patients at risk are better knownPatients at risk are better known

• The timing of the risk is better understood The timing of the risk is better understood

• Diagnosis is improvingDiagnosis is improving

• Criteria now exist for defining invasive mycosisCriteria now exist for defining invasive mycosis

the importance of epidemiology in the diagnosis of invasive fungal infections j peter donnelly bsc...

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invasive fungal infections

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