Perché è Difficile

Diagnosticare e Trattare

l’Aspergillosi Invasiva?

Perché è Difficile

Diagnosticare e Trattare

l’Aspergillosi Invasiva?

TOPICSTOPICS

•Behavior of AspergillusBehavior of Aspergillus

-characteristics-characteristics

•Principles of managementPrinciples of management

-detection-detection

-treatment-treatment

when and when and

whatwhat

TOPICSTOPICS

•Behavior of AspergillusBehavior of Aspergillus

-characteristics-characteristics

•Principles of managementPrinciples of management

-detection-detection

-treatment-treatment

when and when and

whatwhat

INFECTION!INFECTION!

INFECTION!INFECTION!

fungifungi

bacteria

viruses

EUKARYOTIC ORGANISM!! MRS. FUNGUSEUKARYOTIC ORGANISM!! MRS. FUNGUS

cell membrane -ergosterol

cell wall

cholesterol

ASPERGILLUSASPERGILLUS

FIRST DESCRIPTION“brush-shaped structure”

FIRST DESCRIPTION“brush-shaped structure”

1729172917291729

MICHELIcatholic priest

MICHELIcatholic priest

ASPERGILLUS IS EVERYWHEREASPERGILLUS IS EVERYWHERE

moss soil decaying material

environment

According to Odds

DEFENSE SYSTEMSDEFENSE SYSTEMS

Mucosa / Skin

Granulocytes

Commensal flora

Humoral immunity

T-cell function

removes viruses, fungi and tumor cellsremoves viruses, fungi and tumor cells

antibody production

micro-organisms in the gut

against bacteria – pus formationagainst bacteria – pus formation

border control of our bodyborder control of our body

day 40 100

DEFENSE SYSTEMSDEFENSE SYSTEMS

Mucosa / Skin

Granulocytes

Commensal flora

Humoral immunity

T-cell function

day 40 100

MucosaMucosa

GranulocytesGranulocytes

Commensal flora

Humoral immunity

T-cell function

/ Skin / Skin

COURSE OF DEFENSE SYSTEMS

COURSE OF DEFENSE SYSTEMS

INFECTIOUS AGENTS IN RELATION TO THE COURSE OF DEFENSE SYSTEMS

Garcia-Vidal et al. Clin Infect Dis 2008; 47:1041-1050

INFECTIOUS AGENTS IN RELATION TO THE COURSE OF DEFENSE SYSTEMS

Garcia-Vidal et al. Clin Infect Dis 2008; 47:1041-1050

time

BASIC RISK FACTORS FOR FUNGAL INFECTIONSBASIC RISK FACTORS FOR FUNGAL INFECTIONS

Adapted from RH Rubin, Boston

OPPORTUNISTS!OPPORTUNISTS!OPPORTUNISTS!OPPORTUNISTS!

xxxxxxxxxx

TRENDS INCIDENCE INVASIVE FUNGAL INFECTIONS

Pagano et al. Haematologica 2006; 91:1068-1075

TRENDS INCIDENCE INVASIVE FUNGAL INFECTIONS

Pagano et al. Haematologica 2006; 91:1068-1075

0

10

20

30

40

50

60

70

80

87-88 92-93 97-98 2002-2003

nu

mb

er

of

cases

ASPERGILLUS

INVASIVE FUNGAL DISEASE AFTER NON-MYELOABLATIVE ALLO-BMT

Fukuda et al. Blood 2003; 102:827-833

INVASIVE FUNGAL DISEASE AFTER NON-MYELOABLATIVE ALLO-BMT

Fukuda et al. Blood 2003; 102:827-833

22% non-relapse mortality

39% mould-related

9% mould-re

lated deaths

n = 163

MORTALITY OF INVASIVE ASPERGILLOSISMORTALITY OF INVASIVE ASPERGILLOSIS

Variation due to: •timing of intervention •timely diagnosis•patients’ defense system•treatment given

MORTALITY OF INVASIVE ASPERGILLOSISMORTALITY OF INVASIVE ASPERGILLOSIS

Variation due to: •timing of intervention •timely diagnosis•patients’ defense system•treatment given

97%

42%

GROWTH OF ASPERGILLUSGROWTH OF ASPERGILLUS

1-2 cm per 24 hours1-2 cm per 24 hours

MAKE YOUR CHOICE!MAKE YOUR CHOICE!

ONE WEEK LATER….ONE WEEK LATER….

INFECTION -- DISEASEINFECTION -- DISEASE

TOPICSTOPICS

•Behavior of AspergillusBehavior of Aspergillus

-characteristics-characteristics

•Principles of managementPrinciples of management

-detection-detection

-treatment-treatment

when and when and

whatwhat

TOPICSTOPICS

•Behavior of AspergillusBehavior of Aspergillus

-characteristics-characteristics

•Principles of managementPrinciples of management

-detection-detection

-treatment-treatment

when and when and

whatwhat

TOPICSTOPICS

•Behavior of AspergillusBehavior of Aspergillus

-characteristics-characteristics

•Principles of managementPrinciples of management

-detection-detection

-treatment-treatment

when and when and

whatwhat

WELCOME TO MYCOLOGYWELCOME TO MYCOLOGY

ASPERGILLUSASPERGILLUS

spore

hyphae

spores

ADMISSION TO THE HUMAN BODYADMISSION TO THE HUMAN BODY

Caso MK - 5Caso MK - 5

EVOLUTION OF AN INFECTION AND MORTALITYEVOLUTION OF AN INFECTION AND MORTALITY

FUNGAL BURDEN

TRADITIONAL DIAGNOSIS

97%

42%

97%

42%

AWAY FROM EMPIRISM?AWAY FROM EMPIRISM?

FUNGAL BURDEN

diagnostics

TRADITIONAL DIAGNOSIS

NEW TOOLS

0 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 DAYS

0 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 DAYS

55 patients 55 patients

FIRST TEST POSITIVE FOR ASPERGILLOSIS IN HEMATOLOGICAL MALIGNANCIES

Florent et al. J Infect Dis 2006;193:741-747

FIRST TEST POSITIVE FOR ASPERGILLOSIS IN HEMATOLOGICAL MALIGNANCIES

Florent et al. J Infect Dis 2006;193:741-747

culturehistology

CTserology

TOPICSTOPICS

•Behavior of AspergillusBehavior of Aspergillus

-characteristics-characteristics

•Principles of managementPrinciples of management

-detection-detection

-treatment-treatment

when and when and

whatwhat

TOPICSTOPICS

•Behavior of AspergillusBehavior of Aspergillus

-characteristics-characteristics

•Principles of managementPrinciples of management

-detection-detection

-treatment-treatment

when and when and

whatwhat

TOPICSTOPICS

•Behavior of AspergillusBehavior of Aspergillus

-characteristics-characteristics

•Principles of managementPrinciples of management

-detection-detection

-treatment-treatment

when when and and

whatwhat

100%

75%

50%

ADMINISTRATION OF ANTIMICROBIALS IN ADMINISTRATION OF ANTIMICROBIALS IN RELATION TO THE COURSE OF RELATION TO THE COURSE OF NEUTRNEUTROPENIAOPENIA

ADMINISTRATION OF ANTIMICROBIALS IN ADMINISTRATION OF ANTIMICROBIALS IN RELATION TO THE COURSE OF RELATION TO THE COURSE OF NEUTRNEUTROPENIAOPENIA

antibacterialsantibacterials

<100GR

AN

ULO

CY

TES

1000

500

>1000

0 10 20 30 days

ESTIMATING TIME FOR INTERVENTIONESTIMATING TIME FOR INTERVENTION

AspergillusAspergillus

day 1 5 7 12 // 28 > 42day 1 5 7 12 // 28 > 42

antigenantigenantigenantigen

Persisting fever +

• very high risk or• a suggestive symptom or• a suspected sign or• any positive test

infiltrateinfiltrateinfiltrateinfiltrate

TACTICSTACTICS

ITALIAN:

-strong defense-efficient attack

BRAZILIAN:

-no defense-no defense-intuitive attack-intuitive attack

TOPICSTOPICS

•Behavior of AspergillusBehavior of Aspergillus

-characteristics-characteristics

•Principles of managementPrinciples of management

-detection-detection

-treatment-treatment

when and when and

whatwhat

PACE OF DEVELOPMENT OF NEW ANTIFUNGAL AGENTSPACE OF DEVELOPMENT OF NEW ANTIFUNGAL AGENTS

19501950 19601960 19701970 19801980 19901990 20002000

Adapted from Rex & Edwards, 1997Adapted from Rex & Edwards, 1997

AmBisomeAmBisomeAmBisomeAmBisome

fluconazolefluconazolefluconazolefluconazole

AmphocilAmphocilAmphocilAmphocil

AbelcetAbelcetAbelcetAbelcet

itraconazoleitraconazoleitraconazoleitraconazole

ketoconazoleketoconazoleketoconazoleketoconazole

miconazolemiconazolemiconazolemiconazole

5-flucytosine5-flucytosine5-flucytosine5-flucytosine

terbinafineterbinafineterbinafineterbinafine

Amphotericin BAmphotericin BAmphotericin BAmphotericin B

NystatinNystatinNystatinNystatin

GriseofulvinGriseofulvinGriseofulvinGriseofulvin

isavuconazole

isavuconazole

caspofungin

caspofungin

anid

ulaf

ungi

n

anid

ulaf

ungi

n

mica

fungin

mica

fungin

voriconazole

voriconazole posaconazole

posaconazole

0

10

20

30

40

50

60% response

RESULTS FIRST LINE TREATMENT OFINVASIVE ASPERGILLOSIS

Herbrecht et al N Engl J Med 2002; 347:408-415 Cornely et al. Clin Infect Dis 2007; 44:1289-1297

Viscoli et al. J Chemother 2007; 19, suppl 5:36

RESULTS FIRST LINE TREATMENT OFINVASIVE ASPERGILLOSIS

Herbrecht et al N Engl J Med 2002; 347:408-415 Cornely et al. Clin Infect Dis 2007; 44:1289-1297

Viscoli et al. J Chemother 2007; 19, suppl 5:36

EORTC EORTC IFICGIFICG

VoriconazoleAmpho B Lipo-AmB Caspofungin

OUTCOME OF ASPERGILLOSIS IN RELATION TO INITIAL ANTIFUNGAL THERAPYNivoix, Y et al. Clin Infect Dis 2008; 47:1176-1184

OUTCOME OF ASPERGILLOSIS IN RELATION TO INITIAL ANTIFUNGAL THERAPYNivoix, Y et al. Clin Infect Dis 2008; 47:1176-1184 n = 289

SURVIVAL

n = 62 n = 51 n = 127

70%70%

47%47%

P=0.016P=0.016

40

30

20

10

0

OUTCOME OF THERAPY FOR ASPERGILLOSIS ARISING DURING AML IN DAILY PRACTICE

Pagano et al. SEIFEM 2008

OUTCOME OF THERAPY FOR ASPERGILLOSIS ARISING DURING AML IN DAILY PRACTICE

Pagano et al. SEIFEM 2008

140 cases

vori

conazo

le

vori

conazo

le

L-Am

B

L-Am

Bca

spofu

ngi

n

casp

ofu

ngi

nco

mbo

com

bo

28%28%

27%27%

21%21% 16

%16%

First line therapyFirst line therapyFirst line therapyFirst line therapyN

° of

pati

en

ts

treate

dN

° of

pati

en

ts

treate

d

OUTCOME OF THERAPY FOR ASPERGILLOSIS ARISING DURING AML IN DAILY PRACTICE

Pagano et al. SEIFEM 2008

OUTCOME OF THERAPY FOR ASPERGILLOSIS ARISING DURING AML IN DAILY PRACTICE

Pagano et al. SEIFEM 2008

140 cases

vori

conazo

le

vori

conazo

le

L-Am

B

L-Am

Bca

spofu

ngi

n

casp

ofu

ngi

nco

mbo

com

bo

18%18%

24%24%

32%32%

23%23%

40

30

20

10

0

N°

of

pati

en

ts

treate

dN

° of

pati

en

ts

treate

d

Aspergillosis attributable Aspergillosis attributable mortalitymortality

Aspergillosis attributable Aspergillosis attributable mortalitymortality

CORTICOSTEROIDS AND SURVIVAL OF ASPERGILLOSIS IN HSCT

Cordonnier et al. Clin Infect Dis 2006;42:955-963

CORTICOSTEROIDS AND SURVIVAL OF ASPERGILLOSIS IN HSCT

Cordonnier et al. Clin Infect Dis 2006;42:955-963

low dose corticosteroidslow dose corticosteroids

high dosehigh dose

S

U

R

V

I

V

A

L

S

U

R

V

I

V

A

L

51 patients with aspergillosis

41 allo HSCT

10 auto

RELATION OUTCOME OF FUNGAL INFECTIONSAND GRANULOCYTE COUNT

RELATION OUTCOME OF FUNGAL INFECTIONSAND GRANULOCYTE COUNT

n = 63n = 63

INCREASING GRANULOCYTES

Response 86%

DECREASING GRANULOCYTES

Response 36%

RELATION OUTCOME OF FUNGAL INFECTIONSAND STATE OF UNDERLYING DISEASE

RELATION OUTCOME OF FUNGAL INFECTIONSAND STATE OF UNDERLYING DISEASE

n = 63n = 63

SUCCESSFUL OUTCOME

REFRACTORYUNDERLYING

DISEASE8%8%

REMISSIONREMISSION61%61%

EVOLUTION OF EVOLUTION OF ASPERGILLUSASPERGILLUS INFECTIONS INFECTIONS AMONGST PATIENTS WITH ACUTE LEUKEMIAAMONGST PATIENTS WITH ACUTE LEUKEMIA

Pagano et al. Clin Infect Dis 2007; 44:1524-1525

EVOLUTION OF EVOLUTION OF ASPERGILLUSASPERGILLUS INFECTIONS INFECTIONS AMONGST PATIENTS WITH ACUTE LEUKEMIAAMONGST PATIENTS WITH ACUTE LEUKEMIA

Pagano et al. Clin Infect Dis 2007; 44:1524-1525

0

3

6

9

12

15

1987-1998 1999-2003 2006

Incid

en

ce (

%)

attributable mortality

60%

50%

40%

30%

20%

10%

CRUCIAL ELEMENTS IN AVOIDANCE OF DISASTERS

CRUCIAL ELEMENTS IN AVOIDANCE OF DISASTERS

Knowledge on behavior of the Knowledge on behavior of the

offenderoffender

High awarenessHigh awareness

Early recognitionEarly recognition

Early treatmentEarly treatment

ASPERGILLUS IS EVERYWHERE*****

IT IS AN OPPORTUNIST*****

EARLY DIAGNOSIS REQUIRES CONTINUOUS, SPECIFIC

SCREENING*****

ANTIFUNGALS MAY KEEP A PATIENT ALIVE

but CURE NEEDS RECOVERY OF

THE IMMUNE SYSTEM

CONCLUSIONSCONCLUSIONS

Grazie, Ben!Grazie, Ben!

Buona conferenza a tutti voi!

Buona conferenza a tutti voi!