perché è difficile diagnosticare e trattare l’aspergillosi invasiva?
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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!
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