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Perché è Difficile
Diagnosticare e Trattare
l’Aspergillosi Invasiva?
TOPICS
•Behavior of Aspergillus
-characteristics
•Principles of management
-detection
-treatment
when and what
TOPICS
•Behavior of Aspergillus
-characteristics
•Principles of management
-detection
-treatment
when and what
INFECTION!
INFECTION!
bacteria
viruses
fungi
EUKARYOTIC ORGANISM!! MRS. FUNGUS
cell membrane
-ergosterol
cell wall
cholesterol
ASPERGILLUS
1729
MICHELI
catholic priest
FIRST DESCRIPTION
“brush-shaped structure”
ASPERGILLUS IS EVERYWHERE
environment
moss
soil
decaying material
According to Odds
DEFENSE
SYSTEMS
removes viruses, fungi and tumor cells
T-cell function
Humoral immunity
Commensal flora
antibody production
micro-organisms in the gut
against bacteria – pus formation
Granulocytes
Mucosa
/
Skin
border control of our body
DEFENSE
SYSTEMS
T-cell function
Humoral immunity
Commensal flora
Granulocytes
Mucosa
day
/
Skin
40
100
COURSE OF
DEFENSE SYSTEMS
T-cell function
Humoral immunity
Commensal flora
Granulocytes
Mucosa
day
/ Skin INFECTIONS
ASPERGILLUS
40
100
INFECTIOUS AGENTS IN RELATION TO THE
COURSE OF DEFENSE SYSTEMS
Garcia-Vidal et al. Clin Infect Dis 2008; 47:1041-1050
ASPERGILLUS
time
BASIC RISK FACTORS FOR FUNGAL INFECTIONS
immuno-
epidemiologic
suppression
exposure
Adapted from RH Rubin, Boston
OPPORTUNISTS!
money
shops
xxxxx
TRENDS INCIDENCE
INVASIVE FUNGAL INFECTIONS
number of cases
Pagano et al. Haematologica 2006; 91:1068-1075
80
70
60
50
ASPERGILLUS
40
30
20
10
0
87-88
92-93
97-98
2002-2003
INVASIVE FUNGAL DISEASE AFTER
NON-MYELOABLATIVE ALLO-BMT
Fukuda et al. Blood 2003; 102:827-833
22% non-relapse mortality
39% mould-related
n = 163
MORTALITY OF INVASIVE ASPERGILLOSIS
Variation due to:
•timing of intervention
•timely diagnosis
•patients’ defense system
•treatment given
MORTALITY OF INVASIVE ASPERGILLOSIS
97%
42%
Variation due to:
•timing of intervention
•timely diagnosis
•patients’ defense system
•treatment given
GROWTH OF ASPERGILLUS
1-2 cm per 24 hours
MAKE YOUR CHOICE!
ONE WEEK LATER….
INFECTION -- DISEASE
TOPICS
•Behavior of Aspergillus
-characteristics
•Principles of management
-detection
-treatment
when and what
TOPICS
•Behavior of Aspergillus
-characteristics
•Principles of management
-detection
-treatment
when and what
TOPICS
•Behavior of Aspergillus
-characteristics
•Principles of management
-detection
-treatment
when and what
WELCOME TO MYCOLOGY
spores
hyphae
spore
ASPERGILLUS
ADMISSION TO THE HUMAN BODY
Caso MK - 5
EVOLUTION OF AN INFECTION AND MORTALITY
TRADITIONAL
DIAGNOSIS
97%
42%
FUNGAL BURDEN
AWAY FROM EMPIRISM?
TRADITIONAL
DIAGNOSIS
NEW
TOOLS
42%
FUNGAL BURDEN
97%
diagnostics
FIRST TEST POSITIVE FOR ASPERGILLOSIS
IN HEMATOLOGICAL MALIGNANCIES
Florent et al. J Infect Dis 2006;193:741-747
serology
0
2
3
CT
4
5
6
7
8
culture
histology
9
10 11
12
13
14 15 16
DAYS
55 patients
TOPICS
•Behavior of Aspergillus
-characteristics
•Principles of management
-detection
-treatment
when and what
TOPICS
•Behavior of Aspergillus
-characteristics
•Principles of management
-detection
-treatment
when and what
TOPICS
•Behavior of Aspergillus
-characteristics
•Principles of management
-detection
-treatment
when and what
ADMINISTRATION OF ANTIMICROBIALS IN
RELATION TO THE COURSE OF NEUTROPENIA
100%
antibacterials
GRANULOCYTES
75%
50%
>1000
Empirical antifungals
1000
500
<100
0
10
20
30
days
ESTIMATING TIME FOR INTERVENTION
Aspergillus
Persisting fever +
• very high risk
or
• a suggestive symptom
or
• a suspected sign
or
• any positive test
day 1
5
infiltrate
antigen
7
12 //
28
> 42
TACTICS
ITALIAN:
-strong defense
-efficient attack
BRAZILIAN:
-no defense
-intuitive attack
TOPICS
•Behavior of Aspergillus
-characteristics
•Principles of management
-detection
-treatment
when and what
PACE OF DEVELOPMENT OF
NEW ANTIFUNGAL AGENTS
Adapted from
Rex & Edwards, 1997
Amphotericin B
AmBisome
Amphocil
Abelcet
itraconazole
fluconazole
terbinafine
ketoconazole
miconazole
5-flucytosine
Nystatin
Griseofulvin
1950
1960
1970
1980
1990
2000
EORTC
IFICG
RESULTS FIRST LINE TREATMENT OF
INVASIVE 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
% response
60
50
40
30
20
10
0
42/133
(32%)
76/144
(53%)
Ampho B Voriconazole
53/107
(50%)
25/51
(49%)
Lipo-AmB
Caspofungin
OUTCOME OF ASPERGILLOSIS IN RELATION
TO INITIAL ANTIFUNGAL THERAPY
n = 289
Nivoix, Y et al. Clin Infect Dis 2008; 47:1176-1184
n = 62
S
U
R
V
I
V
A
L
n = 51
n = 127
P=0.016
70%
47%
OUTCOME OF THERAPY FOR ASPERGILLOSIS
ARISING DURING AML IN DAILY PRACTICE
Pagano et al. SEIFEM 2008
N° of patients treated
140 cases
First line therapy
40
30
20
10
0
28%
27%
21%
16%
OUTCOME OF THERAPY FOR ASPERGILLOSIS
ARISING DURING AML IN DAILY PRACTICE
Pagano et al. SEIFEM 2008
N° of patients treated
140 cases
Aspergillosis attributable mortality
40
30
20
10
0
18%
24%
32%
23%
CORTICOSTEROIDS AND SURVIVAL
OF ASPERGILLOSIS IN HSCT
Cordonnier et al. Clin Infect Dis 2006;42:955-963
51 patients with
aspergillosis
S
U
R
V
I
V
A
L
low dose corticosteroids
high dose
41 allo HSCT
10 auto
RELATION OUTCOME OF FUNGAL INFECTIONS
AND GRANULOCYTE COUNT
n = 63
INCREASING
GRANULOCYTES
Response
86%
DECREASING
GRANULOCYTES
Response
36%
RELATION OUTCOME OF FUNGAL INFECTIONS
AND STATE OF UNDERLYING DISEASE
SUCCESSFUL OUTCOME
REMISSION
n = 63
8%
61%
REFRACTORY
UNDERLYING
DISEASE
EVOLUTION OF ASPERGILLUS INFECTIONS
AMONGST PATIENTS WITH ACUTE LEUKEMIA
Pagano et al. Clin Infect Dis 2007; 44:1524-1525
new
antifungals
Incidence (%)
15
12
60%
50%
40%
9
30%
6
3
serological
tests
20%
CT-scan
10%
0
1987-1998
1999-2003
2006
attributable mortality
CRUCIAL ELEMENTS IN AVOIDANCE OF
DISASTERS
Knowledge on behavior of the offender
High awareness
Early recognition
Early treatment
CONCLUSIONS
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
Buona conferenza
a tutti voi!
Grazie, Ben!