THE MIRACULOUS RETURN OF'

1
THE MIRACULOUS RETURN OF.
2
BASIC RISK FACTORS FOR FUNGAL INFECTIONS
Adapted from RH Rubin, Boston
3
TRANSPLANTATION A HYPE?
4
SYSTEMIC FUNGAL INFECTIONS AND GROUPS AT RISK
Neutropenia and BMT
Invasive fungal infections
5
TIMING OF FUNGAL INFECTIONS AFTER SOLID ORGAN
TRANSPLANTSnydman Clin Infect Dis. 2001 33 S5
CMV
Candida
Aspergillus
Cryptococcus
Endemic fungi
Pneumocystis
1
2
3
4
5
6
7
8
0
6
INVASIVE FUNGAL INFECTIONS IN ALLO-PBSCTINCIDENCE
AND DISTRIBUTION Martino et al. Brit J Haematol
2002116475-82
7
INVASIVE FUNGAL INFECTIONS AFTER ALLOGENEIC,
NON-ABLATIVE TRANSPLANTSMaris, Marr et al
Focus 2003, P-23
163 patients 1997-2001
Incidence
IFI
moulds
Candida
Aspergillus
Risk factors GvHD, CMV, corticosteroids
8
INVASIVE FUNGAL INFECTIONS DURING MINI-PERIPHERAL
BLOOD STEM CELL TRANSPLANTSWALSH et al. ICAAC,
SAN DIEGO 2002 Abstr M1233
48 patients
23 invasive fungal infections
31 candidemia
9
INCIDENCE OF INVASIVE FUNGAL INFECTIONS AMONG
SOLID ORGAN TRANSPLANT RECIPIENTSSingh Clin
Infect Dis. 2001 31 545
Aspergillus
Candida

• Transplant IFI
• Renal 1.4 - 14
• Heart 5 - 21
• Liver 7 - 42
• Lung heart/lung 15 - 35
• Small bowel 40 - 59
• Pancreas 18 - 38

10
FACTORS ANNOUNCING OCCURRENCE OF INVASIVE CANDIDA
INFECTIONS
11
COLONIZATION-INVASION
Initial situation integument damage
invasion
12
OCCURRENCE OF CANDIDIASIS IN RELATION TO
NEUTROPENIAGoodrich et al. J Infect Dis 1991
164731-40
Hepatosplenic candidiasis
candidemia
bacteremia
13
INVASIVE FUNGAL INFECTIONS DURING SMALL BOWEL
TRANSPLANTSKWAK et al. ICAAC, SAN DIEGO 2002
Abstr K1231
96 patients
45 suspected invasive fungal infections
high risk hemodialysis
14
THE BASIS FOR EMPIRICAL ANTIFUNGAL THERAPY IN
FEBRILE NEUTROPENICS PIZZO et al Am J Med 1982
72101-10
fungal infections
15
EARLY EMPIRICAL ANTIFUNGAL THERAPY IN FEBRILE
NEUTROPENICS EORTC. Am J Med 1989 86668-72
16
FLUCONAZOLE 400 mg/day AS PROPHYLAXISIN LIVER
TRANSPLANT RECIPIENTSWINSTON et al.
Ann.Intern.Med. 1999131729-37
PLACEBO n 117
FLUCONAZOLE n 119
SYSTEMIC FUNGUS SUPERFICIAL FUNGUS COLONIZATIO
N OVERALL SURVIVAL FUNGAL DEATH RATE
6 4 70 --gt 28 11 2
23 28 60 --gt 90 14 13
C. glabrata prevalent species
17
PROPHYLAXIS WITH FLUCONAZOLEIN BONE MARROW
TRANSPLANTATIONGOODMAN et al. N.ENGL.J.MED 1992,
326 845
PLACEBO n 177
FLUCONAZOLE n 179
SYSTEMIC FUNGUS SYSTEMIC CANDIDIASIS SUPERFICIAL
FUNGUS SYSTEMIC AMPHO-B FATAL FUNGUS
3 0 8 56 1
16 10 33 66 6
18
EVOLVING CANDIDEMIAS IN US ICUS Trick et al CID
2002 35 627-32.
NNIS data from 1116 ICUs/ 311 hospitals. From
data for 3,041,585 patients
Candidemia per 10,000 CVC days
C. albicans
C. krusei
C. parapsilosis
C. tropicalis
19
MORTALITY DUE TO INVASIVE MYCOSESMCNEIL MM, ET
AL. CLIN INFECT DIS 200133641-7
Candida albicans
Other Mycoses
20
EVOLUTION MORTALITY OF INVASIVE CANDIDIASIS
Martino et al. Ann Hematol 200281233-43
63
53
25
22
8
21
MORTALITYASSOCIATED WITH INVASIVE
ASPERGILLOSISLin, Schranz, Teutsch. Clin Infect
Dis 200132358

100
50
n 178
0
days
0
60
120
180
240
300
360
22
INVASIVE ASPERGILLOSIS AND UNDERLYING DISEASE
Denning Clin Infect Dis 2001 26 pp781-805

• Condition range ()
• Lung heart transplant 19-26
• Liver transplant 1.5-10
• Renal transplant 0.5-10
• Allogeneic HSCT 4-9
• Autologous HSCT 0.5-6

23
INCIDENCE OF ASPERGILLOSIS AMONG SOLID ORGAN
TRANSPLANT RECIPIENTSSingh Clin Infect Dis. 2001
31 545
25
Number in UNOS 1995-1996
20
Incidence ()
15
10
5
0
gut
pancreas
kidney
liver
heart
lung
41
129
11031
3573
2313
811
24
ASPERGILLOSIS IN TRANSPLANT RECIPIENTSPATERSON
SINGH Medicine 1999 78123
25
MORTALITY OF INVASIVE ASPERGILLOSISIN RELATION
TO UNDERLYING DISEASELin, Schranz, Teutsch Clin
Infect Dis 200132358
100 90 80 70 60 50 40 30 20 10
leukemia /lymphoma
AIDS
26
ASPERGILLOSIS IN TRANSPLANT RECIPIENTSPATERSON
SINGH Medicine 1999 78123
10-15 of all deaths due to aspergillosis
27
INVASIVE FUNGAL INFECTIONS AFTER ALLOGENEIC,
NON-ABLATIVE TRANSPLANTSMaris, Marr et al
Focus 2003, P-23
163 patients 1997-2001
Incidence
IFI
moulds
Candida
Aspergillus
Risk factors GvHD, CMV, corticosteroids
28
INVASIVE FUNGAL INFECTIONS IN ALLO-PBSCTASSOCIATE
D MORTALITY Martino et al. Brit J Haematol
2002116475-82
29
RELATION OUTCOME AND STATE OF FUNGAL INFECTION
time
odds to control the infection
evolution of the infection
30
IN TIME?
31
RESPONSES AT WEEK 12 IMPACT OF EARLY
DIAGNOSIS Herbrecht et al N Engl J Med 2002
347408-15
Voriconazole OLAT
Ampho B OLAT
32
DIAGNOSTIC DILEMMAS IN ASPERGILLUS INFECTIONS

• Clinical symptoms are not characteristic
• Manifestations on imaging are seldom specific
• Fungi can be both colonizers and pathogens, hence
  vigilance is required in the interpretation of
• -superficial cultures
• -antigen tests, PCR screening, presence of
  antibodies
• 
  and/or metabolites
• Non-invasive techniques have not been validated
• Biopsy is often precluded by co-morbidity
• Objective evidence usually occurs late in the
  course of the infection

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ASPERGILLOSIS IN LUNG TRANSPLANTATIONRuffini et
al. ICAAC 2001, Chicago. Abstr J-1635
All cultures negative 17 Disseminated
aspergillosis 2 Tracheobronchitis
5 Pulmonary aspergillosis 9 Colonization
4
fatal
38 lung transplants
Sputum
recovered
34
AEROSOLIZED LIPOSOMAL AMPHOTERICIN B AS
PROPHYLAXIS IN LUNG TRANSPLANTATIONRUFFINI et
al. ICAAC, SAN DIEGO 2002 abstr M1237
80 pat
56 patients discharged after transplant
12 colonizers 5 tracheobronchitis 5 pulmonary
aspergillosis 1 disseminated aspergillosis
35
AMPHOTERICIN-B FOR FEVER PERSISTING 4-7 DAYS
Pizzo et al AJM 1982 16 vs 18 pat
EORTC AJM 1989 64 vs 68 pat
PERCENTAGE OF SYSTEMIC FUNGUS
NO AMPHO-B AMPHO-B
31 6
9 2
could be from gt50 better to 8 worse than no
therapy
p0.057
36
EMPIRICAL AMPHOTERICIN-B VERSUS AMBISOME 1 and 3
mg/kg/d IN HEMATOLOGICAL MALIGNANCIESPRENTICE
et al, BRIT.J. HAEMATOL. 1997
AMPHO-B
AMBISOME
AMBISOME
1 mg/kg/24 hrs n 102
1 mg/kg/24 hrs n 118
3 mg/kg/24 hrs n 118
DEFERVESCENCE DEATH DUE TO FUNGAL INFECTION
49 1
64 1
58 1
37
AMBISOME VERSUS AMPHOTERICIN-B AS EMPIRICAL
THERAPY Walsh et al. N Engl J Med 1999340764
AMPHO-B
AMBISOME
0.6 mg/kg/24 hrs n 344
3 mg/kg/24 hrs n 343
DEFERVESCENCE BREAKTHROUGH FUNGAL
INFECTION DEATH DUE TO FUNGAL INFECTION
58 8 3
58 3 1
38
LIPOSOMAL NYSTATIN VERSUS AMPHOTERICIN-B AS
EMPIRICAL THERAPY Powles et al, ICAAC, San
Francisco, 1999
AMPHO-B
NYSTATIN
0.6-0.8 mg/kg/24 hrs n 268
2 mg/kg/24 hrs n 270
SUCCESS -survival for 3-5 days
-defervescence -no fungal infection
-tolerance SURVIVAL 30 days
NOT DIFFERENT
39
36
39
AMPHOTERICIN-B VERSUS ITRACONAZOLE iv --gt oral
solution AS EMPIRICAL THERAPY BOOGAERTS et al.
Ann Intern Med 2001 135412-22
AMPHO-B
ITRACONAZOLE
0.7-1 mg/kg/24 hrs n 181
200mg 2-4x daily, 2-12 days iv 200mg 2x daily,
max 14 days po n 179
RESPONSE TIME TO DEFERVESCENCE DOCUMENTED
BREAKTHROUGH FUNGAL INFECTION ADVERSE EVENTS
drug cessation NEPHROTOXICITY DEATH
38 7 days 3 54 38 24 14
47 8.5 days 3 5 19 5 11
40
EFFICACY OF AMBISOME VERSUS ABELCET AS
EMPIRICAL THERAPY WINGARD et al, Clin Infect Dis
2000311155-63
AMBISOME
ABELCET
3 mg/kg/24 hrs n 85
5 mg/kg/24 hrs n 81
5 mg/kg/24 hrs n 78
DEFERVESCENCE MORTALITY BREAKTHROUGH
FUNGAL INFECTION DEATH DUE TO FUNGAL INFECTION
40 5 2.4 1
42 2.5 2.5 0
33 14 3.8 4
41
EMPIRICAL VORICONAZOLE vs AMBISOMEFOR
PERSISTENTLY FEBRILE NEUTROPENICS IIWalsh et al.
ICAAC Toronto 2000. Abstr L1, Addendum p. 20-21
VORICONAZOLE AMBISOME
Patients Success Survival breakthrough
fungus
415 26 87 2
422 31 90 5
42
EMPIRICAL VORICONAZOLE vs AMBISOMEBREAKTHROUGH
INVASIVE FUNGAL INFECTIONSWalsh et al, ICAAC
Toronto 2000
Organism Voriconazole
AmBisome
Aspergillus spp lung Candida spp
blood Zygomycetes Dematacious moulds
TOTAL
4 4 2 1 2 0 8
13 9 6 6 0 2 21

43
VALIDATION OF EMPIRICAL THERAPY FOR ASPERGILLOSIS
IN NEUTROPENIC PATIENTS
Peter Donnelly Ben dePauw
STUDYPOPULATION
prophylaxis setting
Maertens et al Blood 2001971604-1610
44
VALIDATION OF EMPIRICAL THERAPY FOR ASPERGILLOSIS
IN NEUTROPENIC PATIENTS II
Peter Donnelly Ben dePauw
STUDYPOPULATION
proven
probable
No persisting fever
fever
empirical setting
45
Management of aspergillosis
Peter Donnelly Ben dePauw
Aspergillus
underlying disease
neutropenia
infection
antibiotics
GvHD
steroids
CMV
prophylaxis
empirical
pre-emptive
46
VALIDATION OF EMPIRICAL THERAPY FOR ASPERGILLOSIS
IN NEUTROPENIC PATIENTS IV
Peter Donnelly Ben dePauw
probable
proven
STUDYPOPULATION
possible
fever
No persisting fever
clinical empirical setting
47
POSSIBLE CAUSES OF FEVER AFTER ORGAN
TRANSPLANTATION

• Bacteria
• Graft-versus host disease/
• Organ rejection
• Fungi ?? Yeasts // moulds
• Viruses
• Pyrogenic substances drugs
• 
  cytokines, toxins
• 
  bloodproduct-antigens
• Parasites

48
VALIDATION OF EMPIRICAL THERAPY FOR ASPERGILLOSIS
IN NEUTROPENIC PATIENTS V
Peter Donnelly Ben dePauw
probable
proven
possible
No persisting fever
variable study population
49
TIME FOR ACTION?
50
RISK GROUP SELECTION WHEN THE PREVALENCE IS LOW
51
RISK OF ASPERGILLUS INFECTIONS AMONGST TRANSPLANT
RECIPIENTS
ALLOGENEIC BMT / PBSC
graft-versus-host disease elderly
patients lung abnormalities late take
30
mismatched donor matched, unrelated
donor corticosteroids
10-15
chronic myelogenous leukemia and
other conditions not requiring induction
chemotherapy
lt5
52
FEATURES OF ASPERGILLUS INFECTIONSDURING BONE
MARROW TRANSPLANTATIONWALD, BOWDEN et al. J
Infect Dis 1997
2496 patients 6 proven and
probable aspergillosis
gt1000
1000
500
lt100
0 10 20 30 40 50
60 70 80 90 100
110 120 days
risk factors

• overall
• age
• neutropenia
• hospital
• reconstructions

53
INVASIVE FUNGAL INFECTIONS IN ALLO-PBSCTRISK
FACTORS IN RELATION TO INCIDENCE Martino et al.
Brit J Haematol 2002116475-82
54
OUTCOME STEM CELL TRANSPLANT AFTER PRIOR
ASPERGILLOSISMarr et al Focus 2003, P-22
45 patients prior aspergillosis
2264 patients no prior aspergillosis
55
ORGAN DISTRIBUTION OF DISSEMINATEDASPERGILLUS
INFECTIONS
ASPERGILLUS
LUNG GASTROINTESTINAL TRACT LIVER SPLEEN BRAIN
HEART KIDNEYS SKIN THYROID
100 50 30 15 60 15 30 5 25
56
EVOLUTION OF PULMONARYLESIONS IN
ASPERGILLOSISaccording to CAILLOT et al.
JClinOncol 200119253
halo - - - atypical - - - air crescent
57
MEANING OF A POSITIVE ASPERGILLUS CULTURE IN
RELATION TO RISK GROUPS Perfect et al. Clin
Infect Dis 2001331824-33
High Intermediate Low risk
alloBMT neutropenia hematol malignancy
autoBMT steroids HIV
58
GROWTH OF ASPERGILLUS FROM SPUTUMPATERSON, SINGH
Medicine 1999 78123
Risk for aspergillosis 60-80 15 40-70 30
-45
50 pos
Bone marrow tx Lung transplant Liver
transplant Kidney transplant
59
GALACTOMANNAN SCREENING IN ALLOGENEIC STEM CELL
RECIPIENTSMaertens et al, J Infect Dis
2002331297-1306
100 patients
60
GALACTOMANNAN IN BAL FLUID OF PATIENTS WITH
TYPICAL CT-ABNORMALITIES IIBecker et al. Brit J
Haematol 2003121449-57
n GM in BAL fluid
Prospective 198 patients
Proven IPA Probable Radiologically
probable Possible Empirical ampho B Other IFI No
IFI
100 89 75 42 0 0 0
3 10 9 13 2 3 158
61
ASPERGILLUS PCR IN BONE MARROW TRANSPLANT
RECIPIENTSHebart, Einsele et al. J Infect Dis
2000 1811713-9
84 patients // 1193 blood samples
69 without Aspergillosis 17 (24) - PCR pos ?
52 (76) -- PCR neg
15 false positive 0 false negative
Median time gain to diagnosis positive
PCR first clinical sign diagnosis
2 days 9 days

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DIRECT HIT?
63
GUIDELINES
If there are no scientific data one has to rely
on wisdom Unfortunately, this is an even more
exceptional item