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Can we rely on imaging and
biomarkers for preemptive
antifungal therapy in
hematological patients?
Claudio Viscoli
Professor of Infectious Disease, University of Genova
Chief, Division of Infectious Disease, San Martino University
Hospital, Genova, Italy
A comprehensive approach to the
diagnosis of IFI
Host
Laboratory
Diagnosis
Imaging
Clinical aspects
Underlying disease in invasive
aspergillosis
6%
595 patients
2%
7%
BMT/Auto
9%
BMT/Allo
Hematologic
6%
25%
8%
Solid
Transplant
AIDS
Other
Immune
Pulm
9%
Other
None
Patterson et al, Medicine, 2000
28%
Underlying disease phase and
primary site of infections
1st Induction
Maintenance
Other
5%
2nd Induction
AHSCT
None
Consolidation
HSCT
7%
6%
4%
2%
n° 391
patients
6%
59%
11%
69%
Sino nasal
CNS involvement
Disseminated
Gastrointestinal
Blood
Skin
Lung
Pagano et al, Haematologica 2001
1%
1%
1%
15%
6%
7%
CHARACTERISTIC PATTERNS OF INVASIVE
ASPERGILLOSIS IN COMMONLY AFFECTED PATIENT
GROUPS
UNDERLYING CONDITION
TIMING OF INVASIVE
ASPERGILLOSIS
Acute Leukemia;
Multiple Mieloma, stage II/III;
Chronic leukemia in blast crisis;
aplastic anemia;
autologous bone marrow or PSC
transplantation
During induction chemotherapy
(75%);
During maintenance or consolidation
treatments (25%).
Maily related to neutropenia
Allogeneic bone marrow or PSC
transplantation, especially if
matched unrelated or mismatched
donor
Early during neutropenia (20-30%);
Late (median 100 days) (75%),
mainly related to severe GVHD and
high-dose steroids
• 8988 admissions
• 71 positive cultures for Aspergillus
• Incidence rate 0.4% (37
proven/probable diseases as from
EORTC-MSG criteria)
A comprehensive approach to the
diagnosis of IFI
Host
Laboratory
Diagnosis
Imaging
Clinical aspects
Aspergillosis syndrome
•
•
•
•
•
•
•
•
Cough (92%)
Thoracic pain (76%)
Hemoptysis (54%)
Fever
Neurological signs
Nasal bleeding
Nasal discharge
Skin lesions
CLINICAL SYMPTOMS IN 45 CASES OF IA
IN HSCT PATIENTS
Fever
34/45 (75%)
Cough
12/45 (27%),
Dyspnoea
12/45 (27%)
Chest pain
9/45 (20%).
No sign or symptom
3 (positive GM with
multiple pulmonary nodules on CT scan).
 Radiological pulmonary lesions were mainly
represented by nodules (8/42, 19%), cavitations
(10/42, 24%) and wedge-shaped consolidations
(4/42, 10%).
Notably, the halo sign was never found.
Mikulska et al, BMT 2009
A comprehensive approach to the
diagnosis of IFI
Host
Laboratory
Diagnosis
Imaging
Clinical aspects
Invasive pulmonary aspergillosis
IPA
Normal lung
IPA occurs in ~7%
of acute leukaemia
patients, 10-15%
allogeneic BMT
patients
www.aspergillus.man.ac.uk
Unequivocal ‘Halo sign’ surrounding a nodule
Halo sign
Herbrecht, Denning et al, NEJM 2002;347:408-15.
CT scan evolution during IPA
Peripheral halo triangolar shape Air-crescent sign
d0 - d5
High value
d5 - d10
not
specific
Neutropenia
d10 - d20
delayed
PMN >> 500
Caillot et al. J Clin Oncol. 2001; 19: 253-9.
Early use of high-resolution CT
scan for the diagnosis of pulmonary
aspergillosis
• Allows significantly earlier diagnosis and
therapy (5-10 days)
• Associated with overall improved
survival
• Allows early surgical resection
Caillot et al, JCO, 1997
Heussel et al, JCO, 1999
Improved management of invasive pulmonary aspergillosis in
neutropenic patients using early thoracic computed tomographic
scan and surgery
(CAILLOT et al. J Clin Oncol 1997)
S
U
R
V
I
V
A
L
120
100
systematic CT-scan
80
60
CT-scan on indication
40
20
0
0
50
100
150
200 days
RETROSPECTIVE
ANALYSIS
n = 37
SYSTEMATIC CT-SCAN
BEFORE
AFTER
DAYS TO DIAGNOSIS
FROM HOSPITAL ADMISSION
FROM FIRST SUSPICION
SUGGESTIVE CT-SCAN PRE-DIAGN
31 ± 9
7±5
1/8
21 ± 5
2±1
23 / 25
CLINICAL SYMPTOMS IN 45 CASES OF IA
IN HSCT PATIENTS
Fever
34/45 (75%)
Cough
12/45 (27%),
Dyspnoea
12/45 (27%)
Chest pain
9/45 (20%).
No sign or symptom
3 (positive GM with
multiple pulmonary nodules on CT scan).
 Radiological pulmonary lesions were mainly
represented by nodules (8/42, 19%), cavitations
(10/42, 24%) and wedge-shaped consolidations
(4/42, 10%).
Notably, the halo sign was never found.
Mikulska et al, BMT 2009
A comprehensive approach to the
diagnosis of IFI
Host
Laboratory
Diagnosis
Imaging
Clinical
presentation
Aspergillosis: obtaining a diagnosis
Sputum
Bronchoalveolar
lavage
Galacto
mannan,
glucan,
PCR
Galactomannan,
glucan,
PCR
CT scan
Fine
needle
biopsy
Surgical
biopsy
(adapted from Ben de Pauw, 2001)
Traditional methods
• Positive blood culture
• Candida, Fusarium, Cryptococcus and others; not
Aspergillus, Mucor
• Positive histology from site of infection
• allows generic diagnosis of fungal infection
• requires positive culture for etiological definition
• Positive culture from site of infection
• limitation due to contamination/colonization problems
• may require positive histology for confirmation,
depending on site
EORTC
IFICG
NON INVASIVE DIAGNOSTIC TESTS
FOR FUNGAL INFECTIONS
Species specific
PCR
PCR
Genus specific
Fungi
galactomannan
mannan
capsular antigen
Panfungal-PCR
(13)-ß-D-glucan
Fungi and
bacteria
C-Reactive Protein (CRP),
procalcitonin (PCT),
interleukin-6 (IL-6)
(13)-ß-D-glucan (BDG)
CHARACTERISTICS
It’s a component of the fungal cell wall
There are 4 differnt commercial system
FDA approved 2004 as a support for the diagnosis of IFI
PANFUNGAL TEST
Positive in
Aspergillus
Candida
Pneumocystis carinii
Fusarium
Trichosporon
Saccharomyces cerevisiae
Acremonium
Histoplasma capsulatum
Doe’nt detect
Cryptococcus
Zygomicetes
(13)-ß-D-glucan (BDG)
LIMITS
•Need of glucan-free tools;
•Important risk of contamination (glucan is
ubiquitarious)
FALSE POSITIVE







Emodyalisis membranes (Miyazaki 1995, Yoshioka 1989)
Albumin (Usami 2002, Ohata 2003)
Immunoglobulins (Ogawa 2004)
Gauzes (Kimura 1995)
Hyperbilirubinemia, hypertriglyceridemia (Pickering 2004)
Antibiotics (amoxicillin-clavulanate) (Mennink-Kersten 2006)
Pseudomonas aeruginosa infections (Mennink-Kersten 2008)
(13)-ß-D-glucan (BDG)
Obayashi et al. CID 2008:
Comparison of empirical and PCR-based
preemptive antifungal therapy in 408 allogeneic
stem cell transplant recipients
• PCR screening twice weekly during stay in hospital and once weekly after
discharge until D100
• Antifungal therapy initiation
– PCR group: in PCR+ patients with signs of infection and in patients with 2
consecutive PCR +
– Empirical treatment group: 5d of febrile neutropenia
Antifungal therapy
Proven invasive aspergilosis
PCR based
n = 196
Empiric
n = 207
109 (56%)
11
76 (37%)
16
(p<0.05)
• Reduction in early mortality (D30) in patients receiving PCR-based therapy
but no difference in mortality at D100 and D180
(Hebart et al. ASH 2004)
Clinical Infectious Disease 2005; 41:1242-50
136
episodes
16%
117
febrile episodes
19
no fever
+
82
defervesence
9 cases
positive CT
10
positive GM antigen
19 cases for
pre-emptive antifungals
19
no fever
35%
136
episodes
117
febrile episodes
82
defervesence
30
persistent fever
11
unexplained relapses
41 candidates
empirical antifungals
PREVERT Study Design
• Prospective multicentric, unblinded, randomised (1:1)
trial run in 12 French centers between April 2003February 2006
• Non-inferiority trial (< 8% difference in ITT and PP)
• Randomisation stratified on center, induction vs
consolidation, and antifungal prophylaxis
• Proven and probable IFI: EORTC-MSG definitions
• Primary endpoint: survival either 14 days after
recovery from neutropenia or at 60 days if persistent
neutropenia
Cordonnier et al. ASH 2006
Empirical v. Preemptive antifungal therapy in high risk
neutropenic patients
PREVERT STUDY
Overall survival
p=ns
Invasive fungal infections
*p<0.02
Current situation
• Pre-emptive therapy logical, feasible, safe and probably costeffective
• However, not all centers can perform lung CT scan and GM
monitoring as often as required
• For this reason, empirical therapy remains standard practice in
some smaller centers
• Big centers start approaching pre-emptive therapy
• No drug has been tested in a comparative way for this
indication
• Drugs approved for empirical or targeted therapy are likely
working (caspo, L-AmB, vorico).
My opinion
• Diagnosis of IFI is a complex intellectual exercise
leading to different degrees of diagnostic certainty
and requiring experience, prudence and the
availability of relatively sophisticated and/or invasive
diagnostic tools (culture, biopsy, CT, GM, glucan?)
• The lower the risk (host factors) the higher the
evidence required
• The strategy of how using the antigen-detection tests
and/or PCR is still controversial and subject to
personal interpretations
• Pre-emptive therapy has been shown to be safe and
effective