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,

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Can we rely on imaging and biomarkers for
preemptive antifungal therapy in hematological
patients?Claudio ViscoliProfessor of
Infectious Disease, University of GenovaChief,
Division of Infectious Disease, San Martino
University Hospital, Genova, Italy
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A comprehensive approach to the diagnosis of IFI
Host
Clinical aspects
Laboratory
Diagnosis
Imaging
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Underlying disease in invasive aspergillosis
595 patients
Patterson et al, Medicine, 2000
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Underlying disease phase and primary site of
infections
n 391 patients
Pagano et al, Haematologica 2001
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CHARACTERISTIC PATTERNS OF INVASIVE ASPERGILLOSIS
IN COMMONLY AFFECTED PATIENT GROUPS
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• 8988 admissions
• 71 positive cultures for Aspergillus
• Incidence rate 0.4 (37 proven/probable diseases
  as from EORTC-MSG criteria)

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A comprehensive approach to the diagnosis of IFI
Host
Clinical aspects
Laboratory
Diagnosis
Imaging
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Aspergillosis syndrome

• Cough (92)
• Thoracic pain (76)
• Hemoptysis (54)
• Fever
• Neurological signs
• Nasal bleeding
• Nasal discharge
• Skin lesions

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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
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A comprehensive approach to the diagnosis of IFI
Host
Clinical aspects
Laboratory
Diagnosis
Imaging
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Invasive pulmonary aspergillosis
Normal lung
IPA
IPA occurs in 7 of acute leukaemia patients,
10-15 allogeneic BMT patients
www.aspergillus.man.ac.uk
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Unequivocal Halo sign surrounding a nodule
Halo sign
Herbrecht, Denning et al, NEJM 2002347408-15.
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CT scan evolution during IPA
Peripheral halo
triangolar shape
Air-crescent sign
d0 - d5
d10 - d20
d5 - d10
not specific
High value
delayed
Neutropenia
PMN gtgt 500
Caillot et al. J Clin Oncol. 2001 19 253-9.
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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
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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
systematic CT-scan
CT-scan on indication
RETROSPECTIVE ANALYSIS n 37
0 50 100 150 200 days
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
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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
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A comprehensive approach to the diagnosis of IFI
Host
Clinical presentation
Laboratory
Diagnosis
Imaging
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Aspergillosis obtaining a diagnosis
Galactomannan,glucan, PCR
(adapted from Ben de Pauw, 2001)
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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

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NON INVASIVE DIAGNOSTIC TESTS FOR FUNGAL
INFECTIONS
Species specific
PCR
PCR galactomannan mannan capsular antigen
Genus specific
Panfungal-PCR (1?3)-ß-D-glucan
Fungi
Fungi and bacteria
C-Reactive Protein (CRP), procalcitonin
(PCT), interleukin-6 (IL-6)
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(1?3)-ß-D-glucan (BDG)
CHARACTERISTICS

• Its 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 Doent detect
• Aspergillus Cryptococcus
• Candida Zygomicetes
• Pneumocystis carinii
• Fusarium
• Trichosporon
• Saccharomyces cerevisiae
• Acremonium
• Histoplasma capsulatum

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(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)

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(1?3)-ß-D-glucan (BDG)
Obayashi et al. CID 2008 46 (15 June)
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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
• PCR based Empiric
• n 196 n 207
• Antifungal therapy 109 (56) 76 (37) (plt0.05)
• Proven invasive aspergilosis 11 16
• 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)
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Clinical Infectious Disease 2005 411242-50
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136 episodes

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136 episodes
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PREVERT Study Design

• Prospective multicentric, unblinded, randomised
  (11) trial run in 12 French centers between
  April 2003-February 2006
• Non-inferiority trial (lt 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
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Empirical v. Preemptive antifungal therapy in
high risk neutropenic patientsPREVERT STUDY
Overall survival
Invasive fungal infections
plt0.02
pns
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Current situation

• Pre-emptive therapy logical, feasible, safe and
  probably cost-effective
• 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).

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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