can we rely on imaging and biomarkers for preemptive antifungal therapy in hematological patients?...
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Can we rely on imaging and Can we rely on imaging and biomarkers for preemptive biomarkers for preemptive
antifungal therapy in antifungal therapy in hematological patients?hematological patients?
Claudio ViscoliClaudio ViscoliProfessor of Infectious Disease, University of GenovaProfessor of Infectious Disease, University of Genova
Chief, Division of Infectious Disease, San Martino University Chief, Division of Infectious Disease, San Martino University Hospital, Genova, ItalyHospital, Genova, Italy
Laboratory Clinical aspects
Imaging
Diagnosis
A A comprehensive approach to the comprehensive approach to the diagnosis of IFIdiagnosis of IFI
Host
Underlying disease in invasive Underlying disease in invasive aspergillosisaspergillosis
7%
25%
28%
9%
8%
6%
9%
6% 2% BMT/Auto
BMT/Allo
Hematologic
SolidTransplant
AIDS
OtherImmune
Pulm
Other
None
595 patients
Patterson et al, Medicine, 2000
Underlying disease phase and Underlying disease phase and primary site of infectionsprimary site of infections
2%
6%
7%
4%
11%
6% 59%
5%
1st Induction 2nd Induction ConsolidationMaintenance AHSCT HSCTOther None
Pagano et al, Haematologica 20016%
1%
1%
1%
69%
15%
7%
Sino nasalCNS involvementDisseminatedGastrointestinalBloodSkinLung
n° 391 patients
CHARACTERISTIC PATTERNS OF INVASIVE ASPERGILLOSIS IN COMMONLY AFFECTED PATIENT GROUPS
Early during neutropenia (20-30%);Late (median 100 days) (75%), mainly related to severe GVHD and high-dose steroids
Allogeneic bone marrow or PSC transplantation, especially if matched unrelated or mismatched donor
During induction chemotherapy (75%);During maintenance or consolidation treatments (25%).Maily related to neutropenia
Acute Leukemia; Multiple Mieloma, stage II/III; Chronic leukemia in blast crisis; aplastic anemia; autologous bone marrow or PSC transplantation
TIMING OF INVASIVE ASPERGILLOSIS
UNDERLYING CONDITION
• 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 A comprehensive approach to the diagnosis of IFIdiagnosis of IFI
Laboratory Clinical aspects
Imaging
Diagnosis
Host
AspergillosisAspergillosis syndrome syndrome
• Cough (92%)
• Thoracic pain (76%)
• Hemoptysis (54%)
• Fever
• Neurological signs
• Nasal bleeding
• Nasal discharge
• Skin lesions
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.
CLINICAL SYMPTOMS IN 45 CASES OF IA IN HSCT PATIENTS
Mikulska et al, BMT 2009
A comprehensive approach to the A comprehensive approach to the diagnosis of IFIdiagnosis of IFI
Laboratory Clinical aspects
Imaging
Diagnosis
Host
Invasive pulmonary aspergillosis
www.aspergillus.man.ac.uk
Normal lungIPA
IPA occurs in ~7% of acute leukaemia patients, 10-15% allogeneic BMT
patients
Unequivocal ‘Halo sign’ surrounding a noduleUnequivocal ‘Halo sign’ surrounding a nodule
Herbrecht, Denning et al, NEJM 2002;347:408-15.
Halo sign
Neutropenia PMN >> 500
CT scan evolution during IPACT scan evolution during IPA
High value notspecific delayed
Peripheral halo triangolar shape Air-crescent sign
d0 - d5 d5 - d10 d10 - d20
Caillot et al. J Clin Oncol. 2001; 19: 253-9.
Early use of high-resolution CT Early use of high-resolution CT scan for the diagnosis of scan for the diagnosis of pulmonary aspergillosispulmonary 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 Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic neutropenic patients using early thoracic computed tomographic
scan and surgeryscan and surgery ((CAILLOT et al. J Clin Oncol 1997)CAILLOT et al. J Clin Oncol 1997)
Improved management of invasive pulmonary aspergillosis in Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic neutropenic patients using early thoracic computed tomographic
scan and surgeryscan and surgery ((CAILLOT et al. J Clin Oncol 1997)CAILLOT et al. J Clin Oncol 1997)
SURVIVAL
0 50 100 150 200 days
systematic CT-scan
CT-scan on indication
RETROSPECTIVEANALYSIS
n = 37
RETROSPECTIVEANALYSIS
n = 37
DAYS TO DIAGNOSISFROM HOSPITAL ADMISSIONFROM FIRST SUSPICIONSUGGESTIVE CT-SCAN PRE-DIAGN
31 ± 9 7 ± 5
1 / 8
21 ± 5 2 ± 1
23 / 25
SYSTEMATIC CT-SCANBEFORE AFTER
0
20
40
60
80
100
120
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.
CLINICAL SYMPTOMS IN 45 CASES OF IA IN HSCT PATIENTS
Mikulska et al, BMT 2009
A comprehensive approach to the A comprehensive approach to the diagnosis of IFIdiagnosis of IFI
Laboratory Clinical presentation
Imaging
Diagnosis
Host
Aspergillosis: obtaining a diagnosisAspergillosis: obtaining a diagnosis
Fine needle biopsy
Fine needle biopsy
SputumSputumBroncho-alveolar lavage
Surgical biopsy
Surgical biopsy
CT scan
Galacto-mannan, glucan,
PCR
(adapted from Ben de Pauw, 2001)
Galactomannan,glucan,
PCR
Traditional methodsTraditional 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
NON INVASIVE DIAGNOSTIC TESTS NON INVASIVE DIAGNOSTIC TESTS FOR FUNGAL INFECTIONSFOR FUNGAL INFECTIONS
NON INVASIVE DIAGNOSTIC TESTS NON INVASIVE DIAGNOSTIC TESTS FOR FUNGAL INFECTIONSFOR FUNGAL INFECTIONS
EORTC EORTC IFICGIFICG
PCRPCR
PCRPCR
galactomannangalactomannanmannanmannan
capsular antigencapsular antigen
Panfungal-PCRPanfungal-PCR
(1(13)-ß-D-glucan3)-ß-D-glucan
C-Reactive Protein (CRP),C-Reactive Protein (CRP),procalcitonin (PCT),procalcitonin (PCT),interleukin-6 (IL-6)interleukin-6 (IL-6)
Species specific
Genus specific
Fungi
Fungi and bacteria
(13)-ß-D-glucan (BDG)
It’s a component of the fungal cell wall
There are 4 differnt commercial systemFDA approved 2004 as a support for the diagnosis of IFI
PANFUNGAL TEST
Positive in Doe’nt detect
Aspergillus Cryptococcus Candida ZygomicetesPneumocystis carinii FusariumTrichosporonSaccharomyces cerevisiaeAcremoniumHistoplasma capsulatum
CHARACTERISTICS
(13)-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)
Obayashi et al. CID 2008: 46 (15 June)
(13)-ß-D-glucan (BDG)
• 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 Empiricn = 196 n = 207
Antifungal therapy 109 (56%) 76 (37%)
(p<0.05)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
Comparison of empirical and PCR-based preemptive antifungal therapy in 408 allogeneic
stem cell transplant recipients
(Hebart et al. ASH 2004)
Clinical Infectious Disease 2005; 41:1242-50
136episodes
136episodes
10 positive GM antigen
10 positive GM antigen
9 cases positive CT
9 cases positive CT
8282 defervesencedefervesence
8282 defervesencedefervesence
19 cases for pre-emptive antifungals
19 cases for pre-emptive antifungals
16%16%16%16%
1919 no feverno fever
1919 no feverno fever
117 febrile episodes
117 febrile episodes
++
136episodes
136episodes
11 unexplained relapses
11 unexplained relapses
30 persistent fever
30 persistent fever
8282 defervesencedefervesence
8282 defervesencedefervesence
1919 no feverno fever
1919 no feverno fever
117 febrile episodes
117 febrile episodes
41 candidates empirical antifungals
41 candidates empirical antifungals
35%35%35%35%
PREVERT Study Design• Prospective multicentric, unblinded, randomised (1:1)
trial run in 12 French centers between April 2003-February 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
*p<0.02*p<0.02p=ns
Overall survival Invasive fungal infections
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).
My opinionMy 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