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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.

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Presentation on theme: "Can we rely on imaging and biomarkers for preemptive antifungal therapy in hematological patients? Claudio Viscoli Professor of Infectious Disease, University."— Presentation transcript:

1 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

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

3 Underlying disease in invasive aspergillosis 595 patients Patterson et al, Medicine, 2000

4 Underlying disease phase and primary site of infections Pagano et al, Haematologica 2001 n° 391 patients

5 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

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7 8988 admissions 71 positive cultures for Aspergillus Incidence rate 0.4% (37 proven/probable diseases as from EORTC-MSG criteria)

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

11 Aspergillosis syndrome Cough (92%) Thoracic pain (76%) Hemoptysis (54%) Fever Neurological signs Nasal bleeding Nasal discharge Skin lesions

12 Fever 34/45 (75%) Cough 12/45 (27%), Dyspnoea 12/45 (27%) Chest pain9/45 (20%). No sign or symptom3 (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

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

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16 Invasive pulmonary aspergillosis www.aspergillus.man.ac.uk Normal lung IPA IPA occurs in ~7% of acute leukaemia patients, 10-15% allogeneic BMT patients

17 Unequivocal Halo sign surrounding a nodule Herbrecht, Denning et al, NEJM 2002;347:408-15. Halo sign

18 Neutropenia PMN >> 500 CT scan evolution during IPA High value not specific delayed Peripheral halotriangolar shapeAir-crescent sign d0 - d5 d5 - d10 d10 - d20 Caillot et al. J Clin Oncol. 2001; 19: 253-9.

19 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, 1997Heussel et al, JCO, 1999

20 Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery ( CAILLOT et al. J Clin Oncol 1997) SURVIVALSURVIVAL 0 50 100 150 200 days systematic CT-scan CT-scan on indication RETROSPECTIVE ANALYSIS n = 37 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 SYSTEMATIC CT-SCAN BEFORE AFTER

21 Fever 34/45 (75%) Cough 12/45 (27%), Dyspnoea 12/45 (27%) Chest pain9/45 (20%). No sign or symptom3 (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

22 A comprehensive approach to the diagnosis of IFI Laboratory Clinical presentation Imaging Diagnosis Host

23 Aspergillosis: obtaining a diagnosis Fine needle biopsy Sputum Broncho- alveolar lavage Surgical biopsy CT scan Galacto- mannan, glucan, PCR (adapted from Ben de Pauw, 2001) Galacto mannan, glucan, PCR

24 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

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

26 (1 3)-ß-D-glucan (BDG) 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 inDoent detect Aspergillus Cryptococcus CandidaZygomicetes Pneumocystis carinii Fusarium Trichosporon Saccharomyces cerevisiae Acremonium Histoplasma capsulatum CHARACTERISTICS

27 (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)

28 Obayashi et al. CID 2008: 46 (15 June) (1 3)-ß-D-glucan (BDG)

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33 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 = 196n = 207 Antifungal therapy109 (56%)76 (37%)(p<0.05) Proven invasive aspergilosis1116 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)

34 Clinical Infectious Disease 2005; 41:1242-50

35 136 episodes 10 positive GM antigen 9 cases positive CT 82 defervesence defervesence 19 cases for pre-emptive antifungals 16% 19 no fever no fever 117 febrile episodes +

36 136 episodes 11 unexplained relapses 30 persistent fever 82 defervesence defervesence 19 no fever no fever 117 febrile episodes 41 candidates empirical antifungals 35%

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38 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

39 Empirical v. Preemptive antifungal therapy in high risk neutropenic patients PREVERT STUDY *p<0.02 p=ns Overall survival Invasive fungal infections

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42 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).

43 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


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