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A comprehensive approach to the diagnosis of IFI

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.

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A comprehensive approach to the diagnosis of IFI

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  1. Can werely on imaging and biomarkersforpreemptiveantifungaltherapy in hematologicalpatients?Claudio ViscoliProfessor ofInfectiousDisease, Universityof GenovaChief, DivisionofInfectiousDisease, San Martino University Hospital, Genova, Italy

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

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

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

  5. 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 CHARACTERISTIC PATTERNS OF INVASIVE ASPERGILLOSIS IN COMMONLY AFFECTED PATIENT GROUPS

  6. 8988 admissions • 71 positive cultures for Aspergillus • Incidence rate 0.4% (37 proven/probable diseases as from EORTC-MSG criteria)

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

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

  9. 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

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

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

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

  13. 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 >> 500 Caillot et al. J Clin Oncol. 2001; 19: 253-9.

  14. 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

  15. 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

  16. 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

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

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

  19. 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

  20. 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)

  21. (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 Doe’nt detect • Aspergillus Cryptococcus • Candida Zygomicetes • Pneumocystis carinii • Fusarium • Trichosporon • Saccharomyces cerevisiae • Acremonium • Histoplasma capsulatum

  22. (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)

  23. (13)-ß-D-glucan (BDG) Obayashi et al. CID 2008: 46 (15 June)

  24. 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 = 196n = 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 (Hebart et al. ASH 2004)

  25. Clinical Infectious Disease 2005; 41:1242-50

  26. 19 no fever 117 febrile episodes 82 defervesence 9 cases positive CT 10 positive GM antigen 19 cases for pre-emptive antifungals 136 episodes + 16%

  27. 19 no fever 117 febrile episodes 82 defervesence 30 persistent fever 11 unexplained relapses 41 candidates empirical antifungals 136 episodes 35%

  28. 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

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

  30. 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).

  31. 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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