Pathogeny and epidemiology E. Carreras MD, PhD

Transcription

1 Fungal infections Pathogeny and epidemiology E. Carreras MD, PhD

2 100 % Protective mechanisms Candida Aspergillus physical barriers neutrophil T lymphocytes antibodies spleen barriers neutrophil T lymphocytes antibodies spleen 1 3 T lymphocytes antibodies spleen antibodies spleen months JM

3 IFI in HSCT TRANSNET ( ) 24 USA centres HSCT (Allo 41%, Auto 59%) Median age: 50 y. IFI: 998 Cumulative Incidence (1 y): Allo 8.6%; Auto 1.6% Mortalidad global a los 90 días Overal mortality at 90 days Aspergilosis Candidiasis Kontoyiannis et al. CID 2010

4 Fungal infections prophylaxis Protective environment

5 Patients Invasive Aspergillosis in HSCT - Epidemiology - 20 allohsct autohsct > 180 Days after-sct Wald et al. JID 1997

6 Filter Pre-filter HEPA or LAF rooms Retain dust High-efficiency HEPA 90% particles >0,3 μ 99.97% particles >0,3 μ Retain fungi, bacteria & virus

7 Complements to HEPA rooms E. Carreras Portable HEPA FFP3 (N95) masks

8 HEAPA and LAF isolation and survival after HSCT bacteria fungi TRM SRV Passweg, et al. BMT 1998

9 Calgary experience Rusell, et al. BB&MT allo-hsct (112 unrelated or mismatch) cotrimoxazole, cipro, NO antifungals latitude Calgary: 51º 1 free circulation in/out hospital deaths by IFI: 4 Aspergillus (<1%) (2 after ICU) Stockholm experience 36 allo-hsct at home vs 54 inpatient free in/out latitude hospital, Estocolmo: no HEPA 59º 21' deaths by IFI: 2.2% Ottawa experience Svahn, et al. Blood 2002 McDiarmid et al. EBMT meeting allo-hsct at home vs 196 in hospital only cotrimoxazole latitude Otawa: 45º 22' infectious-deaths 3. 2% vs. 8.9% (p=0.03)

10 Fungal infections prophylaxis Pharmacological prophylaxis

11 Risk group (%) Prophylaxis Low (1-4%) Not indicated Intermediate (5-10%) To be considered High (>10%) Recommended Risk groups for IFI Neutropenia / disease / treatment <7days MM, NHL, CLL Auto-HSCT 7-14 days AML consolidation Allo-HSCT (standard) 14 days AML/MDS induction* Allo-HSCT (high-risk)** GvHDa>II, GVHDc ext. Candida colonization*** * Or refractory or in relapse; ** unrelated, >40 y, CBT; *** tropicalis in one or other spp. in >2 localizations SEQ/AEHH consensus, De la Cámara et al Med. Clin (Barc.) 2010 IF: PRD >2 mg/kg >2 w Severe mucositis CD34+ selection / TCD / Campath the risk one level

12 Prophylaxis with fluconazole in HSCT recipients Allogeneic Survival Autologous Survival Fluco Fluco Placebo Placebo Marr et al. Blood 2000

13 Itraconazole solution vs. fluconazole for prophylaxis in HSCT Multicentre* Seattle # IFI incidence - Global Itra = - Breakthrough Itra Itra - Moulds Itra Itra - Candida Itra = Toxicity - GI Itra Itra - Hepatic = Itra Mortality - Global = = - Due to IFI Itra = *Winston et al. Ann Intern Med 2003 / # Marr et al. Blood 2004

14 Micafungin vs. fluconazole for prophylaxis in HSCT Micafungin Fluconazole Overall efficacy 80% 73% Colonization Breakthrough infecc. Toxicity Mortality identical in both arms Van Burik et al. CID 2005

15 Voriconazole for fungal prophylaxis in allo-hsct Randomized, Double-Blind ( ) Cumulative Fluconazole incidence IFI 400 mg/day Voriconazole 400 mg/day till day or +180 (if PDR or TCD y <200 CD4+ Survival Wingard et al, Blood 2010; 116: 5111

16 Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease Ullmann et al. NEJM 2007

17 Voriconazole vs itraconazole for Prophylaxis (IMPROVIT)

18 Azole plasma levels / Posaconazole 90.5% of patients failed to reach the higher putative target of 0.7 microg/ml, and 76.2% failed to reach the lower target of 0.5 microg/ml. Bryant et al, Int J Antimicrob Ag 2010

19 Prophylaxis with new azoles oral PROS E. Carreras oral, good biodisponibility (?) broad spectrum Proved efficacy against aspergillus limited toxicity acceptable price

20 Prophylaxis with new azoles CONS Emergent Mycoses Candidas no-albicans -- fluconazole Mucormicosis voriconazole (?) Candida glabrata -- micafungin Cardiotoxicity Voriconazole - posaconazole Interference with CsA and Tacro Variability of their levels Role on galactomannan? (in all prophylaxis) E. Carreras

21 Liposomal AmB inhalated Invasive pulmonary aspergillosis Intent-to-treat on-treatment Rijnders et al. CID 2008; 46: 1409

22 Recommended antifungal prophylaxis in AML/MDS - HSCT - Summary - ECIL 3 recommendations Acute Leuk Allo SCT Allo+ GvHD Fluconazole (400 mg qd oral) CI AI CI Itraconazole (200 mg bid oral solution) CI BI BI Posaconazole (200 mg tid oral) AI id AI Voriconazole (200 mg bid oral) AI AI Equinocandins (IV) id -- id Micafungin (50 mg qd IV) -- CI -- Polyenes (IV) CI CI CI AmphoB-L (inhalated+fluco oral) BI BII id id= insufficient data ECIL3 Bone Marrow Transplantation 2010 Jul 26.

23 IFI diagnosis Histopathology Imaging techniques - Chest x-ray, CT, MRI - Biopsy guided by TC Microbiology - Direct examination, fluorescence - Culture - Serological: Ag and Ab detection - PCR techniques E. Carreras

24 Histopathology Gold standard

25 A positive chest x-ray is enough to establish the diagnosis. An unremarkable chest x-ray should be followed by a CT scan to reliably detect or to accurately exclude early pulmonary infection in these patients. E. Carreras

26 Halo sign Reverse halo sign Zygomycosis E. Carreras Crescent sign CT findings in invasive pulmonary aspergillosis

27 Angio-invasive AL - neutropenia Airway-invasive Allo-SCT immunosup E. Carreras Bergeron et al, Blood 2012

28 Air-crescent Nonspecific Halo CID 2007

29 Imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo sign halo sign log-rank p<.01 no halo sign Greene et al. Clin Infect Dis. 2007

30 Brodoefel H, et al Long-Term CT Follow-Up in 40 Non-HIV Immunocompromised Patients with Invasive Pulmonary Aspergillosis: Kinetics of CT Morphology and Correlation with Clinical Findings and Outcome Am J Roentgenology 2006; 187: days

31 Biopsy guided by CT

32 IFI diagnosis Histopathology Imaging techniques - Chest x-ray, CT, MRI - Biopsy guided by TC Microbiology - Direct examination, fluorescence - Culture - Serological: Ag and Ab detection - PCR techniques E. Carreras

33 Direct examination: in BAL sputum, CRL,... calcofluor silver stain Gram Giemsa

34 Skin biopsy

35 Cultures: moulds

36 Culture: yeasts

37 Serological methods Detection of fungal components: - Galactomannan Platelia Aspergillus (only in aspergillus and penicilium) - Glucan Glucatell (G test) (all but cryptococcus and zygomycetes) - Others mannan + antimannan Ab Germ tubes Ab (C. Albicans) E. Carreras

38 First GM+ and other events Cut off 0.5 GM first Days before X-ray thorax 12/15 (80%) 8 HRTC 12/15 (80%) 6 Cultures + 16/18 (89%) 9 Diagnostic 16/18 (89%) 14 Treatment 16/18 (89%) 6 Death 17/18 (94%) cut-off approved by FDA in 2003 Maertens et al. J Infect Dis 2002

39 Antifungal therapy decreases sensitivity of Aspergillus Galactomannan Without prophylactic or empirical therapy With therapy or prophylaxis Marr et al. CID. 2005

40 Galactomannan in Broncoalveolar lavage GM index 0.8 Sensitivity: 86% Specifiocity: 91% D Hoese et al. Clin Microbiol 2012

41 Galactomannan / false positive Allo-HSCT Children Pollution cotton Other moulds Cyclophosphamide Antibiotics Technical mucositis / food Bifidobacterium glucopiranose same galactomannan crossed reaction Pipera-Tazob / Amoxi contamination Wheat. Transpl Infect Dis 2003

42 Therapeutic approaches to IFI in neutropenic patients Probability of IFI 0% 100% Early treatment Anticipated Prophylaxis antifungal to all patients (primary or secondary) Empirical antifungal due to fever unresponsive to antibact. Pre-emptive antifungal based on lab or imagine tests Treatment antifungal based on proven IFI E. Carreras ~ 80% unnecessary treat. (IFI incidence <20%)

43 Fungal infections Early treatment

44 Preemptive antifungal therapy Early treatment when: E. Carreras Patients with high risk of IFI (HSCT or AL) (proved only in neutropenic w/o prophylaxis) + GM positive 2 x >0.5 (2 x week, be careful w false positive) or GM(-ve) but HRVT(+ve) + GM(+ve) in BAL [if HRCT (+) and both GM (-ve) caution: treat as a non-aspergillus infection]

45 Galactomannan (GM) and computed tomography (CT) -based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection. GM+ GM- CT+ BAL+ GM- CT+ BAL- GM- CT- Antifungal treatment NO Antifungal treatment 41/116 (30%) episodes would have had classical empirical therapy Only 9/41 (22%) were treated 2 c. glabrata 1 zygomycosis were not correctly treated Maertens et al. Clin Infect Dis. 2005

46 Role of the preemtive antifungal therapy in the era of systematic prophylaxis with azoles?? Delayed preemptive - Decreased sensibility of galactomannan therapy!! - Higher incidence of zygomycoses - Impact of early treatment

47 Fungal infections Directed treatment (against Candida and Mucor, see ECIL 5)

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49 Random: Vorico + placebo Vorico + anidulafungin

50 JM Combination of antifungals for IA treatment? CNS affectation respiratory failure or severe sepsis criteria pulmonary cavitation or extensive lesion (?) NO monotherapy w voriconazole (or AmB liposomal) YES association of voriconazole + anidulafungin (or AmB + caspo) (CI)

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52 Pneumocystis jiroveci (formerly carinii) E. Carreras ECIL 5:

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