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Directed therapy for fungal infections - latest advances Rosemary Barnes Focus on aspergillosis.

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Presentation on theme: "Directed therapy for fungal infections - latest advances Rosemary Barnes Focus on aspergillosis."— Presentation transcript:

1 Directed therapy for fungal infections - latest advances Rosemary Barnes Focus on aspergillosis

2 Problem Antifungal expenditure is completely out of proportion with the scale of the problem Incidence of IFD in ICU (candida) <0.6% Aspergillus infection in haematological malignancy (0.5-12%) Aspergillus in SOT <5% Harrison D et al Fungal Infection Risk Evaluation (FIRE) Study. Health Technol Assess 2013; 17(3). Pagano L et al. Haematologica 2006; 91: 1068-1075 Pagano L et al. Clin Infect Dis 2007; 45: 1161-1170 Total UK antifungal expenditure c £112 million Rising by 9% pa

3 Reasons Infection associated with significant morbidity and mortality Signs and symptoms of systemic infection are nonspecific Conventional diagnostic techniques are suboptimal Delays in treatment associated with poorer outcome

4 Choices choices choices Diagnosis Empirical therapy Change antibiotics Febrile despite antibiotics Febrile despite antibiotics

5 Fever yes no Decision tree

6 Fever No diagnosis yes no yes no Decision tree

7 Fever Anxiety No diagnosis yes no yes no Decision tree

8 Fever Out of hours Anxiety No diagnosis yes no yes no yes no yes no Decision tree

9 Fever Out of hours Anxiety No diagnosis yes no yes no yes no yes no Decision tree No therapy Empirical therapy

10 include all patients likely to have invasive fungal infection and treat them with the safest and most effective drug Aim of a directed strategy exclude all patients unlikely to have invasive fungal disease and adopt a WAIT-and- SEE policy

11 Maertens et al. (2012) Haematologica 97(3): 325-327.

12 Consensus criteria Aimed to provide definitions for proven, probable and possible fungal infection that could facilitate clinical research Designed for use in clinical trials Highly selective population Not representative of real life clinical practice Focus on specific radiological signs Focus on defining DISEASE needs to shift towards INFECTION Needs a diagnostic approach biomarkers De Pauw et al CID 2008, 46

13 The biomarkers Antigen tests Galactomannan (aspergillus) Beta D glucan (pan-fungal-ish) Lateral flow device Molecular Aspergillus specific Panfungal Commercial (…….)

14 Galactomannan - in serum useful test in surveillance: high NPV Performance in haematological malignancy better than in SOT neutropenic > corticosteroid treated group Adults >children Influenced by pre-test probability (ie sensitivity increases with prevalence) EORTC/MSG criteria heavily dependent on test being performed Recommended by ECIL

15 Galactomannan – meta-analyses 30 studies > 7000 patients Prevalence 7.7% sensitivity78% (61% to 89%) specificity 81% (72% to 88%). cut-off 0.5: 100 patients: 2 patients with IA, will be missed, 17 patients will be treated unnecessarily cut-off 1.5 OD: 3 IA patients will be missed 5 patients will be treated unnecessarily results were very heterogeneous. Insufficient data to look at clinical utility

16 PUO GM pos CT BAL Pre test probability Maertens et al CID 2009 BAL 0.5 approved by FDA On the basis of clinical validity PPV of GM BAL is 100% at an OD index cutoff of ≥3 only 76% at ≥ 0.5 (but NPV is high)

17 Beta D Glucan 4 different commercial tests Heterogenous data : retrospective vs. prospective; Different cut offs “panfungal” – except cryptococcus and mucoracous moulds Sensitivity, specificity variable but NPV high High false-positives: up to 30% - bacteraemia, antibiotics, pre-/analytical contaminations complex analytical procedures Analytical validity established Utility data limited Included in EORTC/MSG criteria

18 Beta D Glucan-meta-analysis 16 studies in 2979 patients Included case-controlled studies Included critical care, HM and solid organ cancer patients Cut off 10-1000 pg/ml Sensitivity 76.8% (67.1%–84.3%) specificity 85.3% (79.6%–89.7%) “area under ROC curve 0.89” “good diagnostic accuracy” Karageorgopoulos et al Clin Infect Dis 2011;52(6):750

19 PCR The UK Fungal PCR consensus group 2004 technically validated candida PCR Made recommendations for aspergillus PCR 2006 European Aspergillus PCR Initiative set up 86 participants in 69 centres in 24 countries defined a standard for PCR for Aspergillus Whole blood Serum plasma optimal methodology to evaluate the performance and impact QCMD available White et al J Molec Diagn 2006; 8: 376 White et al J Clin Micro 2010: 48 1231

20 Mengoli et al Lancet Infectious Diseases. 2009; 9: 89-96 PCR Single negative PCR to exclude disease 2 consecutive PCRs to diagnose IA Sensitivity 88% Specificity 75% DOR22

21 “Directed/pre-emptive” therapy ReferencesCountryClinicalHRCTGM Micro- biological PCR Non-comparative studies Maertens 2005BelgiumXXX Girmenia 2010ItalyX(X)X Aguilar-Guisado 2010SpainXXX Barnes 2009 UK XXXX Dignan 2009 UK X Randomised, comparative studies Cordonnier 2009FranceXX(X) Hebart 2009GermanyX Observational studies Pagano 2012ItalyX(X)

22 Galactomannan EIA Open study 136 episodes of neutropenia Patients receiving flucon prophylaxis daily EIA GM + early CT scanning in neutropenic febrile episodes Antifungal given if 2 consecutive EIA GM results +ve (index ≥ 0.5) and confirmed by BAL or CT Maertens et al. Clin Infect Dis 2005; 41: 1242

23 Maertens et al 35% of episodes met criteria for empirical antifungal but only7.7% treated on basis of pre- emptive therapy Duration of fever not affected 22 cases of IFD only one missed 3 breakthrough infections 2 candidaemias 1 mucorales No excess mortality or fungal related death No impact on overall antifungal usage despite deceased empirical use

24 Cordonnieret al CID 2009 48:1043 293 patients randomised empirical or pre-emptive therapy empirical arm received antifungals if they had persistent/recurrent fever after 4 days pre-emptive patients given antifungal only if they showed clinical and radiological signs of pneumonia/sinusitis positive GM index ≥ 1.5 Aspergillus colonization Septic shock CNS signs/periorbital inflammation Diarrhoea/mucositis ≥ grade 3 fever > 14 days

25 Cordonnieret al Survival was not significantly “Non inferiority” demonstrated pre-emptive patients had more IFI 9.1% vs 2.7% pre-emptive patients received significantly less antifungals no significant cost savings were achieved Used ampho B deoxycholate first -line

26 Empirical vs. pre-emptive antifungal therapy Empirical Pre-emptive IFI in Pre- emptive IFI in Empirical Cordonnier et al, Clin Infect Dis, 2009; 48: 1042-1051

27 Pagano et al Haematologica 2011; 96:1363 Observational: Empiric versus “pre-emptive” Data collection 397 HM patients 190 empiric ; 207”pre-emptive” More IFD in pre-emptive arm Increased mortality and antifungal use in “pre- emptive arm” Fever driven, no screening, diagnostic work up not standardized some GM usage, no PCR Pre-emptive group largely diagnosed on basis of HRCT

28 PCR randomised study of a PCR directed versus an empirical antifungal more than 400 SCT patients Safe Improved survival at 30 days (not 100) No reduction in antifungal drug use. Nested PCR to guide antifungal therapy 42 patients with cancer, neutropenia AmB required in only 2 patients Hebart et al. Blood 2004;104: 59A. Lin et al. Clin Infect Dis. 2001;33:1621-1627

29 In Cardiff 549 high-risk haematology patients entering neutropenic pathway 2005-2010 audited and followed up for a minumum of 12 months Twice weekly antigen and PCR testing (or GvHD) Itraconazole prophylaxis or AmBisome 7mg/kg/weekly Empiric antifungals not used unless Clinical/mycological evidence of disease Itraconazole levels were subtherapeutic or unmeasured First 125 patients analysed for safety and proof of concept Data collected on compliance, incidence of IFD and efficacy of prophylaxis Barnes et al Journal of Clinical Pathology 2009

30 Incidence of IFD (2005-2011) Invasive aspergillosis 9.6% 6 histologically proven (2 postmortem) 4 pulmonary (2 with dissemination) 2 invasive sinusitis 47 probable (23 possible IA) Invasive Candidal infection 2% 12 proven 4 C. albicans, 3C. glabrata, 2C. tropicalis, 1C. parapsilosis, 1C. guilliermondii, 1 mixedC. albicans + C. glabrata 1 probable 2 non-aspergillus moulds 1 Mucoraceous mould, 1 Scedosporium prolificans Incidence of proven/probable IFD 12.3%

31 IA disease status of subjects By EORTC/MSG diagnostic criteria Proven – 6 Probable – 47 Possible – 23 NEF – 473 248 of NEF showed some signs suggestive of IA EIA positive n=36 PCR positive n=136 EIA and PCR positive n=75 Aspergillus isolated n=5

32 Diagnostic accuracy Explore analytical validity. Clinical validity, clinical utility Sensitivity specificity PPV, NPV, LR, DORs Use ROC analysis to explore different thresholds for defining “cases” EORTC/MSG EORTC – GM EIA EORTC + PCR Dual biomarker positivity Multiple positives versus single

33 Population Assay Positivity Threshold Sensitivity (%)Specificity (%)PPV (%)NPV (%)LR+LR-DOR Proven a, probable b vs No IFD c EIA Single96.2 (87.3-99.0)76.7 (72.7-80.3)31.7 (25.0-39.2)99.5 (98.0-99.9)4.140.0584.15 Multiple62.3 (48.8-74.1)91.8 (88.9-93.9)45.8 (34.8-57.3)95.6 (93.3-97.1)7.550.4118.36 Proven a, probable b, possible d vs No IFD c EIA Single67.1 (55.9-76.6)76.7 (72.7-80.3)31.7 (25.0-39.2)93.6 (93.7-97.6)2.890.436.73 Multiple43.4 (32.9-54.6)91.8 (88.9-93.9)45.8 (34.8-57.3)91.0 (88.1-93.2)5.270.628.54 Proven a, probable incorporating PCR e vs No IFD c EIA Single72.9 (61.5-81.9)76.7 (72.7-80.3)31.7 (25.0-39.2)95.0 (92.4-96.8)3.130.358.86 Multiple47.1 (35.9-58.7)91.8 (88.9-93.9)45.8 (34.8-57.3)92.1 (89.4-94.3)5.720.589.93 Proven a, probable b vs No IFD c PCR Single92.5 (82.1-97.0)55.6 (51.1-60.0)18.9 (14.6-24.1)98.5 (96.2-99.4)2.080.1415.34 Multiple73.6 (60.4-83.6)79.9 (76.1-83.3)29.1 (22.1-37.3)96.4 (94.1-97.9)3.660.3311.08 Proven a, probable b, possible d vs No IFD c PCR Single86.8 (77.5-92.7)55.6 (51.1-60.0)23.9 (19.3-29.3)96.3 (93.4-98.0)1.960.248.27 Multiple65.8 (54.6-75.5)79.9 (76.1-83.3)34.5 (27.2-42.5)93.6 (90.7-95.6)3.280.437.65 Proven a, probable incorporating PCR e vs No IFD c PCR Single94.3 (86.2-97.8)55.6 (51.1-60.0)23.9 (19.3-29.3)98.5 (96.2-99.4)2.120.1020.66 Multiple71.4 (60.0-80.7)79.9 (76.1-83.3)34.5 (27.2-42.5)95.0 (92.4-96.7)3.560.369.95 Proven a, probable b vs No IFD c PCR or ELISA Single98.1 (93.4-100)47.8 (42.0-53.5)17.4 (11.9-22.9)99.6 (98.5-100)1.880.0447.6 Multiple79.2 (65.3-93.2)76.7 (71.9-81.6)27.6 (0.19-36.7)97.1(94.9-99.2)3.410.2712.6 Proven a, probable b, possible d vs No IFD c PCR or ELISA Single90.8 (82.5-99.1)47.8 (42.0-53.5)21.8 (16.0-27.6)97.0 (94.2-99.8)1.740.199.0 Multiple69.7 (56.6-82.9)76.7 (71.9-81.6)32.5 (23.341.7)94.0 (91.0-97.1)3.000.397.6 Proven a, probable incorporating PCR e vs No IFD c PCR or ELISA Single98.6 (92.3-100)47.8 (42.0-53.5)21.8 (0.17-0.28)99.6 (96.1-100)1.890.0363.13 Multiple90.0 (80.8-95.1)76.7 (71.9-81.6)36.4 (27.6-46.2)98.1 (95.5-99.3)3.870.1329.7 Proven a, probable b vs No IFD c Both PCR and ELISA Single90.6 (79.8-95.9)84.4 (80.8-87.4)39.3 (31.1-48.2)98.8 (97.1-99.5)5.790.1151.76 Multiple (1 assay)71.7 (56.2-87.2)87.7 (84.0-91.5)39.6 (27.1-52.1)96.5 (94.3-98.7)5.850.3218.13 Multiple (both assays)56.6 (43.3-69.1)94.9 (92.6-96.6)55.6 (42.4-68.0)95.1 (92.8-96.7)11.160.4624.40 Proven a, probable b, possible d vs No IFD c Both PCR and ELISA Single63.2 (51.9-73.1)84.4 (80.8-87.4)39.3 (31.1-48.2)93.4 (90.7-95.4)4.040.449.24 Multiple (1 assay)50.0 (35.7-91.5)87.7 (84.0-91.5)39.6 (27.1-52.1)91.6 (88.4-94.904.080.577.16 Multiple (both assays)39.5 (29.3-50.7)94.9 (92.6-96.6)55.6 (42.4-68.0)90.7 (87.8-93.0)7.780.6412.20 Proven a, probable incorporating PCR e vs No IFD c Both PCR and ELISA Single68.6 (57.0-78.2)84.4 (80.8-87.4)39.3 (31.1-48.2)94.8 (92.2-96.5)4.380.3711.76 Multiple (1 assay)54.3 (39.4-69.2)87.7 (84.0-91.5)39.6 (27.1-52.1)92.8 (89.8-95.9)4.430.528.5 Multiple (both assays)42.9 (31.9-54.5)94.9 (92.6-96.6)55.6 (42.4-68.0)91.8 (89.1-93.9)8.450.6014.03

34 Statistical parameters Sensitivity Specificity PPVNPVLR+LR-DOR Proven, probable vs No IFD PCR or GM EIA Single98.147.817.499.61.880.0447.6 multiple79.276.727.697.13.410.2712.6 PCR and GM EIA single90.684.439.398.85.790.1151.76 multiple56.694.955.695.111.160.4624.4 By EORTC/MSG criteria

35 Proven/probable disease versus no IFD Diagnostic odds ratio Ascertainment bias

36 Positive likelihood ratio 15.8 11.2 10.5

37 Negative likelihood ratio 0.03 0.05

38 ROC plot curve (AUC): 0.910 (95% CI: 0.872-0.948) PCR + EIA Proven/prob/poss Proven/prob

39 Performance of PCR Utility in proven/probable n=53 First marker positive PCR in 23 EIA in 15 PCR and EIA simultaneously positive in 7 radiological features in 8 In 85% biomarkers preceded specific radiological signs (range 1-118d)

40 Diagnostic accuracy Screening by PCR AND GM EIA can enable a diagnosis of IA to be excluded Positive PCR +GM EIA or multiple positive PCRs or EIAs can be used to accurately diagnosis IA specificity 84.4%; sensitivity >90% DOR>50 Biomarkers are earliest markers in 85% of cases Use antifungals more cost effectively

41 Antifungal expenditure Similar units typically spending £1-2 mill pa

42 Use of biomarkers Regular screening throughout period or risk Screening during fever only Diagnostic testing during refractory fever only Confirmation when specific radiological signs are present None - empiric therapy

43 Strategy Used Influenced by Risk of IFD Prevalence affects utility of diagnostic tests ECIL recommend screening if IFD 5-10% Prophylaxis used Mould active reduces utility of diagnostic tests Availability of Diagnostic tests Protective environments/HEPA filtered air

44 Incidence of IFD after posaconazole therapy Pagano et al Haematological 2012; 97:963

45 Effect of antifungal therapy Group Days post infection 12345 Test qPCRGMPCRGMPCRGMPCRGMPCRGM Infected controls2/30/33/31/33/3 Amphotericin B2/31/33/3 Caspofungin1/3 3/32/33/3 2/3 Posaconazole1/30/31/32/33/3 1/32/3 Uninfected controls 0/3 McCulloch et al J Clin Path 2012; 65:83 Marr K A et al. Clin Infect Dis. 2005;40:1762-1769

46 Example High risk patient Prevalence8- ≥10% No Mould active prophylaxis – Screening regime Mould active prophylaxis used – Diagnostic regime Twice weekly screening of blood samples: Galactomannan, And Aspergillus PCR HRCT and BAL when infection suspected Diagnostic testing during refractory fever with Beta D glucan (serum) and Aspergillus PCR (BAL and blood or serum), galactomannan (BAL and serum) Targeted antifungal therapy for clinically diagnosed infection only with biomarker confirmation Single Positive biomarker Continue screening process >1 biomarker positive* triggers diagnostic workup to include relevant radiology and BAL if indicated No consistent clinical signs or symptoms indicates need for possible pre-emptive therapy Any consistent clinical signs or symptoms indicates need for antifungal therapy *For example: PCR and GM, or Multiple GM

47 at riskinfectiondisease exposure

48 Any Questions?

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