Presentation on theme: "Directed therapy for fungal infections - latest advances"— Presentation transcript:
1 Directed therapy for fungal infections - latest advances Rosemary BarnesFocus on aspergillosis
2 Total UK antifungal expenditure c £112 million Rising by 9% paProblemAntifungal expenditure is completely out of proportion with the scale of the problemIncidence 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:Pagano L et al. Clin Infect Dis 2007; 45:
3 Reasons Infection associated with significant morbidity and mortality Signs and symptoms of systemic infection are nonspecificConventional diagnostic techniques are suboptimalDelays in treatment associated with poorer outcome
7 Decision tree Fever No diagnosis Anxiety yes no yes yes no yes no no
8 Decision tree Fever No diagnosis Anxiety Out of hours yes no yes yes
9 Decision tree Fever Empirical therapy No diagnosis Anxiety yesnoyesyesnonoyesyesnoyesnoyesFeveryesnonoEmpiricaltherapyNo diagnosisAnxietyOut of hoursnoyesyesyesnonoyesnonoyesyesnonoyesnoNo therapy
10 Aim of a directed strategy include all patients likely to have invasive fungal infection and treat them with the safest and most effective drugexclude 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 Designed for use in clinical trials Aimed to provide definitions for proven, probable and possible fungal infection that could facilitate clinical researchDesigned for use in clinical trialsHighly selective populationNot representative of real life clinical practiceFocus on specific radiological signsFocus on defining DISEASEneeds to shift towards INFECTIONNeeds a diagnostic approachbiomarkersDe Pauw et al CID 2008, 46
13 The biomarkers Antigen tests Molecular Galactomannan (aspergillus) Beta D glucan (pan-fungal-ish)Lateral flow deviceMolecularAspergillus specificPanfungalCommercial (…….)
14 Galactomannan - in serum useful test in surveillance: high NPVPerformance inhaematological malignancy better than in SOTneutropenic > corticosteroid treated groupAdults >childrenInfluenced by pre-test probability (ie sensitivity increases with prevalence)EORTC/MSG criteria heavily dependent on test being performedRecommended by ECIL
15 Galactomannan – meta-analyses 30 studies > 7000 patientsPrevalence 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 unnecessarilycut-off 1.5 OD:3 IA patients will be missed5 patients will be treated unnecessarilyresults were very heterogeneous.Insufficient data to look at clinical utility
16 BAL 0.5 approved by FDA On the basis of clinical validity PPV of GM BAL is 100% at an OD index cutoff of ≥3only 76% at ≥ 0.5 (but NPV is high)Pre test probabilityPUO GM pos CT BALMaertens et al CID 2009
17 Beta D Glucan 4 different commercial tests Heterogenous data : retrospective vs. prospective;Different cut offs“panfungal” – except cryptococcus and mucoracous mouldsSensitivity, specificity variable but NPV highHigh false-positives: up to 30% - bacteraemia, antibiotics, pre-/analytical contaminationscomplex analytical proceduresAnalytical validity establishedUtility data limitedIncluded in EORTC/MSG criteria
18 Beta D Glucan-meta-analysis 16 studies in 2979 patientsIncluded case-controlled studiesIncluded critical care, HM and solid organ cancer patientsCut off pg/mlSensitivity 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 PCRMade recommendations for aspergillus PCR2006 European Aspergillus PCR Initiative set up86 participants in 69 centres in 24 countriesdefined a standard for PCR for AspergillusWhole bloodSerumplasmaoptimal methodology to evaluate the performance and impactQCMD availableWhite et al J Molec Diagn 2006; 8: 376White et al J Clin Micro 2010:
20 PCR Single negative PCR to exclude disease 2 consecutive PCRs to diagnose IASensitivity 88%Specificity 75%DOR22Mengoli et al Lancet Infectious Diseases. 2009; 9: 89-96
22 Maertens et al. Clin Infect Dis 2005; 41: 1242 Galactomannan EIAOpen study136 episodes of neutropeniaPatients receiving flucon prophylaxisdaily EIA GM + early CT scanning in neutropenic febrile episodesAntifungal given if 2 consecutive EIA GM results +ve (index ≥ 0.5)and confirmed by BAL or CTMaertens et al. Clin Infect Dis 2005; 41: 1242
23 Maertens et al35% of episodes met criteria for empirical antifungal but only7.7% treated on basis of pre-emptive therapyDuration of fever not affected22 cases of IFD only one missed3 breakthrough infections2 candidaemias1 mucoralesNo excess mortality or fungal related deathNo impact on overall antifungal usage despite deceased empirical use
24 Cordonnieret al CID 2009 48:1043 293 patients randomised empirical or pre-emptive therapyempirical arm received antifungals if they had persistent/recurrent fever after 4 dayspre-emptive patients given antifungal only if they showedclinical and radiological signs of pneumonia/sinusitispositive GM index ≥ 1.5Aspergillus colonizationSeptic shockCNS signs/periorbital inflammationDiarrhoea/mucositis ≥ grade 3fever > 14 days
25 Cordonnieret al Survival was not significantly “Non inferiority” demonstratedpre-emptive patients had more IFI9.1% vs 2.7%pre-emptive patients received significantly less antifungalsno significant cost savings were achievedUsed ampho B deoxycholate first -line
26 Empirical vs. pre-emptive antifungal therapy IFI in Pre-emptiveIFI in EmpiricalCordonnier et al, Clin Infect Dis, 2009; 48:
27 Pagano et al Haematologica 2011; 96:1363 Observational: Empiric versus “pre-emptive”Data collection 397 HM patients190 empiric ; 207”pre-emptive”More IFD in pre-emptive armIncreased mortality and antifungal use in “pre-emptive arm”Fever driven, no screening, diagnostic work up not standardizedsome GM usage, no PCRPre-emptive group largely diagnosed on basis of HRCT
28 PCR Nested PCR to guide antifungal therapy 42 patients with cancer, neutropeniaAmB required in only 2 patientsrandomised study of a PCR directed versus an empirical antifungalmore than 400 SCT patientsSafeImproved survival at 30 days (not 100)No reduction in antifungal drug use.Lin et al. Clin Infect Dis. 2001;33:Hebart et al. Blood 2004;104: 59A.
29 In Cardiff549 high-risk haematology patients entering neutropenic pathwayaudited and followed up for a minumum of 12 monthsTwice weekly antigen and PCR testing (or GvHD)Itraconazole prophylaxis or AmBisome 7mg/kg/weeklyEmpiric antifungals not used unlessClinical/mycological evidence of diseaseItraconazole levels were subtherapeutic or unmeasuredFirst 125 patients analysed for safety and proof of conceptData collected on compliance, incidence of IFD and efficacy of prophylaxisOf the 549 patients, 238 were stem cell transplant patients while 310 were high/intermediate risk haematology patientsSuffering mainly from leukaemias and lymphomas.Not really empiric therapy as there is some evidence of diseaseBarnes 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 sinusitis47 probable(23 possible IA)Invasive Candidal infection 2%12 proven4 C. albicans, 3C. glabrata, 2C. tropicalis, 1C. parapsilosis, 1C. guilliermondii, 1 mixedC. albicans + C. glabrata1 probable2 non-aspergillus moulds1 Mucoraceous mould, 1 Scedosporium prolificansIncidence of proven/probable IFD 12.3%Incidence within our study group
31 IA disease status of subjects By EORTC/MSG diagnostic criteriaProven – 6Probable – 47Possible – 23NEF – 473248 had clinical signs including haemoptysis, pleuritic chest pain, abnormal CXRs, persistent fever225 truly had NEFHaving both EIA and PCR positive shows the tests are not likely to be false negatives248 of NEF showed some signs suggestive of IAEIA positive n=36PCR positive n=136EIA and PCR positive n=75Aspergillus isolated n=5
32 Diagnostic accuracyExplore analytical validity. Clinical validity, clinical utilitySensitivity specificityPPV, NPV, LR, DORsUse ROC analysis to explore different thresholds for defining “cases”EORTC/MSGEORTC – GM EIAEORTC + PCRDual biomarker positivityMultiple positives versus single
34 Statistical parameters SensitivitySpecificityPPVNPVLR+LR-DORProven, probable vs No IFDPCR or GM EIASingle98.147.817.499.61.880.0447.6multiple79.276.727.697.13.410.2712.6PCR and GM EIAsingle90.684.439.398.85.790.1151.7656.694.955.622.214.171.12424.4By testing biomarkers twice weekly it is possible to use the data obtained to get the best diagnostic statistics (see those highlighted)Comparing proven and probable results against those with no evidence of fungal disease using both biomarkers either independently or together allows ruling out disease (NPV) as well as giving strong indications to those with disease (PPV)In essence, Multiple positives show a good accuracy for diagnosing Invasive fungal disease (PPV) whilst single positives could indicate that more diagnostic procedures are necessary (NPV)NPV high throughout all permutations of the data showing it is possible to confidently rule out disease using these tests.PPV low as low prevalence of disease and EORTC criteria downgraded from infection to disease in 2002The DOR of over 50 shows the test to have good diagnostic utility.By EORTC/MSG criteria
35 Proven/probable disease versus no IFD Diagnostic odds ratio Ascertainment biasThis graph shows all permutations of biomarker results, incorporating them into the diagnostic criteria to see those which gave us the best accuracy.Can see that point here from the table previously. However, if we incorporate PCR into the diagnostic criteria we were able to increase the utility of these tests further by using a singly positive EIA or PCR give an even better diagnostic utility.The large cone using a singly positive EIA is an ascertainment bias as EIA is used in the original EORTC criteria.
39 Performance of PCR Utility in proven/probable n=53 First marker positivePCR in 23EIA in 15PCR and EIA simultaneously positive in 7radiological features in 8In 85% biomarkers preceded specific radiological signs (range 1-118d)So looking at the performance of PCR within the proven and probable group shows it was often the 1st marker of disease.Out of 53
40 Diagnostic accuracy Use antifungals more cost effectively Screening by PCR AND GM EIA can enable a diagnosis of IA to be excludedPositive PCR +GM EIA or multiple positive PCRs or EIAs can be used to accurately diagnosis IAspecificity 84.4%; sensitivity >90% DOR>50Biomarkers are earliest markers in 85% of casesUse antifungals more cost effectivelyCan be excluded because of the high negative predictive value.If doing multiple biomarker testing you can select the best diagnostic utility by choosing the best combinations to get the best statistical evidence.
41 Antifungal expenditure What all this means is that antifungals can be used more selectively and so more cost effectively.The graph shows antifungal expenditure fell in first 6 months and remained on a downward trend with minor fluctuations since, which contrasts with other sites of similar size where expenditure has increasedSimilar units typically spending £1-2 mill pa
42 Use of biomarkers Regular screening throughout period or risk Screening during fever onlyDiagnostic testing during refractory fever onlyConfirmation when specific radiological signs are presentNone - empiric therapy
43 Strategy Used Influenced by Risk of IFD Prophylaxis used Prevalence affects utility of diagnostic testsECIL recommend screening if IFD 5-10%Prophylaxis usedMould active reduces utility of diagnostic testsAvailability ofDiagnostic testsProtective environments/HEPA filtered air
44 Incidence of IFD after posaconazole therapy Pagano et al Haematological 2012; 97:963
45 Effect of antifungal therapy GroupDays post infection12345TestqPCRGMPCRInfected controls2/30/33/31/3Amphotericin BCaspofunginPosaconazoleUninfected controlsMcCulloch et al J Clin Path 2012; 65:83Marr K A et al. Clin Infect Dis. 2005;40:
46 Example High risk patient Prevalence8- ≥10% No Mould active prophylaxis – Screening regimeMould active prophylaxis used – Diagnostic regimeTwice weekly screening of blood samples:Galactomannan,And Aspergillus PCRHRCT and BAL when infection suspectedDiagnostic testing during refractory fever with Beta D glucan (serum) andAspergillus PCR (BAL and blood or serum), galactomannan (BAL and serum)Targeted antifungal therapy for clinically diagnosed infection only with biomarker confirmationSingle Positive biomarkerContinue screening process>1 biomarker positive* triggers diagnostic workup to include relevant radiology and BAL if indicatedNo consistent clinical signs or symptoms indicates need for possible pre-emptive therapyAny consistent clinical signs or symptoms indicates need for antifungal therapy*For example: PCR and GM, or Multiple GM
47 at riskexposureinfectiondiseasePre-emptiveProphylaxisTargetted
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