Controversies in management: prophylaxis or diagnostics

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1 5 th Advances Against Aspergillosis Controversies in management: prophylaxis or diagnostics Caveats in the use of biological markers for early diagnosis Drosos E. Karageorgopoulos, MD Researcher, Alfa Institute of Biomedical Sciences Consultant Physician, Hellenic Center for Disease Control and Prevention Istanbul,

2 Background on the management of invasive aspergillosis (IA) in hematology patients Invasive fungal infections and, particularly, invasive pulmonary aspergillosis is a potentially serious complication Not all patients have the same risk Induction therapy for acute leukemia/mds Allogeneic hematopoietic stem cell transplantation GVHD (neutropenic phase) pre-engraftment phase Use of particular chemotherapeutic agents The prevalence of IA, as diagnosed in clinical practice, is not very high Autopsy studies provide evidence that invasive fungal infections account for a substantial proportion of patients with prolonged neutropenia who have persistent fever Segal BH, et al. Clin. Infect. Dis 2007; 44:

3 Treatment and outcome Early treatment is important to reduce the mortality associated with invasive aspergillosis in neutropenic hematology patients The diagnosis can delay because: It requires imaging and invasive studies that may not be readily available in every center The patient may be a poor candidate for bronchoscopy or, particularly, (lung) biopsy, because of bleeding diathesis or a compromised general clinical status The clinical course is often protracted and it may be cumbersome for the patient to undergo invasive tests at every occasion of otherwise unexplained fever von Eiff M, et al. Respiration 1995; 62:

4 Management strategies Prophylactic therapy Empirical therapy Pre-emptive therapy

5 Prophylactic therapy All patients at risk for certain fungal pathogens Effectiveness (reduction in mortality) has been shown in clinical trials Prolonged duration Toxicity Resistance Costs Prophylactic, empirical and preemptive therapy Empirical therapy Almost all of the high-risk patients will be treated When to stop if no IFI diagnosis? Likelihood for unnecessary toxicity/costs Pre-emptive therapy Reservation of antifungal therapy for specific patients with evidence of an IFI Effectiveness relies on the availability of early diagnostic markers

6 Diagnostic markers for invasive aspergillosis Candidate markers need ideally to be noninvasive, have rapid turn-around time, be accurate, widely available, and of low cost Galactomannan and (1 3)-β-D-Glucan (BDG) Components of Aspergillus cell wall Released into surrounding tissue during fungal growth entry into circulation Can be detected in serum/plasma Polymerase chain reaction Not widely available Marr KA, et al. J Infect Dis 2004; 190: Mennink-Kersten MASH, et al. J Clin Microbiol 2006; 44:

7 BioRad Platelia Aspergillus: sandwich-elisa assay for the detection of galactomannan ELISA A ratio (optical density index) is calculated by dividing the optical density of the patient s serum sample by the mean optical density of two control samples Mennink-Kersten MASH, et al. Lancet Infect Dis 2004; 4:

8 Principles of the BDG assay: activation of the horseshoe crab amebocyte lysate pathway Hope WW, et al. Lancet Infect Dis 2005; 5:

9 Meta-analysis of galactomannan for the diagnosis of invasive aspergillosis Summary receiveroperating characteristic (ROC) curve for galactomannan (Platelia; Bio-Rad) in both proven or probable cases of IA vs. controls Pfeiffer CD, et al. Clin Infect Dis 2006; 42:

10 Meta-analysis of BDG for the diagnosis of invasive fungal infections Summary hierarchical ROC curve of serum/plasma (1 3)-b-D-glucan for the diagnosis of proven or probable invasive fungal infections Karageorgopoulos DE, et al. Clin Infect Dis 2011; 52:

11 BDG sensitivity for Candida vs. Aspergillus IFIs Karageorgopoulos DE, et al. Clin Infect Dis 2011; 52:

12 Characteristics/ metrics GM Comparison of GM and BDG metaanalyses BDG Studies Total cases Proven or probable cases Sensitivity (95% CI) 71% (68% 74%) 76.8% (67.1% 84.3%) Specificity (95% CI) 89% (88% 90%) 85.3% (79.6% 89.7%) AUC 0.89 ( ) Heterogeneity χ 2 : P < I 2 : 95% Pfeiffer CD, et al. Clin Infect Dis 2006; 42: Karageorgopoulos DE, et al. Clin Infect Dis 2011; 52:

13 Potential sources of heterogeneity limitations of the meta-analysis Study design: case-control/cohort, retro-/pro-spective Diagnostic criteria: EORTC/MSG or similar Study population: underlying disease, disease status, concurrent conditions, characteristics of the control group Handling of possible cases in the analysis Assay used (for BDG only) Cut-off point(s) Sampling: number, frequency and timing of samples Criteria for a positive test Concurrent administration of antifungal agents Marr KA, Leisenring W. Clin Infect Dis 2005; 41:S381-S386

14 Factors that could account for false-negative test results Factor GM BDG Prior antifungal therapy +? (echinocandins?) No neutropenia + Anti-galactomannan Ab + Aspergillus species A. fumigatus Site of infection?? Technical factors + + Hirata Y, et al. Leukemia & Lymphoma 2010; 51:

15 Factors that can account for false-positive test results Factor GM BDG β-lactam antibiotics Piperacillin/tazobactam Piperacillin/tazobactam, amoxicillin/clavulanate Gram-negative endotoxinemia + Severe mucositis + + Neonates + + Renal insufficiency/failure + + Gluconate containing solutions + Filtered blood products + Hemodialysis (cellulose membranes) + Gauzes containing BDG + Fungal colonization/ mucosal or chronic infection + + Other IFI Histoplasma Almost all fungal pathogens except for Zygomycetes and Cryptococcus Mennink-Kersten MASH, et al. Lancet Infect Dis 2004; 4: Kedzierska A, et al. Eur J Clin Microbiol Infect Dis 2007; 26:

16 BDG for PCP Karageorgopoulos DE, at al. Clin Microbiol Infect. Epub ahead of print

17 Application of the findings of the meta-analyses into clinical practice The clinically relevant parameters of interest are positive and negative predictive values Likelihood that the disease is truly present/absent when the test is positive/negative Both depend on pre-test probability Can be considered to be equal to disease prevalence Clinical judgment can modify the pre-test probability for the individual patient Relatively low prevalence (5-20%) of IA in hematological patients, particularly with antifungal prophylaxis e.g., decrease from 12.3% to 1.5% with micafungin prophylaxis High negative predictive value if a test has high sensitivity A test must have very high specificity for the positive predictive value to be adequately high Hirata Y, et al. Leukemia & Lymphoma 2010; 51: Leeflang MM, et al. Cochrane Database Syst Rev 2008; :CD007394

18 Positive and negative predictive value of GM by prevalence of IA Pfeiffer CD, et al. Clin Infect Dis 2006; 42:

19 Can we improve the utility of the diagnostic markers? The results of the tests are scale (continuous) variables The distributions of the values for the populations with and without the disease intersect The interpretation is dichotomous (positive/negative), using a defined cut-off level

20 Dispersion of BDG values for different patient groups Highest value per patient Values < 200 pg/ml Pickering JW, et al. J. Clin. Microbiol 2005; 43:

21 A proposed future approach to the interpretation of diagnostic tests Each test value plausibly corresponds to a different probability for the disease being present/absent The determination of this probability would require data from a very large sample size Prospective registry of actual clinical data

22 Predictive value of different BDG levels Retrospective study of 871 patients evaluating the accuracy of the first BDG test for the prediction of an IFI within 1 week Koo S, et al. Clin Infect Dis 2009; 49:

23 We can modify the cut-off level (diagnostic threshold) We may aim for a test with a high negative predictive value Exclude the disease when the test is negative and defer antifungal therapy Many patients can be spared from unnecessary empirical therapy We need a relatively low cut-off level to ascertain that patients with the disease are not left untreated Increase in sensitivity loss in specificity

24 Implications of a lower specificity Increase in false positive cases To avoid unnecessary treatment, a more elaborate test may be used for the appropriate categorization of these patients Necessary for species-level diagnosis in the case of BDG Combination of BDG with GM? Bronchoalveolar lavage fluid galactomannan Aspergillus and/or Candida PCR/RT-PCR in serum/bal Pazos C, et al. J. Clin. Microbiol 2005; 43: ; Persat F, et al. J. Clin. Microbiol 2008; 46: Guo Y-L, et al. Chest 2010 Hadrich I, et al. Med Mycol 2011; 49:

25 Current cut-off levels for GM Cut-off has been lowered to an ODI of 0.5 (from 1.5) Loss in specificity (from 93% to 70%) The requirement for two positive samples for test positivity can increase specificity (from 85.1% to 98.6%) Sensitivity remained stable at 96.5% Sensitivity of 92.1% and specificity of 97.5% has been found in a study of 239 hematology cases Marr KA, et al. Clin Infect Dis 2005; 40: Maertens J, et al. Br J Haematol 2004; 126: Maertens JA, et al. Clin Infect Dis 2007; 44:

26 GM diagnostic performance in a range of cut-off values Maertens JA, et al. Clin Infect Dis 2007; 44:

27 BDG cut-off levels (Fungitell assay) Reference values <60 pg/ml pg/ml => 80 pg/ml Interpretation Negative Indeterminate Positive

28 Early diagnosis Detection of the presence of IA presymptomatic patients at risk for the disease Requires a structured sampling protocol Twice weekly sampling with serum GM GM was positive in 65% of cases in the week prior to diagnosis (EORTC/MSG) Sensitivity reached 79.5% in the week just after diagnosis Maertens JA, et al. Clin Infect Dis 2007; 44:

29 GM for early diagnosis: effect of antifungal prophylaxis A. No antifungal therapy B. Antifungal therapy Marr KA, et al. Clin Infect Dis 2005; 40:

30 BDG for early diagnosis Senn L, et al. Clin. Infect. Dis 2008; 46:

31 Multicenter clinical trial data for use of galactomannan for early diagnosis Pre-emptive vs. empirical therapy in febrile neutropenic patients Pre-emptive therapy was started when clinical, imaging, or galactomannan-antigen-assay evidence suggested an IFI Antifungal prophylaxis according to local protocol Twice weekly galactomannan testing (until recovery from neutropenia) Cut-off: OD index 1.5 Cordonnier C, et al. Clin Infect Dis 2009; 48:

32 Results (pre-emptive vs. empirical therapy) No inferiority with regard to overall survival Increase in probable or proven IFIs Lower use of antifungal treatment Utility of galactomannan testing: Positive galactomannan with persistent fever was present in 2 patients in the empirical treatment group and 3 in the pre-emptive group If 0.5 had been used as the galactomannan cut-off, 2 additional patients in the preemptive treatment arm would have been treated Cordonnier C, et al. Clin Infect Dis 2009; 48:

33 BDG screening (twice weekly) for IFIs in hematological malignancy patients Retrospective study on 1143 samples from 91 patients during 104 treatment cycles Many false positive tests (75% of the samples) Cefepime use, bacteremia, severe mucositis (GVHD), IVIG Racil Z, et al. J. Med. Microbiol 2010; 59:

34 Conclusions GM and BDG are both candidate markers for non-invasive, early diagnosis of invasive aspergillosis in at-risk patients GM is specific for Aspergillus, better studied and with greater experience accumulated in clinical practice May be used for early diagnosis of presymptomatic disease, according to a defined screening protocol BDG appears to have good diagnostic accuracy but a screening strategy has not been established It could be used to exclude a diagnosis of IA, if negative; this requires a low cut-off value A second confirmatory test would be needed if positive None of the diagnostic markers can be entirely relied upon for medical decision making There are several factors that can compromise their diagnostic performance Their utility in the era of antifungal prophylaxis needs further evaluation