Presentation on theme: "Kieren Marr MD Fred Hutchinson Cancer Research Center"— Presentation transcript:
1 Early Diagnosis and Pre-emptive Therapy of Fungal Pneumonia in High Risk Patients: Current Thinking Kieren Marr MDFred Hutchinson Cancer Research CenterUniversity of WashingtonSeattle, WA
2 58 year old F with Hodgkin’s lymphoma received autologous BMT after conditioning with “BuMELT”. 2 days after BMT noted to have what appeared to be a cellulitis in R foot, CNS bacteremia. Treated with imipenem and vancomycin.3 days afterwards, developed hypotension requiring 3 pressors, acute renal failure, severe metabolic acidosis, DIC. Small myocardial infarct likely by enzymes; TTE showed good EF.Exam revealed early gangrenous lesion on R 2nd toe. CXR- ‘bibasilar atelectasis’. Received imipenem, ciprofloxacin, vancomycin, caspofungin. Hemodialysis as tolerated.3 days later, better. Off pressors. Exam: foot worse (all toes). Pelvic ‘ischemia’ (no signs of soft tissue infection). Blood cultures all without growth.A case
3 CT abd and pelvis: fluid. Lungs: BL consolidations What do you want to do:BAL. Continue current antifungal therapyBAL. Change to caspofungin to voriconazoleBAL. Change to lipid based amphotericin B formulationChange to voriconazole empirically. Obtain serum GM EIANone of the above
4 Early Diagnosis and Pre-emptive Therapy Antifungal therapy administered late is rarely successfulDependent on immune system of the host and extent of diseaseWhat is late??With culture documentation of diseaseHigh disease burden when radiographic abnormalities become apparentSensitivity of culture is very poorOrganisms are difficult to cultivate in the labEstablishing culture-defined diagnoses are difficultReview of 391 cases of IFI in patients with hematological malignancies, 20011Diagnosis made pre-mortem 79%BAL culture sensitivity 66%1Pagano et al. Haematologica 86 (2001)
5 How to Diagnose Early CXR screening lacks sensitivity Patients at risk require screening based on more sensitive parametersEarly CT scans with signs / symptoms of diseaseSerial CT scans in patients at riskDay 0: haloDay 4: size, haloDay 7: air crescentCaillot et al, J Clin Oncol 2001: 19(1)
6 Lee et al. Brit J Radiol 78 (2005) Halo SignsLee et al. Brit J Radiol 78 (2005)
8 Post-engraftment IAKojima et al. BBMT 11(7): (2005)
9 1Horger et al. Eur J Radiol 55 (2005) Sequential CT characterized in 45 patients with IPA1No radiographic finding predicted outcomePET scans may be useful for early diagnosis 2,3Radiography1Horger et al. Eur J Radiol 55 (2005)2Hot et al. ICAAC 2006 M13073Li et al. ICAAC 2006 M1684
10 BAL for diagnosisNonspecific findings warrant evaluation for microbial etiologyDifferent therapies; frequent co-pathogensProblem:BAL culture is not sensitiveSensitivity 50-65% of cases of documented IAWays to make facilitate diagnosis?Culture under different conditionsAdjunctive testsSerum based assaysGalactomannan EIA, qPCR, glucanAdjunctive assays on BAL fluidGalactomannan EIA, qPCR
11 Diagnostic Tests for Aspergillosis Natural history of infection not well understoodWhen do people become infected?How do you analyze sensitivity and specificity with multiple test results in one patient?Per-patient analysisPer-test analysisImperfect gold standard testsFalse or true positive?Diagnostic Tests for AspergillosisMarr and Leisenring. Clin Infect Dis 2005:41: S381
12 GM Evolution of Testing Methods dsELISA: Bio Rad Platelia EIAMeasures GM using rat EBA-2 monoclonal antibody as acceptor and detector0.5-1 ng/mL galactomannanResults: OD indexGM Evolution of Testing MethodsMennenk-Kersten et al Lancet Infect Dis
13 Aspergillosis Galactomannan EIA Frequent false-positives in childrenMarr and Leisenring Clin Infect Dis 2005; 41:S381
14 Issues Antifungal administration decreases sensitivity of the assay1 Variability in the literatureChallenges current preventative paradigmsFalse positive tests occurb lactam antibiotics containing GM (or cross-reactive antigen)GI tract translocation of GM (or cross-reactive antigen)Other infections:Histoplasmosis31Marr et al. Clin Infect Dis 2005; 40:2Machetti and Viscoli. Antimicrob Agents Chemother (9)3Wheat et al. ICAAC 06
15 Diagnostic tests relying on identification of (1-3)--D-Glucan Activates Limulus amebocyte lysateFactor G initiates cascade. Output measured byTurbidity after gel clot: WB003 (Wako Pure Chem. Indust.)1Chromogenic substrate: Fungitec G test (Seikagaku) and Fungitell, (Assoc. Cape Cod)2Endotoxin(1-3)-b-D-glucanFactor C Activated Fact. C Activated Fact G Factor GFactor B Activated Fact. BProclotting Enzyme Clotting EnzymeCoagulogen Coagulin (gel) 1Chromogenic method 2
16 Ostrosky-Zeichner et al. Clin Infect Dis 2005; 41:654 Performance not calculated from large numbers of patients with fungal pneumoniaSmaller studies: sensitivity in setting of IA – 80%Recent observations555 assays, 320 patients74 positive tests49 patients proven / probable IFISensitivity 71%Positive in several IFIsPCPb D glucanOstrosky-Zeichner et al. Clin Infect Dis 2005; 41:654Koo et al. ICAAC 2006 (M-1600)Marty et al. ICAAC 2006 (M-1606)
17 Utility of Galactomannan Detection in BAL Samples # pt160Sens(%)SpecPPVNPVSerum47937382BAL8510088Becker et al. Br J Haematol 2003; 121: 448Musher et al. J Clin Microbiol 2004: 42(12):
18 Early DiagnosticsCurrent standard of relying on culture based detection of filamentous fungi is not adequateNeed to incorporate adjunctive diagnostic tests in patients who have signs of disease (radiographic abnormalities)Can these tests be used “pre- emptively”?
19 Pre-emptive Therapy ? -7 7 14 21 28 35 42 49 56 -14 0.1 1 10 714212835424956-140.1110GranulocytesDayProphylaxisEmpiricalPre-emptive approachRisk based approachBiomarker approach63Among other potential preventative strategies being explored is the use of circulating antigen to apply mould-active drugs (similar to CMV).
20 Screening for Early Diagnosis PCR assays and immunoassays (GM EIA) have been studiedParticularly strong negative predictive valuesCan diagnostic assays be used to spare empiric therapy in patients who are receiving prophylaxis?Nested PCR to guide antifungal therapy142 patients with cancer, neutropeniaAmB required in only 2 patients1Lin et al. Clin Infect Dis. 2001;33:
21 Maertens et al. Clin Infect Dis 2005; 41: 1242 Galactomannan EIAFollowed 136 episodes to neutropenia to see if GM EIA can be used to avoid empirical therapyPatients receiving fluconazole prophylactically3 breakthrough infections2 candidemias1 ZygomycetesMaertens et al. Clin Infect Dis 2005; 41: 1242
22 Risk-based approach: Posaconazole in SCT Recipients with GVHD Randomized, double-blindPosa: 200 mg po tid (301 Pts)Flu: 400 mg po qd (299 Pts)Drug: GVHD-- to 112 days (16 wks)Outcomes measured after 16 weeksDecreased probability of IFI; IAMany patients who developed IA had a positive GM EIA at randomizationCan this be used to guide therapy?Ullmann AJ, et al. Presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. Dec , Washington, DC.
23 Targeted therapyConsider observation that everyone exposed to this organism, yet only 10% develop diseaseAre there “biologic risks” that can be measured and more predictive than clinical variables?Epidemiologic studies: role of cellular immunity in conferring risks for late IA1CD4+ T cells with Th1-type cytokine: protectiveImmune-reconstitution studies confirmed importance of cellular immunity2Developed functional assays to measure Aspergillus-specific PBMC responsesUpcoming study to measure Aspergillus-specific immune reconstitution in allogeneic HSCT patients1Marr et al. Blood; 100(13): (2002) 2Storek et al. Blood; 97(11) (2001)
24 Our patient Serum GM EIA- negative BAL performed No growth on culture Galactomannan index 0.8 / 1.4qPCR (light cycler assay) detected fungal DNA, but not AspergillusWhat would you do?Continue caspofunginChange caspofungin to voriconazoleChange caspofungin to AmbisomeAdd voriconazoleAdd AmbisomeOur patient
25 Rhizopus microsporus var. rhizopodiformis Progressive pulmonary infection; therapy withdrawnAutopsyLarge fungal infarcts in both upper and lower lung lobes bilaterallyErythema and necrosis of vagina, urethra, lower ¾ of bladder mucosa and uterine cervix: invasive mouldGangrenous foot with vascular involvement of mouldSplenic infarctsCulture of lungs, pelvic swabOutcomeRhizopus microsporus var. rhizopodiformis
26 Conclusions Early therapy is an important goal Microbe-specific given toxicities, differential activities of drugs, and changing epidemiologyCurrent culture-based standards are not adequateMultiple adjunctive tests being developedNeed to learn how to apply themClinical study is tricky given inadequate ‘gold standard’ (culture)
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