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Early Diagnosis and Pre-emptive Therapy of Fungal Pneumonia in High Risk Patients: Current Thinking

Early Diagnosis and Pre-emptive Therapy of Fungal Pneumonia in High Risk Patients: Current Thinking. Kieren Marr MD Fred Hutchinson Cancer Research Center University of Washington Seattle, WA. A case.

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Early Diagnosis and Pre-emptive Therapy of Fungal Pneumonia in High Risk Patients: Current Thinking

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  1. Early Diagnosis and Pre-emptive Therapy of Fungal Pneumonia in High Risk Patients: Current Thinking Kieren Marr MD Fred Hutchinson Cancer Research Center University of Washington Seattle, WA

  2. A case 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.

  3. CT abd and pelvis: fluid. Lungs: BL consolidations • What do you want to do: • BAL. Continue current antifungal therapy • BAL. Change to caspofungin to voriconazole • BAL. Change to lipid based amphotericin B formulation • Change to voriconazole empirically. Obtain serum GM EIA • None of the above

  4. Early Diagnosis and Pre-emptive Therapy • Antifungal therapy administered late is rarely successful • Dependent on immune system of the host and extent of disease • What is late?? • With culture documentation of disease • High disease burden when radiographic abnormalities become apparent • Sensitivity of culture is very poor • Organisms are difficult to cultivate in the lab • Establishing culture-defined diagnoses are difficult • Review of 391 cases of IFI in patients with hematological malignancies, 20011 • Diagnosis made pre-mortem 79% • BAL culture sensitivity 66% 1Pagano et al. Haematologica 86 (2001)

  5. Day 0: halo Day 7: air crescent Day 4: size, halo How to Diagnose Early • CXR screening lacks sensitivity • Patients at risk require screening based on more sensitive parameters • Early CT scans with signs / symptoms of disease • Serial CT scans in patients at risk Caillot et al, J Clin Oncol 2001: 19(1)

  6. Halo Signs Lee et al. Brit J Radiol 78 (2005)

  7. Radiographic Abnormalities Vary

  8. Post-engraftment IA Kojima et al. BBMT 11(7): 506-11 (2005)

  9. Radiography • Sequential CT characterized in 45 patients with IPA1 • No radiographic finding predicted outcome • PET scans may be useful for early diagnosis 2,3 1Horger et al. Eur J Radiol 55 (2005) 2Hot et al. ICAAC 2006 M1307 3Li et al. ICAAC 2006 M1684

  10. BAL for diagnosis • Nonspecific findings warrant evaluation for microbial etiology • Different therapies; frequent co-pathogens • Problem: • BAL culture is not sensitive • Sensitivity 50-65% of cases of documented IA • Ways to make facilitate diagnosis? • Culture under different conditions • Adjunctive tests • Serum based assays • Galactomannan EIA, qPCR, glucan • Adjunctive assays on BAL fluid • Galactomannan EIA, qPCR

  11. Diagnostic Tests for Aspergillosis • Natural history of infection not well understood • When do people become infected? • How do you analyze sensitivity and specificity with multiple test results in one patient? • Per-patient analysis • Per-test analysis • Imperfect gold standard tests • False or true positive? Marr and Leisenring. Clin Infect Dis 2005:41: S381

  12. GMEvolution of Testing Methods • dsELISA: Bio Rad Platelia EIA • Measures GM using rat EBA-2 monoclonal antibody as acceptor and detector • 0.5-1 ng/mL galactomannan • Results: OD index Mennenk-Kersten et al Lancet Infect Dis 2004 4 349

  13. AspergillosisGalactomannan EIA • Frequent false-positives in children Marr and Leisenring Clin Infect Dis 2005; 41:S381

  14. Issues • Antifungal administration decreases sensitivity of the assay1 • Variability in the literature • Challenges current preventative paradigms • False positive tests occur • b lactam antibiotics containing GM (or cross-reactive antigen) • GI tract translocation of GM (or cross-reactive antigen) • Other infections: • Histoplasmosis3 1Marr et al. Clin Infect Dis 2005; 40: 1762-9 2Machetti and Viscoli. Antimicrob Agents Chemother 2005 49(9) 3Wheat et al. ICAAC 06

  15. Diagnostic tests relying on identification of (1-3)--D-Glucan • Activates Limulus amebocyte lysate • Factor G initiates cascade. Output measured by • Turbidity after gel clot: WB003 (Wako Pure Chem. Indust.)1 • Chromogenic substrate: Fungitec G test (Seikagaku) and Fungitell, (Assoc. Cape Cod)2 (1-3)-b-D-glucan Endotoxin Factor C Activated Fact. C Activated Fact G Factor G Factor B Activated Fact. B Proclotting Enzyme Clotting Enzyme Coagulogen Coagulin (gel) 1 Chromogenic method 2

  16. b D glucan • Performance not calculated from large numbers of patients with fungal pneumonia • Smaller studies: sensitivity in setting of IA – 80% • Recent observations • 555 assays, 320 patients • 74 positive tests • 49 patients proven / probable IFI • Sensitivity 71% • Positive in several IFIs • PCP Ostrosky-Zeichner et al. Clin Infect Dis 2005; 41:654 Koo et al. ICAAC 2006 (M-1600) Marty et al. ICAAC 2006 (M-1606)

  17. Utility of Galactomannan Detection in BAL Samples Becker et al. Br J Haematol 2003; 121: 448 Musher et al. J Clin Microbiol 2004: 42(12): 5517-22

  18. Early Diagnostics • Current standard of relying on culture based detection of filamentous fungi is not adequate • Need to incorporate adjunctive diagnostic tests in patients who have signs of disease (radiographic abnormalities) • Can these tests be used “pre-emptively”?

  19. Pre-emptive approach Empirical Risk based approach Biomarker approach 10 Prophylaxis Granulocytes 1 0.1 -14 -7 0 7 14 21 28 35 42 49 56 63 Day Pre-emptive Therapy ?

  20. Screening for Early Diagnosis • PCR assays and immunoassays (GM EIA) have been studied • Particularly strong negative predictive values • Can diagnostic assays be used to spare empiric therapy in patients who are receiving prophylaxis? • Nested PCR to guide antifungal therapy1 • 42 patients with cancer, neutropenia • AmB required in only 2 patients 1Lin et al. Clin Infect Dis. 2001;33:1621-1627.

  21. Galactomannan EIA • Followed 136 episodes to neutropenia to see if GM EIA can be used to avoid empirical therapy • Patients receiving fluconazole prophylactically • 3 breakthrough infections • 2 candidemias • 1 Zygomycetes Maertens et al. Clin Infect Dis 2005; 41: 1242

  22. Risk-based approach: Posaconazole in SCT Recipients with GVHD • Randomized, double-blind • Posa: 200 mg po tid (301 Pts) • Flu: 400 mg po qd (299 Pts) • Drug: GVHD-- to 112 days (16 wks) • Outcomes measured after 16 weeks • Decreased probability of IFI; IA • Many patients who developed IA had a positive GM EIA at randomization • Can this be used to guide therapy? Ullmann AJ, et al. Presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. Dec. 16-19, 2005. Washington, DC.

  23. Targeted therapy • Consider observation that everyone exposed to this organism, yet only 10% develop disease • Are there “biologic risks” that can be measured and more predictive than clinical variables? • Epidemiologic studies: role of cellular immunity in conferring risks for late IA1 • CD4+ T cells with Th1-type cytokine: protective • Immune-reconstitution studies confirmed importance of cellular immunity2 • Developed functional assays to measure Aspergillus-specific PBMC responses • Upcoming study to measure Aspergillus-specific immune reconstitution in allogeneic HSCT patients 1Marr et al. Blood; 100(13):4358-66 (2002)2Storek et al. Blood; 97(11) 3380-89 (2001)

  24. Our patient • Serum GM EIA- negative • BAL performed • No growth on culture • Galactomannan index 0.8 / 1.4 • qPCR (light cycler assay) detected fungal DNA, but not Aspergillus • What would you do? • Continue caspofungin • Change caspofungin to voriconazole • Change caspofungin to Ambisome • Add voriconazole • Add Ambisome

  25. Outcome • Progressive pulmonary infection; therapy withdrawn • Autopsy • Large fungal infarcts in both upper and lower lung lobes bilaterally • Erythema and necrosis of vagina, urethra, lower ¾ of bladder mucosa and uterine cervix: invasive mould • Gangrenous foot with vascular involvement of mould • Splenic infarcts • Culture of lungs, pelvic swab Rhizopus microsporus var. rhizopodiformis

  26. Conclusions • Early therapy is an important goal • Microbe-specific given toxicities, differential activities of drugs, and changing epidemiology • Current culture-based standards are not adequate • Multiple adjunctive tests being developed • Need to learn how to apply them • Clinical study is tricky given inadequate ‘gold standard’ (culture)

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