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

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Presentation on theme: "Early Diagnosis and Pre-emptive Therapy of Fungal Pneumonia in High Risk Patients: Current Thinking 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 MD Fred Hutchinson Cancer Research Center University of Washington Seattle, WA

2 A case 58 year old F with Hodgkins 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 2 nd 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 n CT abd and pelvis: fluid. Lungs: BL consolidations n What do you want to do: 1.BAL. Continue current antifungal therapy 2.BAL. Change to caspofungin to voriconazole 3.BAL. Change to lipid based amphotericin B formulation 4.Change to voriconazole empirically. Obtain serum GM EIA 5.None of the above

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

5 How to Diagnose Early n CXR screening lacks sensitivity n 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 Day 0: halo Day 4: size, halo Day 7: air crescent 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): (2005)

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

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

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

12 GM Evolution of Testing Methods n dsELISA: Bio Rad Platelia EIA – Measures GM using rat EBA-2 monoclonal antibody as acceptor and detector – ng/mL galactomannan n Results: OD index Mennenk-Kersten et al Lancet Infect Dis

13 l Frequent false-positives in children Aspergillosis Galactomannan EIA Marr and Leisenring Clin Infect Dis 2005; 41:S381

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

15 Diagnostic tests relying on identification of (1-3)- -D-Glucan n Activates Limulus amebocyte lysate n 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 Endotoxin (1-3)- -D-glucan 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 D glucan n Performance not calculated from large numbers of patients with fungal pneumonia n Smaller studies: sensitivity in setting of IA – 80% n Recent observations – 555 assays, 320 patients – 74 positive tests – 49 patients proven / probable IFI l Sensitivity 71% – Positive in several IFIs l 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 # pt 160 Sens (%) Spec (%) PPV (%) NPV (%) Serum BAL Becker et al. Br J Haematol 2003; 121: 448 Musher et al. J Clin Microbiol 2004: 42(12):

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

19 Pre-emptive Therapy ?

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

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

22 Risk-based approach: Posaconazole in SCT Recipients with GVHD n Randomized, double-blind – Posa: 200 mg po tid (301 Pts) – Flu: 400 mg po qd (299 Pts) n Drug:GVHD-- to 112 days (16 wks) n Outcomes measured after 16 weeks n Decreased probability of IFI; IA n 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 , Washington, DC.

23 Targeted therapy n 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? n Epidemiologic studies: role of cellular immunity in conferring risks for late IA 1 – CD4+ T cells with Th1-type cytokine: protective n Immune-reconstitution studies confirmed importance of cellular immunity 2 n Developed functional assays to measure Aspergillus-specific PBMC responses – Upcoming study to measure Aspergillus- specific immune reconstitution in allogeneic HSCT patients 1 Marr et al. Blood; 100(13): (2002) 2 Storek et al. Blood; 97(11) (2001)

24 Our patient n Serum GM EIA- negative n BAL performed – No growth on culture – Galactomannan index 0.8 / 1.4 – qPCR (light cycler assay) detected fungal DNA, but not Aspergillus n What would you do? 1.Continue caspofungin 2.Change caspofungin to voriconazole 3.Change caspofungin to Ambisome 4.Add voriconazole 5.Add Ambisome

25 Outcome n Progressive pulmonary infection; therapy withdrawn n 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 n Early therapy is an important goal n Microbe-specific given toxicities, differential activities of drugs, and changing epidemiology n Current culture-based standards are not adequate n 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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