Early Diagnosis and Pre-emptive Therapy of Fungal Pneumonia

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 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.   CT abd and pelvis: fluid. Lungs: BL consolidations 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 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) 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 Day 0: halo Day 4: size, halo Day 7: air crescent Caillot et al, J Clin Oncol 2001: 19(1) Halo Signs Lee et al. Brit J Radiol 78 (2005) Radiographic Abnormalities Vary Postengraftment IA Kojima et al. BBMT 11(7): 506-11 (2005) Radiography  Sequential CT characterized in 45 patients with IPA1 – No radiographic finding predicted outcome 1Horger et al. Eur J Radiol 55 (2005) 2Hot et al. ICAAC 2006 M1307 3Li et al. ICAAC 2006 M1684  PET scans may be useful for early diagnosis 2,3 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 Galactomannan EIA, qPCR – Adjunctive assays on BAL fluid  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 Marr and Leisenring. Clin Infect Dis 2005:41: S381  Imperfect gold standard tests – False or true positive? Evolution of Testing Methods GM  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 Aspergillosis Galactomannan EIA  Frequent false-positives in children Marr and Leisenring Clin Infect Dis 2005; 41:S381 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 crossreactive antigen) et al. Clin Infect Dis 2005; 40: 1762-9 2Machetti and Viscoli. Antimicrob Agents Chemother 2005 49(9) 3Wheat et al. ICAAC 06 1Marr – Other infections:  Histoplasmosis3 Diagnostic tests relying on identification of (1-3)-b-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 Endotoxin Factor C Activated Fact. C Factor B Proclotting Enzyme Coagulogen Activated Fact. B (1-3)-b-D-glucan Activated Fact G Factor G Clotting Enzyme Coagulin (gel) 1 Chromogenic method 2 b D glucan  Performance not calculated from large numbers of patients with fungal pneumonia studies: sensitivity in setting of IA – 80% observations – 555 assays, 320 patients – 74 positive tests – 49 patients proven / probable IFI  Sensitivity  Smaller  Recent 71% Ostrosky-Zeichner et al. Clin Infect Dis 2005; 41:654 Koo et al. ICAAC 2006 (M-1600) Marty et al. ICAAC 2006 (M-1606) – Positive in several IFIs  PCP Utility of Galactomannan Detection in BAL Samples # pt Sens Spec PPV NPV 160 Serum BAL (%) 47 85 (%) 93 100 (%) 73 100 (%) 82 88 Becker et al. Br J Haematol 2003; 121: 448 Musher et al. J Clin Microbiol 2004: 42(12): 5517-22 Early Diagnostics  Current standard of relying on culture based detection of filamentous fungi is not adequate to incorporate adjunctive diagnostic tests in patients who have signs of disease (radiographic abnormalities) these tests be used “preemptively”?  Need  Can Pre-emptive Therapy ? Pre-emptive approach Empirical Risk based approach Biomarker approach Granulocytes 10 Prophylaxis 1 0.1 -14 -7 0 7 14 21 Day 28 35 42 49 56 63 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 required in only 2 patients  AmB 1Lin et al. Clin Infect Dis. 2001;33:1621-1627. 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 candidemias  1 Zygomycetes 2 Maertens et al. Clin Infect Dis 2005; 41: 1242 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. 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? in conferring risks for late IA1 – CD4+ T cells with Th1-type cytokine: protective importance of cellular immunity2  Epidemiologic studies: role of cellular immunity  Immune-reconstitution studies confirmed  Developed functional assays to measure Aspergillus-specific PBMC responses et al. Blood; 100(13):4358-66 (2002) 2Storek et al. Blood; 97(11) 3380-89 (2001) 1Marr – Upcoming study to measure Aspergillus- specific immune reconstitution in allogeneic HSCT patients 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? 1. Continue caspofungin 2. Change caspofungin to voriconazole 3. Change caspofungin to Ambisome 4. Add voriconazole 5. Add Ambisome Outcome  Progressive  Autopsy pulmonary infection; therapy withdrawn – 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 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 adjunctive tests being developed – Need to learn how to apply them – Clinical study is tricky given inadequate „gold standard‟ (culture)  Multiple