early diagnosis and pre-emptive therapy of fungal pneumonia in high risk patients: current thinking...
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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
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. Pagano et al. Haematologica 86 Haematologica 86
(2001)(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 Lee et al. Brit J Radiol 78 (2005)78 (2005)
Radiographic Abnormalities Vary
Post-engraftment IA
Kojima et al. BBMT 11(7): 506-11 (2005)Kojima et al. BBMT 11(7): 506-11 (2005)
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 Horger et al. Eur J Radiol 55 (2005)55 (2005)
22Hot et al. ICAAC 2006 Hot et al. ICAAC 2006 M1307M1307
33Li et al. ICAAC 2006 M1684Li et al. ICAAC 2006 M1684
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
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. Marr and Leisenring. Clin Infect Dis 2005:41: Clin Infect Dis 2005:41:
S381S381
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
Frequent false-positives in children
Aspergillosis
Galactomannan EIA
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– 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
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
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
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 IFISensitivity 71%
– Positive in several IFIsPCP
Ostrosky-Zeichner et al. Clin Ostrosky-Zeichner et al. Clin Infect Dis 2005; 41:654Infect Dis 2005; 41:654
Koo et al. ICAAC 2006 (M-1600)Koo et al. ICAAC 2006 (M-1600)Marty et al. ICAAC 2006 (M-Marty et al. ICAAC 2006 (M-
1606)1606)
Utility of Galactomannan Detection in BAL Samples
# pt
160
Sens
(%)
Spec
(%)
PPV
(%)
NPV
(%)
Serum 47 93 73 82
BAL 85 100 100 88
Becker et al. Br J Haematol 2003; 121: 448
Musher et al. J Clin Microbiol 2004: 42(12): 5517-22
Early Diagnostic
s
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”?
Pre-emptive Therapy ?
-7-7 00 77 1414 2121 2828 3535 4242 4949 5656-14-14
0.10.1
11
1010
Gra
nu
locyte
sG
ran
ulo
cyte
s
DayDay
ProphylaxisProphylaxis
EmpiricalEmpirical
Pre-emptive approachPre-emptive approach
Risk based approachBiomarker approach
6363
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
11Lin et al. Lin et al. Clin Infect DisClin Infect Dis. . 2001;33:1621-1627.2001;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 2 candidemias1 Zygomycetes
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?
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)
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 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
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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