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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.

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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
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.

slide3
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
early diagnosis and pre emptive therapy
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

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)

halo signs
Halo Signs

Lee et al. Brit J Radiol 78 (2005)

post engraftment ia
Post-engraftment IA

Kojima et al. BBMT 11(7): 506-11 (2005)

radiography
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

bal for diagnosis
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
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

gm evolution of testing methods
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

aspergillosis galactomannan eia
AspergillosisGalactomannan EIA
  • Frequent false-positives in children

Marr and Leisenring Clin Infect Dis 2005; 41:S381

issues
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

diagnostic tests relying on identification of 1 3 d glucan
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

b d glucan
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)

utility of galactomannan detection in bal samples
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

early diagnostics
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”?
pre emptive therapy

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 ?
screening for early diagnosis
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.

galactomannan eia
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

risk based approach posaconazole in sct recipients with gvhd
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
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
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
outcome
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
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)