Fungal infections in patients with hematological malignancies: advances in diagnosis and prevention.

1

• Fungal infections in patients with hematological
  malignancies advances in diagnosis and
  prevention.

Yoshinobu Kanda Division of Hematology, Saitama
Medical Center, Jichi Medical University
2
Diagnosis of invasive fungal infection
If we dont do thorough examinations to make a
diagnosis of fungal infection, a proven
diagnosis can be obtained only postmortem.
3
Eligible patients 1) Patients who underwent
chemotherapy and neutropenia (lt500) for at least
10 days was expected. 2) Patients who developed
grade II-IV acute GVHD or extensive chronic GVHD
after allogeneic stem cell transplantation. 3)
Patients who were receiving steroid for at least
3 weeks.
4
Methods

• Blood tests
• Real-time PCR for aspergillus DNA
• (PCR Kami et al. Clin Infect Dis 2001
  33150412)
• ELISA for aspergillus galactomannan antigen
• (GM Platelia)
• Beta-1,3-D-glucan
• (BDG Wako)
• Frequency Once a week.
• Diagnosis
• Proven/probable EORTC
• (Serum test not included)

5
Receiver operating characteristic (ROC) curve
n149 Proven IA 9 Probable IA 2
GM1
Area under the ROC curve was greatest for GM,
using two consecutive positive results.
GM2
PCR1
PCR2
The best cuttoff for the GM was 0.6. Sensitivity
100, Specificity 93 Positive predictive value
55 Negative predictive value 100
BDG1
BDG2
(Kawazu et al. J Clin Microbiol 2004422733-2741)
6
Aspergillus galactomannan detection in the
diagnosis of invasive aspergillosis in cancer
patients
(Herbrecht et al. J Clin Oncol 2002201898-1906)
7
Aspergillus galactomannan enzyme immunoassay for
diagnosis of invasive aspergillosis with
bronchoalveolarlavage fluid
Galactomannan test is a very useful test for the
diagnosis of aspergillosis if the cutoff around
0.6 is used.
(Musher et al. J Clin Microbiol 20044255175522)
8
Retrospective study to evaluate the incidence of
false-positive GM antigen test after allogeneic
stem cell transplantation.
n157
Positive galactomannan two consecutive GM
results with O.D.I above 0.6 Incidence 16 at
day 100, 32 at 1-year, 38 at 2-year
(Asano-Mori et al. J Antimicrob Chemother
200861411-416)
9
Classification of the positive GM episode by
reviewing the clinical information.
The damage of the gastrointestinal tract mucosa
and translocation of dietary GM may be the
cause of false-positive results
False-positive results were frequent, especially
within 100 days after transplantation and in
patients who developed gut GVHD.
(Asano-Mori et al. J Antimicrob Chemother
200861411-416)
10
Prognosis of invasive fungal infection
11
Aspergillosis Fatality rateUnderlying disease
or conditions
Solid organ transplantation
(Lin et al. Clin Infect Dis 200132358-366)
12
Patients proven or probable aspergillosis
(Herbrecht et al. N Engl J Med 2002347408-415)
13
Approaches to prevent overt invasive fungal
infection1. Prophylaxis2. Empiric therapy3.
Preemptive/presumptive therapy
14
Timing to start antifungal agents
?Start of chemotherapy Prophylaxis ?For
persistent febrile neutropenia (FN) Empiric
therapy Preemptive / ?Serological /
Imaging evidence ?Persistent FN
Serological / Imaging evidence Presumptive
therapy ?Proven or probable
diagnosis Targeted treatment
Candida prophylaxis with FLCZ -gt Empiric therapy
with anti-molds
15
IDSA guideline 2002 for neutropenic patients
with cancer
Despite the use of broad antibiotics
..based on very old and small randomized trials
(Clinical Infectious Diseases 2002 34730751)
16
Empiric antifungal therapy in febrile
granulocytopenic patients
132 patients remaining febrile and
granulocytopenic despite broad-spectrum
antibiotic therapy for four days ?
Randomization to receive or not to receive
empiric amphotericin-B (0.6 mg/kg/day iv)
(EORTC Am J Med 198986668-672)
17
Empiric antifungal therapy in febrile
granulocytopenic patients
Amph-B Nil (n68) (n64) Respons
e rate (fever) 69 53 Documented fungal
infection 1 6 Mortality (day
30) 11 14 Cause of death fungal infection
0 4 bacterial infection 1
2 pulmonary infection 1 0
(EORTC Am J Med 198986668-672)
18
More than half of the patients who received
empiric antifungal treatment did not have
invasive fungal infection...
19
Strategies to reduce an unnecessary use of
antifungal agents
20
Presumptive treatment strategy early after
transplantation
Universal prophylaxis with fluconazole Empiric
treatment strategy Fluconazole was empirically
switched to anti-mold agents for patients with
persistent or recurrent FN for 7 days or
longer. Presumptive treatment strategy For
patients with persistent or recurrent FN for 7
days or longer, anti-mold agents were started as
an early presumptive treatment for aspergillosis
only after patients developed positive serum test
and/or infiltrates or nodules on X-ray or
CT-scan.
Chest X-ray, galactomannan test, beta-D-glucan
test Weekly Chest CT scan bi-weekly or at the
discretion of attending physician
21
Presumptive treatment strategy early after
transplantation
114 patients who underwent allogeneic
transplantation between September 2002 and
December 2005. Patients with a previous history
of aspergillosis were excluded. All patients
received antifungal prophylaxis with
fluconazole. Primary endpoint Early invasive
aspergillosis (Until one week after
engraftment) Diagnostic criteria Probable or
proven by EORTC/MSG 2002
(Oshima et al. J Antimicrob Chemother
200760350-355)
22
Considering the low incidence of early invasive
aspergillosis in this series, most patients in
the past might have been unnecessarily exposed to
empiric anti-mold agents.
Treatment and outcome of patients who were
managed in presumptive strategy
Presumptive anti-Aspergillus treatment
Development of early IA
These findings suggested the feasibility of
presumptive strategy for invasive aspergillosis
in transplantation recipients before engraftment,
provided that they were treated in HEPA-filtered
laminar air flow rooms. Anti-mold empiric
therapy early after transplantation might be
unnecessary for patients without a history of
aspergillosis.
Persistent or recurrent FN for 7 days
Beta-D-glucan 1 X-ray or CT scan 3
(Oshima et al. J Antimicrob Chemother
200760350-355)
23
Prophylaxis necessary?
As we administered FLCZ as prophylaxis in these
clinical studies, antifungal agents are
frequently used in daily practice.
24
Fluconazole 400 mg/day as prophylaxisin bone
marrow transplant recipients
However, in patients who underwent chemotherapy
for hematological malignancies, the effect of
fluconazole prophylaxis has been inconsistent.
PLACEBO n 149
FLUCONAZOLE n 152
SYSTEMIC FUNGUS SUPERFICIAL FUNGUS COLONIZATION
SYSTEMIC AMPHO-B DEATH RATE
7 0 77 38 13
18 7 86 55 21
(SLAVIN et al. J. Infect. Dis. 19951711545)
25
Antifungal prophylaxis with fluconazole a
meta-analysis
(Kanda et al. Cancer. 2000891611-1625)
26
Endpoint Proven systemic fungal infection
(Kanda et al. Cancer. 2000891611-1625)
27
Endpoint Proven systemic fungal infection
Arranged by the incidence of systemic fungal
infection in the control patients
Patients who will undergo less intensive
chemotherapy do not need fluconazole prophylaxis.
(Kanda et al. Cancer. 2000891611-1625)
28
Randomized controlled trial comparing fluconazole
vs. itraconazole in allogeneic SCT
(Winston et al. Ann Intern Med 2003138705-713)
29
Incidence of invasive fungal infection
Early phase prophylaxis against Candida
(Winston et al. Ann Intern Med 2003138705-713)
30
Voriconazole vs. Itraconazole as anti-mold
prophylaxis in patients with GVHD after
allogeneic stem cell transplantation.Multicente
r randomized controlled trial on going.
31
Which approach should we choose to prevent
invasive fungal infection?1. Prophylaxis2.
Empiric therapy3. Preemptive/presumptive
therapy depends on the intensity of
immunosuppression and environment where the
patient is treated.
32
For example1. Patients with non-Hodgkins
lymphoma who will undergo CHOP or ESHAP
chemotherapy.2. Patients who will undergo
remission induction chemotherapy for acute
leukemia.3. Patients who will undergo
allogeneic transplatation in a clean unit and who
do not have a history of aspergillosis.4.
Patients who are receiving steroid for chronic
GVHD in an outpatient clinic.
33
Ideal environment for clinical trials of fungal
infection.
Worst environment for stem cell transplantation
recipients.
Everlasting construction!!
Currently, we are administering anti-mold agents
as prophylaxis for most patients with
hematologic malignancies.
Surrounded by nothing but rice paddy fields Very
very humid!!