Fungal infections in patients with hematological malignancies: advances in diagnosis and prevention.
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Fungal infections in patients with hematological malignancies: advances in diagnosis and prevention. Yoshinobu Kanda Division of Hematology, Saitama Medical Center, Jichi Medical University. Diagnosis of invasive fungal infection. If we don’t do thorough examinations

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

Yoshinobu Kanda

Division of Hematology,

Saitama Medical Center, Jichi Medical University


Diagnosis of invasive fungal infection
Diagnosis of invasive fungal infection malignancies: advances in diagnosis and prevention.

If we don’t do thorough examinations

to make a diagnosis of fungal infection,

a proven diagnosis can be obtained only postmortem.


Eligible patients: malignancies: advances in diagnosis and prevention.

1) Patients who underwent chemotherapy and neutropenia (<500) 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.


Methods
Methods: malignancies: advances in diagnosis and prevention.

Blood tests:

Real-time PCR for aspergillus DNA

(PCR; Kami et al. Clin Infect Dis 2001; 33:1504–12)

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)


Receiver operating characteristic roc curve
Receiver operating characteristic (ROC) curve malignancies: advances in diagnosis and prevention.

n=149

Proven IA: 9

Probable IA: 2

GM*1

Area under the ROC curve was greatest for GM, using

two consecutive positive results.

GM*2

PCR*1

PCR*2

The best cuttoff for the GM was 0.6.

Sensitivity 100%, Specificity 93%

Positive predictive value 55%

Negative predictive value 100%

BDG*1

BDG*2

(Kawazu et al. J Clin Microbiol 2004;42:2733-2741)


Aspergillus galactomannan detection in the diagnosis of invasive aspergillosis in cancer patients
Aspergillus galactomannan detection in the diagnosis of invasive aspergillosis in cancer patients

(Herbrecht et al. J Clin Oncol 2002;20:1898-1906)


Aspergillus invasive aspergillosis in cancer patientsgalactomannan 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 2004;42:5517–5522)


Retrospective study to evaluate the incidence of false-positive GM antigen test after allogeneic stem cell transplantation.

n=157

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 2008;61:411-416)


Classification of the positive gm episode by reviewing the clinical information
Classification of the positive GM episode false-positive GM antigen test after allogeneic stem cell transplantation.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 2008;61:411-416)


Prognosis of invasive fungal infection
Prognosis of invasive fungal infection false-positive GM antigen test after allogeneic stem cell transplantation.


Aspergillosis fatality rate underlying disease or conditions
Aspergillosis: Fatality rate false-positive GM antigen test after allogeneic stem cell transplantation.Underlying disease or conditions

Solid organ transplantation

(Lin et al. Clin Infect Dis 2001;32:358-366)


Patients: proven or probable aspergillosis false-positive GM antigen test after allogeneic stem cell transplantation.

(Herbrecht et al. N Engl J Med 2002;347:408-415)


Approaches to prevent false-positive GM antigen test after allogeneic stem cell transplantation.overt invasive fungal infection1. Prophylaxis2. Empiric therapy3. Preemptive/presumptive therapy


Timing to start antifungal agents false-positive GM antigen test after allogeneic stem cell transplantation.

↓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 -> Empiric therapy with anti-molds


IDSA guideline 2002 false-positive GM antigen test after allogeneic stem cell transplantation.

for neutropenic patients with cancer

Despite the use of broad antibiotics

..based on very old and small randomized trials…

(Clinical Infectious Diseases 2002; 34:730–751)


Empiric false-positive GM antigen test after allogeneic stem cell transplantation.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 1989:86;668-672)


Empiric false-positive GM antigen test after allogeneic stem cell transplantation.antifungal therapy

in febrile granulocytopenic patients

Amph-B Nil

(n=68) (n=64)

Response rate (fever) 69% 53%

Documented fungal

infection 1 6

Mortality (day 30) 11 14

Cause of death

fungal infection0 4

bacterial infection 1 2

pulmonary infection 1 0

(EORTC Am J Med 1989:86;668-672)


More than half of the patients who received empiric antifungal treatment did not have invasive fungal infection...


Strategies to reduce an unnecessary use antifungal treatment did not have invasive fungal infection...

of antifungal agents…


Presumptive treatment strategy early after transplantation antifungal treatment did not have invasive fungal infection...

Universal prophylaxis with fluconazole

Empiric treatment strategy

Fluconazole was empiricallyswitched 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


Presumptive treatment strategy early after transplantation antifungal treatment did not have invasive fungal infection...

114 patients who underwent allogeneic transplantationbetween 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 2007;60:350-355)


4 patients antifungal treatment did not have invasive fungal infection...

56 patients

1 patients

1 patients

(-)

60 patients

2 patients

(+)

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 2007;60:350-355)


Prophylaxis necessary
Prophylaxis necessary? antifungal treatment did not have invasive fungal infection...

As we administered FLCZ as prophylaxis in these clinical studies,

antifungal agents are frequently used in daily practice.


F luconazole 400 mg day as prophylaxis in bone marrow transplant recipients

However, in patients who underwent chemotherapy for hematological malignancies, the effect of fluconazole prophylaxis has been inconsistent.

Fluconazole 400 mg/day as prophylaxisin bone marrow transplant recipients

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. 1995;171:1545)


A ntifungal prophylaxis with fluconazole a meta analysis

Trial hematological malignancies, the effect of fluconazole prophylaxis has been inconsistent.

Fluconazole arm

Control arm

(first investigator)

Regimen

Subjects

(BMT)

Regimen

Subjects

(BMT)

Goodman JL

oral 400 mg or iv 200 mg

179

(179)

placebo

177

(177)

Winston DJ

oral 400 mg or iv 200 mg

123

(0)

placebo

132

(0)

Chandrasekar PH

oral 400 mg or iv 400 mg

23

(11)

placebo

23

(11)

Schaffner A

oral 400 mg or iv 200 mg

75

(8)

placebo

76

(7)

Slavin MA

oral 400 mg

152

(152)

placebo

148

(148)

Egger T

oral 400 mg or iv 400 mg

43

(14)

oral nystatin 24000000 U

46

(19)

Kern W

oral 400 mg

36

(0)

none

32

(0)

Rotstein C

oral 400mg

141

(62)

placebo

133

(58)

Akiyama H

oral 200 mg

71

(0)

oral AMPH-B 2400 mg

59

(0)

Ellis ME

oral 200 mg

42

(10)

clotrimazole troche 20 mg

48

(13)

Meunier M

oral 200 mg

30

(9)

oral AMPH-B 1200 mg

29

(9)

Menichetti F

oral 150 mg

420

(420)

oral AMPH-B 2000 mg

400

(0)

Ninane J

oral 3 mg/kg

236

(58)

oral nystatin 200000 U/kg or oral AMPH-B 100 mg/kg

249

(64)

Groll AH

oral 3 mg/kg

25

(0)

oral nystatin 50000 U/kg

25

(0)

Philpott-Howard JN

oral 50 mg

256

(60)

oral nystatin 4000000 U or oral AMPH-B 2000 mg

255

(50)

Rozenberg-Arska M

oral 50 mg

25

(0)

oral AMPH-B 800 mg

25

(0)

Antifungalprophylaxiswith fluconazole: a meta-analysis

(Kanda et al. Cancer. 2000;89:1611-1625)


Endpoint proven systemic fungal infection

100 hematological malignancies, the effect of fluconazole prophylaxis has been inconsistent.

10

(proven systemic fungal infection)

FCZ superior ← → control superior

Odds ratio

1

0.1

0.01

Kern W

Ellis ME

Groll AH

Ninane J

Egger T

Slavin MA

Akiyama H

Meunier M

total (D-L)

total (M-H)

Rotstein C

Winston DJ

Schaffner A

Menichetti F

Goodman JL

low-dose (D-L)

low-dose (M-H)

non-BMT (M-H)

non-BMT (D-L)

high-dose (D-L)

high-dose (M-H)

Chandrasekar PH

Philpott-Howard JN

Rozenberg-Arska M

Endpoint: Proven systemic fungal infection

(Kanda et al. Cancer. 2000;89:1611-1625)


Endpoint proven systemic fungal infection1

100 hematological malignancies, the effect of fluconazole prophylaxis has been inconsistent.

10

FCZ superior ← → control superior

odds ratio

1

0.1

0.01

0

5

10

15

20

25

Incidence of systemic fungal infection (%)

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. 2000;89:1611-1625)


Randomized controlled trial comparing fluconazole vs. itraconazole in allogeneic SCT

(Winston et al. Ann Intern Med 2003;138:705-713)


Incidence of invasive fungal infection

Middle phase: prophylaxis against itraconazole in allogeneic SCTAspergillus

Incidence of invasive fungal infection

Early phase : prophylaxis against Candida

(Winston et al. Ann Intern Med 2003;138:705-713)


Voriconazole vs. Itraconazole as anti-mold prophylaxis in patients with GVHD after allogeneic stem cell transplantation.Multicenter randomized controlled trial on going.


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.


For example infection?…1. Patients with non-Hodgkin’s 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.


Worst environment for infection?

stem cell transplantation recipients.

Ideal environment for

clinical trials of fungal infection.

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!!


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