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 infectionDiagnosis of invasive fungal infection

If we don’t do thorough examinations

to make a diagnosis of fungal infection,

a proven diagnosis can be obtained only postmortem.

Eligible patients:

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:Blood tests:

Real-time PCR for aspergillus DNA(PCR; Kami et al. Clin Infect Dis 2001; 33:1504–1

2)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) Receiver operating characteristic (ROC) curvecurve

GM*1

GM*2

PCR*1

PCR*2

BDG*1

BDG*20

0.2

0.4

0.6

0.8

1

0 0.2 0.4 0.6 0.8 11-Specificity

Sensitivity

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

n=149Proven IA: 9Probable IA: 2

Area under the ROC curve was greatest for GM, usingtwo consecutive positive results.

The best cuttoff for the GM was 0.6.Sensitivity 100%, Specificity 93%Positive predictive value 55%Negative predictive value 100%

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

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

Aspergillus galactomannan enzyme immunoassay for diagnosis of invasive aspergillosis with bronchoalveolar

lavage fluid

(Musher et al. J Clin Microbiol 2004;42:5517–5522)

Galactomannan test is a very useful test for the diagnosis of aspergillosis if the cutoff around 0.6 is used.

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

0 500 1000 1500

0.0

0.2

0.4

0.6

0.8

1.0

days

Pro

babi

lity

Positive galactomannan: two consecutive GM results with O.D.I above 0.6Incidence: 16% at day 100, 32% at 1-year, 38% at 2-year

(Asano-Mori et al. J Antimicrob Chemother 2008;61:411-416)

n=157

Classification of the positive GM episode Classification of the positive GM episode by reviewing the clinical information.by reviewing the clinical information.

Incidence of false-positive GM antigenemia

Total Episodes Episodes

episodes before day100 after day100

True-positive 22 8 14

False-positive 29 15 14

Inconclusive-positive 7 1 6

Total 58 24 34

False-positive rate (%) 50% 62.5% 41.2%

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)

The damage of the gastrointestinal tract mucosa and translocation of dietary GM may be the

cause of false-positive results

Prognosis of invasive fungal infectionPrognosis of invasive fungal infection

Aspergillosis: Fatality rateAspergillosis: Fatality rateUnderlying disease or conditionsUnderlying disease or conditions

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

Solid organ transplantation

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

Patients: proven or probable aspergillosis

Approaches to prevent Approaches to prevent overt invasive fungal infectionovert invasive fungal infection

1. Prophylaxis1. Prophylaxis2. Empiric therapy2. Empiric therapy

3. Preemptive/presumptive therapy3. Preemptive/presumptive therapy

↓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

Timing to start antifungal agents

Candida prophylaxis with FLCZ -> Empiric therapy with anti-molds

IDSA guideline 2002 for neutropenic patients with cancer

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

Despite the use of broad antibiotics

..based on very old and small randomized trials…

Empiric antifungal therapy in febrile granulocytopenic patients

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 1989:86;668-672)

Amph-B Nil (n=68) (n=64)

Response rate (fever) 69% 53%Documented fungal

infection 1 6Mortality (day 30) 11 14Cause of death

fungal infection 0 4bacterial infection 1 2pulmonary infection 1 0

Empiric antifungal therapy in febrile granulocytopenic patients

Empiric antifungal therapy in febrile granulocytopenic patients

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

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

fungal infection...fungal infection...

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

fungal infection...fungal infection...

Strategies to reduce an unnecessary use of antifungal agents…

Universal prophylaxis with fluconazole

Empiric treatment strategyFluconazole was empirically switched to anti-mold agents for patients with persistent or recurrent FN for 7 days or longer.

Presumptive treatment strategyFor 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: WeeklyChest CT scan: bi-weekly or at the discretion of attending physician

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

Presumptive treatment strategy early after transplantation

(Oshima et al. J Antimicrob Chemother 2007;60:350-355)

Treatment and outcome of patients who were managed in presumptive strategy

Presumptive anti-Aspergillus

treatment

60 patients

(+)

(-)

2 patients

1 patients

1 patients

4 patients

56 patients

Development of early IA

(Oshima et al. J Antimicrob Chemother 2007;60:350-355)

Persistent or recurrent FN for

7 days Beta-D-glucan: 1X-ray or CT scan: 3

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.

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.

Prophylaxis necessary?Prophylaxis necessary?Prophylaxis necessary?Prophylaxis necessary?

As we administered FLCZ as prophylaxis in these clinical studies,

antifungal agents are frequently used in daily practice.

Fluconazole 400 mg/day as prophylaxisin bone marrow transplant recipients

Fluconazole 400 mg/day as prophylaxisin bone marrow transplant recipients

SYSTEMIC FUNGUSSYSTEMIC FUNGUS

SUPERFICIAL FUNGUSSUPERFICIAL FUNGUS

COLONIZATIONCOLONIZATION

SYSTEMIC AMPHO-BSYSTEMIC AMPHO-B

DEATH RATEDEATH RATE

7%7%

0%0%

77%77%

38%38%

13%13%

18%18%

7%7%

86%86%

55%55%

21%21%

FLUCONAZOLEn = 152

FLUCONAZOLEn = 152

PLACEBOn = 149

PLACEBOn = 149

(SLAVIN et al. J. Infect. Dis. 1995;171:1545)

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

Antifungal prophylaxis with fluconazole: a meta-analysis

Antifungal prophylaxis with fluconazole: a meta-analysis

Trial 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)

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

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Endpoint: Proven systemic fungal infectionEndpoint: Proven systemic fungal infection

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

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

Endpoint: Proven systemic fungal infectionEndpoint: 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.

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

Randomized controlled trial comparing Randomized controlled trial comparing fluconazole vs. itraconazole in allogeneic SCTfluconazole vs. itraconazole in allogeneic SCT

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

Early phase : prophylaxis against Candida

Middle phase: prophylaxis against Aspergillus

Incidence of invasive fungal infectionIncidence of invasive fungal infection

Voriconazole vs. Itraconazole as anti-mold Voriconazole vs. Itraconazole as anti-mold prophylaxis in patients with GVHD after allprophylaxis in patients with GVHD after all

ogeneic stem cell transplantation.ogeneic stem cell transplantation.

Multicenter randomized controlled trial Multicenter randomized controlled trial on going. on going.

Which approach should we choose to preWhich approach should we choose to prevent invasive fungal infection?vent invasive fungal infection?

1. Prophylaxis1. Prophylaxis2. Empiric therapy2. Empiric therapy

3. Preemptive/presumptive therapy3. Preemptive/presumptive therapy

… depends on the intensity of immunosuppression … depends on the intensity of immunosuppression

and environment where the patient is treated.and environment where the patient is treated.

For example…For example…

1. Patients with non-Hodgkin’s lymphoma who will un1. Patients with non-Hodgkin’s lymphoma who will undergo CHOP or ESHAP chemotherapy.dergo CHOP or ESHAP chemotherapy.

2. Patients who will undergo remission induction chem2. Patients who will undergo remission induction chemotherapy for acute leukemia.otherapy for acute leukemia.

3. Patients who will undergo allogeneic transplatation i3. Patients who will undergo allogeneic transplatation in a clean unit and who do not have a history of aspergn a clean unit and who do not have a history of asperg

illosis.illosis.

4. Patients who are receiving steroid for chronic GVH4. Patients who are receiving steroid for chronic GVHD in an outpatient clinic.D in an outpatient clinic.

Ideal environment for clinical trials of fungal infection.

Surrounded by nothing but rice paddy fields:Very very humid!!

Everlasting construction!!

Worst environment for stem cell transplantation recipients.

Currently, we are administering anti-mold agents as prophylaxis

for most patients with hematologic malignancies.