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Yoshinobu Kanda Division of Hematology, Saitama Medical Center, Jichi Medical University

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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Yoshinobu Kanda Division of Hematology, Saitama Medical Center, Jichi Medical University

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  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 don’t 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 (<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.

  4. Methods: 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)

  5. Receiver operating characteristic (ROC) curve 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)

  6. Aspergillus galactomannan detection in the diagnosis of invasive aspergillosis in cancer patients (Herbrecht et al. J Clin Oncol 2002;20:1898-1906)

  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 2004;42:5517–5522)

  8. 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)

  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 2008;61:411-416)

  10. Prognosis of invasive fungal infection

  11. Aspergillosis: Fatality rateUnderlying disease or conditions Solid organ transplantation (Lin et al. Clin Infect Dis 2001;32:358-366)

  12. Patients: proven or probable aspergillosis (Herbrecht et al. N Engl J Med 2002;347:408-415)

  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 -> 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; 34:730–751)

  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 1989:86;668-672)

  17. Empiric 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)

  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 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

  21. Presumptive treatment strategy early after transplantation 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)

  22. 4 patients 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)

  23. Prophylaxis necessary? As we administered FLCZ as prophylaxis in these clinical studies, antifungal agents are frequently used in daily practice.

  24. 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)

  25. 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) Antifungalprophylaxiswith fluconazole: a meta-analysis (Kanda et al. Cancer. 2000;89:1611-1625)

  26. 100 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)

  27. 100 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)

  28. Randomized controlled trial comparing fluconazole vs. itraconazole in allogeneic SCT (Winston et al. Ann Intern Med 2003;138:705-713)

  29. Middle phase: prophylaxis against Aspergillus Incidence of invasive fungal infection Early phase : prophylaxis against Candida (Winston et al. Ann Intern Med 2003;138:705-713)

  30. Voriconazole vs. Itraconazole as anti-mold prophylaxis in patients with GVHD after allogeneic stem cell transplantation.Multicenter 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 example…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.

  33. Worst environment for 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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