MDS 1990, 1994, 1998, Fig. 1., Fig. 1, MDS, myelodysplastic syndrome 1989, 1993, ,

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1 Jpn. J. Med. Mycol. Vol. 47, 15 24, 2006 ISSN MDS 1990, 1994, 1998, , , 2005 MDS,,., /1,557, 1989, /1,388, 1993, /1,105, 1997, /1,037, 2001, 3.4, 2.7, , MDS , 36.7, 33.9, , GVHD ,. Candida Aspergillus, , 33.3, 2001, 16.9, 54.2, GVHD. Key words: deep seated mycoses, autopsy cases, epidemiology, leukemia, myelodysplastic syndrome MDS, hematopoietic stem cell transplantation,.,, Miyake , Kanda , Hotchi , ,., Yamazaki 5 Kume , , 4.7, 1994, , , ,, Fig. 1., Fig. 1,, 5 MDS, myelodysplastic syndrome, 1989, 1993, , 1993, , , , ,.

2 Total mycoses Aspergillus Candida Cryptococcus Zygomycetes Other % of mycoses year Fig. 1. Changes in rate of mycoses among total autopsy cases and of causative agents of mycoses from 1969 to 2001 in Japan Cases of stillborn babies were excluded from the annual autopsy cases. Visceral mycoses increased noticeably from 1.60 in 1969 and peaked at 4.66 in 1990, with incidences of candidosis and aspergillosis showed the greatest increase. Since 1990, however, the frequency of visceral mycoses has decreased gradually. Until 1989, the predominant causative agent was Candida followed in order by Aspergillus and Cryptococcus. Although the rate of candidosis has decreased by degrees from 1990, the rate of aspergillosis increased and surpassed that of candidosis in Aspergillosis increased conspicuously in 1997 Aspergillus 40.9, Candida 34.8 and in 2001, the rate was even higher Aspergillus 46.0, Candida ,,,,,,,,,, GVHD, The graft-versus-host disease Filemaker Pro version 3.0, Claris Co.,.,,, A, 59, B, 89, No., 35 No.,,. 10,,,,,,,,,, T,,, NK 11.,,.,, 1., 2., 3., 4., 5., 6. 2, 3.,,, 4,, 5.,,, GVHD Table /1,557, 1989, /1,388, 1993, /1,105, /1,037, 2001, 3.4, 2.7,

3 Jpn. J. Med. Mycol. Vol. 47 No. 1, Table 1. Annual frequencies of visceral mycoses and of mycoses without or with leukemia and myelodysplastic syndrome MDS, and mycoses rate in transplantation recipients and in GVHD with leukemia and MDS among the total autopsy cases for the years 1989, 1993, 1997 and 2001* Total autopsy cases Year* Autopsy cases Total no. of autopsies 37,557 31,027 26,681 25,459 Total with infection of total 1, , , , with monopathogen infection 1, , , , with complicated infection** Autopsy cases except leukemia and MDS Year* Total no. of autopsies 36,000 29,819 25,576 24,422 Total with infection s of total 1, with monopathogen infection 1, with complicated infection** Autopsy cases with leukemia and MDS Year* Total no. of autopsies 1,557 1,388 1,105 1,037 Total with infection s of total with monopathogen infection with complicated infection** Total no of cases with trasplantation with total infection s of total Total no of cases with GVHD with total infection s of total *, Annual of the Pathological Autopsy Cases in Japan references, 7, 8, 9 and 10. Cases of stillborn babies were excluded from the annual autopsy cases. **, Mixed infection with more than two kinds of fungi in the infected organ. GVHD, graft-versus-host disease. Table 2-1. Annual frequencies of visceral mycoses in cases with leukemia and MDS by causative agents Agent Number of cases* frequency rate Aspergillus 145/ / / / Candida 146/ / / / Cryptococcus 12/ / / / Zygomycetes 25/ / / / Other 3/ / / / Unknown** 69/ / / / Complicated*** 35/ / / / Total 435/ / / / * Cases of stillborn babies were excluded from the annual autopsy cases. ** An unidentified fungus was observed in the infected organ. *** Mixed infection with two or more kinds of fungi in the infected organ. Table 2-2. Annual frequencies of visceral mycoses in transplantation recipients with leukemia and MDS by causative agents Agent Number of cases* frequency rate Aspergillus 3/ / / / Candida 3/ / / / Cryptococcus Zygomycetes 0 1/ / / Other 0 0 1/ Unknown** 5/ / / / Complicated*** 0 1/ / Total 11/ / / / * Cases of stillborn babies were excluded from the annual autopsy cases. ** An unidentified fungus was observed in the infected organ. *** Mixed infection with two or more kinds of fungi in the infected organ.

4 Table 2-3. Annual frequencies of visceral mycoses in cases with GVHD after transplantation in cases leukemia and MDS by causative agents Agent Number of cases* frequency rate Aspergillus 1/ / / / Candida 0 1/ / / Cryptococcus Zygomycetes 0 1/ Other Unknown** / Complicated*** / Total 1/ / / / * Cases of stillborn babies were excluded from the annual autopsy cases. ** An unidentified fungus was observed in the infected organ. *** Mixed infection with two or more kinds of fungi in the infected organ..,, /11, 1989, /62, 1993, /72, /119, 2001,, GVHD, / 7, 1998, /16, 1993, /22, 1997, /30, 2001, Table 2-1, Table 2-2 Table 2-3. Aspergillus Candida , Zygomycetes , Cryptococcus , Trichosporon , Aspergillus Candida , Zygomycetes 0 7.9, Trichosporon 0 3.7, 3 Aspergillus Candida 2, Aspergillus Cryptococcus 1 Table 2-2., GVHD Aspergillus , Candida , Zygomycetes Table 2-3., 1989 Aspergillus /435, Candida /435, /319, /319, /246, /246, /260, /260, Aspergillus Candida Table 3. Number of complicated mycoses cases with leukemia and MDS by causative agents* Agents No. of cases Aspergillus + Candida Candida + Zygomycetes Aspergillus + Zygomycetes Aspergillus + Cryptococcus Aspergillus + Trichosporon Trichosporon + unknown** Aspergillus + Zygomycetes + Cryptococcus Total *, Data were compiled from Annual of the Pathological Autopsy Cases in Japan references, Cases of stillborn babies were excluded from the annual autopsy cases. **, An unidentified fungus was observed in the infected organ. Table 4-1. Proportion of severe infections for all mycoses with leukemia and MDS Yr No. of cases considered nonsevere severe* Proportion / / / / * Severe cases are defined in Materials and Methods the direct cause of death, infection involving both lobes of the lung, multiorgan systemic infection or fungemia etc., Table 2-1., Table 2-2, GVHD Table 2-3., Table 3, 80 Aspergillus Candida /80, Candida Zygomycetes /80, Aspergillus

5 Jpn. J. Med. Mycol. Vol. 47 No. 1, Zygomycetes /80, Aspergillus Cryptococcus /80, Aspergillus Trichosporon /80, Trichosporon , 80 3 Aspergillus, Zygomycetes Cryptococcus Table 4-2. Proportion of severe infections in cases with leukemia and MDS by causative agents in 1989 and Agent No. of cases considered nonsevere severe* Proportion Aspergillus / Candida / Cryptococcus 4 8 8/ Zygomycetes / Other 1 2 2/ Unknown / Complicated / Agent Total / No. of cases considered nonsevere severe* Proportion Aspergillus / Candida / Cryptococcus 0 5 5/ Zygomycetes / Other 0 1 1/ Unknown / Complicated / Total / * Severe cases are defined in Materials and Methods the direct cause of death, infection involving both lobes of the lung, multiorgan systemic infection or fungemia etc.., Table /435, /319, /246, /260., Table Aspergillus / /141, Zygomycetes / /24, / / , Candida / / Table 5., /768,, /614, /614, / / /47, /47, /146., Table 5. Frequency of visceral involvement in common mycoses infected by monopathogens in cases with leukemia and MDS* Number of infections Infection type or organ Aspergillosis Candidosis Cryptococcosis Zygomycosis n=553 ** n=317 ** n=23 ** n=90 ** Systemic or Fungemia Brain + meninx Mouth + tongue Esophagus Stomach Intestine Liver Larynx + pharynx Lung + bronchus Heart Kidney Bladder Thyroid Spleen Pancreas Others Total no. infections * Data were compiled from references Cases of stillborn babies were excluded from the annual autopsy cases. ** Total no. cases

6 Table 6. Annual frequency of visceral mycoses in cases with leukemia and MDS by histological type 1989 Total no. of patients No. with mycosis Acute leukemia / Chronic leukemia Acute myeloid leukemia / Chronic myeloid leukemia / Acute lymphatic leukemia / Chronic lymphatic leukemia / Monocytic leukemia / Blastic leukemia / Adult T- cell leukemia / Other leukemia / MDS / Total 1, /1, Total no. of patients No. with mycosis Acute leukemia / Chronic leukemia Acute myeloid leukemia / Chronic myeloid leukemia / Acute lymphatic leukemia / Chronic lymphatic leukemia / Monocytic leukemia / Blastic leukemia / Adult T- cell leukemia / Other leukemia / MDS / Total 1, /1, Total no. of patients No. with mycosis Acute leukemia / Chronic leukemia Acute myeloid leukemia / Chronic myeloid leukemia / Acute lymphatic leukemia / Chronic lymphatic leukemia / Monocytic leukemia / Blastic leukemia / Adult T- cell leukemia / Other leukemia / MDS / Total 1, /1, Total no. of patients No. with mycosis Acute leukemia / Chronic leukemia / Acute myeloid leukemia / Chronic myeloid leukemia / Acute lymphatic leukemia / Chronic lymphatic leukemia / Monocytic leukemia / Blastic leukemia / Adult T- cell leukemia / Other leukemia / MDS / Total 1, /1, /553, /317, /23., /90., aspergillosis 12.8 cryptococcosis,, /23, /317, / /553,. Table , , 33.5, MDS , 29.0, T , 21.4, , , , ,259 Table 7. Table 7,, /1,259, , 28 /69.,., Aspergillus 11 13, Zygomycetes 14, Fusarium 15 17, non-albicans Candida spp , Scedosporium , 23, Aspergillus Zygomycetes 24, 25 Fusarium 26 Cryptococcus 27 Candida 28,, 5, 6, 29.,,.,.,,.,,,

7 Jpn. J. Med. Mycol. Vol. 47 No. 1, Table 7. Number of cases with visceral mycoses among those with leukemia and MDS by age, sex and causative agent Age Total No. total Sex M F M F M F M F M F M F M F M F M F M F cases Aspergillus * Candida Cryptococcus Zygomycetes Trichosporon Unknown Complicated Total , No. of total cases , Data were compiled from references 7, 8, 9 and 10. The highest frequency of mycoses was observed for individuals in their 20s, whereas the highest incidence was among those in their 60s. * Age unknown for one case with aspergillosis.,,.,,.,,,.,.,,,,,,.,, MDS, 3 6,,, ,,, 10., 1989,, GVHD 40.,,, 30, 31. Koch ,813 47, , Kieren ,589, 1992,. Thursky 30, GVHD., Nucci 34,., Table 2., 1993,,.. GVHD Aspergillus ,, 1., 1989, 1993,,. 2. non-albicans Candida ,, Aspergillus opportunity.., Asmundsdottir , 3.5, , Schwesinger 37

8 ,,,.,,, /23, /317, /553, /90 2.., / /90., , 38., 3.25, /23.,, 3.25, / Table 7, 60, /235.,., 9.,, , Rosen 40, 1,052 Candida sp.., 63.9, 804 /1,259,. Allam ,, 44, 64.,.,. 42,, Table 8 Table 8, , , /660, /660, /665, /665, /674, /674, /703, /703.,,.,,, PCR 43,,.. Table 8. Annual trends of total deaths and of deaths certified as resulting from mycoses in Japan Yr No. of total deaths of mycoses No. of mycoses among total deaths , , , , Data were extracted from Vital Statistics of Japan, edited by the Minister s Secretariat, Ministry of Health and Welfare 42) for the years 1989,1993, 1997 and 2001.

9 Jpn. J. Med. Mycol. Vol. 47 No. 1, Miyake M, Okudaira M: A statistical survey of deep fungus infections in Japan. Acta Pathol Jpn 17: , Kanda M, Moriyama M, Ikeda M, Kojima S, Tokunaga M, Watanabe G: Astatistical survey of deep mycoses in Japan, with particular reference to autopsy cases of cryptococcosis. Acta Pathol Jpn 24: , Hotchi M, Okada M, Nasu T: Present state of fungal infections in autopsy gases in Japan. Am J Clin Pathol 74: , Okudaira M, Kume H, Kurata H et al.: Recent statistical survey of visceral aspergillosis in Japan, and experimental studies on the pathogenicity of Aspergillus fumigatus rabbits. Zentralbl Bakteriol Mikrobiol Hyg A261: , Yamazaki T, Kume H, Murase S, Yamashita E, Arisawa M: Epidemiology of visceral mycoses: analysis of data in annual of the pathological autopsy cases in Japan. J Clin Miclobiol 37: , Kume H, Yamazaki T, Abe M, Tanuma H, Okudaira M, Okayasu I: Increase in aspergillosis and severe mycotic infection in patients with leukemia and MDS: comparison of the data from the annual of the pathological autopsy cases in Japan in 1989, 1993 and Pathology International 53: , Japanese Society of Pathology. Annual of the Pathological Autopsy Cases in Japan, 1990; 32: Japanese Society of Pathology, Tokyo, Japan in Japanese. 8 Japanese Society of Pathology. Annual of the Pathological Autopsy Cases in Japan, 1994; 36: Japanese Society of Pathology, Tokyo, Japan in Japanese. 9 Japanese Society of Pathology. Annual of the Pathological Autopsy Cases in Japan, 1998; 40: Japanese Society of Pathology, Tokyo, Japan in Japanese. 10 Japanese Society of Pathology. Annual of the Pathological Autopsy Cases in Japan, 2002; 44: Japanese Society of Pathology, Tokyo, Japan in Japanese. 11 Lin Swu-Jane, Schranz J, Teutsch SM: Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis 32: , Guermazi AN, Benchaib N, Zagdanski AM, et al.: Cerebral and spinal cord Involvement resulting from Invasive aspergillosis. Eur Radiol 12: , Singh N, Paterson DL: Aspergillus infections in transplant recipients. Clinical Microbiology Reviews 18 1 : 44 69, Pagano L, Offidani M, Fianchi L, Nosari A, Candoni A, Piccardi M, Corvatta L, D Antonio D, Girmenia C, Martino P, Del Favero A: Mucormycosis in hematologic patients. Haematologica 89 2 : , Letscher Bru V, Campos F, Waller J, et al.: Successful outcome of treatment of a disseminated Infection due to Fusarium dimerum in a leukemia patient. J Clin Microbiol 40: , Jensen TG, Gahrn-Hansen B, Arendrup M, Bruun B: Fusarium fungaemia in immunocompromised patients. Clin Microbiol Infect 10 6 : , Nucci M, Marr KA, Queiroz-Telles F, Martins CA, Trabasso P, Costa S, Voltarelli JC, Colombo AL, Imhof A, Pasquini R, Maiolino A, Souza CA, Anaissie E: Fusarium infection in hematopoietic stem cell transplant recipients. Clin Infect Dis 38 9 : , Kullberg BJ, Oude Lashof AM: Epidemiology of opportunistic invasive mycoses. Eur J Med Res 7: , Specchia G, Pastore D, Montagna MT, Carlucclo P, Cluffreda L, Rizzal R, Liso A: Fungemia in acute leukemia patients: a single institution's experience. New Microbiol 27 4 : , Martin D, Persat F, Plens MA, Picot S: Candida species distribution in bloodstream cultures in Lyon, France, Eur J Clin Microbiol Infect Dis 24 5 : , Husain S, Munoz P, Forrest G, Alexander BD, Somani J, Brennan K, Wagener MM, Singh N: Infections due to Scedosporium apiospermum and Scedosporium prolificans in transplant recipients: clinical characteristics and impact of antifungal agent therapy on outcome. Clin Infect Dis 40 1 : 89 99, ,,,,,, :, : , ,,,,, :,, : , ,,,, : : , ,,,,,,,, : : , : Fusarium solani : , ,,,,,,, : 1 MRI : , ,,,,, : 1. 9: , , : : , Thursky K, Byrnes G, Grigg A, Szer J, Slavin M: Risk factors for post-engraftment invasive aspergillosis in

10 allogeneic stemcell transplantation. Bone Marrow Transplant 34 2 : , Golan Y: Overview of transplant mycology. Am J Health Syst Pharm 62 suppl. 1 : S17 21, Koch S, Hohne FM, Tietz HJ: Incidence of systemic mycoses in autopsy material. Mycoses 47 1 : 40 46, Kieren AM, Rachel AC, Fulvio C, Anna W, Lawrence C: Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 34: , Nucci M: Emerging moulds: Fusarium, Scedosporium and Zygomycetes in transplant recipients, Curr Opin Infect Dis, 16 6 : , Randhawa HS: Respiratory and systemic mycoses: an overview. Indian J Chest Dis Allied Sci 42 4 : , Asmundsdottir LR, Erlendsdottir H, Gottfredsson M: Improving survival of patients with candidaemia: analysis of prognostic factors from a long-term, nationwide study in Iceland. Scand J Infect Dis 37 2 : , Schwesinger G, Junghans D, Schroder G, Bernhardt H, Knoke M: Candidosis and aspergillosis as autopsy findings from 1994 to Mycoses 48 3 : , Salfelder, K: Cryptococcosis. Human Infection with Fungi, Actinomycetes and Algae, Baker, R.D ed., Springer, N.Y , Lewejohann J, Muhl E, Birth M, Kujath P, Bruch HP: Pulmonary zygomycosis - a rare angioinvasive infection. Mycoses 48 Suppl. 1 : , Rosen GP, Nielsen K, Glenn S, Abelson J, Deville J, Moore TB: Invasive fungal infectionsin pediatric oncology patients: 11-year experience at a single institution. J Pediatr Hematol oncol 27 3 : , Allam MF, Serrano Del Castillo A, Diaz-Molina C, Fernandez-Crehuet Navaja R: Invasive pulmonary aspergillosis: retrospective case record review. Rev lberoam Micol 21 1 : 35 38, , 1989, 1993, 1997, Epidemiology of Visceral Mycoses in Patients with Leukemia and MDS Analysis of the Data in Annual of Pathological Autopsy Cases in Japan in 1989, 1993, 1997 and 2001 Hikaru Kume 1, Toshikazu Yamazaki 2, Michiko Abe 3, Hiroyuki Tanuma 4, Masahiko Okudaira 1 and Isao Okayasu 1 1 Dept. of Pathology, School of Medicine, Kitasato University, Kitasato, Sagamihara, Kanagawa , Japan 2 Kamakura Research Laboratories, Chugai Pharmaceutical Co., LTD., 200 Kajiwara, Kamakura, Kanagawa , Japan 3 Faculty of Hygienic Technology, Kitasato University School of Allied Health Sciences, Kitasato, Sagamihara, Kanagawa , Japan 4 Dept. of Dermatology, School of Medicine, Kitasato University, Kitasato, Sagamihara, Kanagawa , Japan To study the changes of visceral mycoses in autopsy cases, data on visceral mycosis cases with leukemia and myelodysplastic syndrome MDS reported in the Annual of the Pathological Autopsy Cases in Japan in 1989, 1993, 1997 and 2001 were analyzed. The frequency rate of visceral mycoses with leukemia and MDS was 27.9% 435/1,557 in 1989, 23.0% 319/1,388 in 1993, 22.3% 246/1,105 in 1997 and 25.1% 260/ 1,037 in 2001, which was clearly higher than the rate of cases without leukemia and MDS: 3.4%, 2.7%, 3.5% and 3.7%, respectively. Furthermore, in comparing the rate of mycoses in recipients of stem cell transplantation with that of non-recipients, that of recipients was about 10% higher. The predominant causative agents were Candida and Aspergillus, at approximately the same rate Candida 33.6%, Aspergillus 33.3% as in However, Aspergillus increased conspicuously in 1993 Candida 22.3% Aspergillus 44.5%, and continued to increase Candida 22.8%, Aspergillus 50.8% in 1997; Candida 16.9%, Aspergillus 54.2% in In aspergillosis and zygomycosis, the lung and bronchi comprised the most commonly infected organs: 74.7% and 75.6% of the total cases, respectively. Among a total of 1,260 cases with mycotic infections in the four years studied, acute lymphatic leukemia and acute myeloid leukemia were the major diseases 35.5% and 33.5%, respectively followed by MDS 29.0%. Given these facts, we emphasize that a greater interest in mycoses should be taken by clinicians, and immunocompromised patients should be protected from opportunistic invasive fungal infections, especially aspergillosis.