Med. Mycol. J. Med. Mycol. J. Vol. 55（No. 4） , 2014 Vol. 55E, E 63 − E 70, 2014 ISSN 2185 − 6486
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Case Report
Fatal Fungemia with Scedosporium prolificans in a Patient with Acute Myeloid Leukemia ઃ
ઃ
Makoto Nishimori , Toshio Takahashi , Eiko Suzuki , Taiichi Kodaka , ઃ ઃ ઃ અ Nobuhiro Hiramoto , Kiminari Itoh , Hiroko Tsunemine , Kyoko Yarita , અ આ ઃ Katsuhiko Kamei , Hiroshi Takegawa , Takayuki Takahashi
Departments of Hematology Shinko Hospital, Kobe Laboratory Medicine, Shinko Hospital, Kobe Medical Mycology Research Center, Chiba University, Chiba # Laboratory Medicine, Kobe City Medical Center General Hospital, Kobe
ABSTRACT Scedosporium prolificans（S. prolificans）is a type of mold, which rarely affects immunocompromised people. We treated a 71-year-old woman with acute myeloid leukemia（AML-M5a）with low-dose cytarabine, acralubicin, and filgrastim as the induction therapy. On day 7 after the initiation of chemotherapy, she became febrile and agranulocytic, and developed anal pain; therefore, we discontinued the chemotherapy on day 8. Broad-spectrum antibiotics, micafungin, and then liposomal amphotericin B were ineffective. The serum concentration of β-D-glucan was 525 pg/mL. She died of multiple organ failure on day 17. S. prolificans was detected from the blood culture on day 13. Physicians should consider Scedosporium spp. infection when principal antifungal agents are ineffective and fungal infection is strongly suspected. Key words：Scedosporium prolificans, acute myeloid leukemia, β-D-glucan, mold
Introduction Scedosporium species（spp.）are ubiquitous fungi, distributed in living environments such as polluted water and soil, and classified as ascomy1） cota in a group of molds . Scedosporium spp. consist of 2 species: Scedosporium prolificans（S. proloficans）and S. apiospermum. S. prolificans was first revealed to be pathogenic in 1984, although the incidence of infection is very low, with 1.33 affected cases per 100,000 people in the 1,2） United States . S. prolificans mostly affects immunocompromised people, such as patients 3） with hematologic diseases . Human infection often results from the inhalation of spores present in the environment into the lungs or paranasal Address for correspondence : Takayuki Takahashi Department of Hematology, Shinko Hospital Received : 30, December 2013, Accepted : 19, August 2014 [email protected]
sinuses, or through direct inoculation, such as in 4） skin puncture . S. prolificans-affected body regions include the blood, lungs, bones, and soft tissue, and S. prolificans disseminates to multiple organs in many cases. Although rare, S. prolificans infection often causes fatal disease; disseminated disease is particularly associated with a 5） high mortality rate of 87.5% , because active antifungal agents against S. prolificans are currently not available. Here, we report a patient with acute myeloid leukemia（AML）who developed fatal fungemia with S. prolificans during induction chemotherapy for AML.
Case report A 71-year-old woman with leukopenia was
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Medical Mycology Journal Volume 55, Number 4, 2014
Table 1．Laboratory findings on admission WBC Neu Eos Bas Mon Lym Blast RBC Hb Ht Plt Reti Fib PT aPTT D-dimer CRP MMP-3 IgA IgG IgM
Hematology 1.8×109/L 46.8% 0.0% 0.8% 1.6% 47.0% 2.8% 3,250×109/L 11.3 g/dL 32.6% 153×109/L 1.0% Coagulation 304 mg/dL 106% 32.3 sec 0.4μg/mL Serology 0.3 mg/dL 63.5 ng/mL 293 mg/dL 1,141 mg/dL 66 mg/dL
Chemistry TP Alb LDH
7.1 g/dL 4.2 g/dL 232 IU/L
AST ALT ALP T-bil BUN
26 IU/L 43 IU/L 191 IU/L 0.9 mg/dL 10.5 mg/dL 0.6 mg/dL
Cre UA Na K Cl
4.5 mg/dL 143 mEq/L 4.2 mEq/L 109 mEq/L
Bone marrow 2.2×104/mL Ncc Megakaryocytes Decreased M/E ratio 4.55 Blasts 31.3% POX （＋） ASD （−） α-NB （+） Karyotype 46, XX
MMP-3: matrix metalloproteinase-3（normally 17.3 to 59.7 ng/dL） ; POX: peroxidase staining; ASD: naphthol AS-D chloroacetate esterase staining; α-NB: α-naphthyl butyrate esterase staining.
admitted to our hospital because of suspected AML. Three years before admission, she had been diagnosed with rheumatoid arthritis（RA）and Sjögren> s syndrome. Two years before admission, she had been treated with tocilizumab（8 mg/kg, weekly）for the acute exacerbation of RA, with improvement of the disease. Two months before admission, she had developed leukopenia（white 9 cell count: 1.8×10 /L） . Therefore, tocilizumab was discontinued with persistent leukopenia, and a bone marrow aspirate led to suspected AML. Thus, she was referred to our hospital. Physical and physiological examinations on admission were unremarkable. Laboratory findings on admission are shown in Table 1. The white 9 blood cell（WBC）count was 1.8×10 /L, with 2.8% blast cells, 46.8% neutrophils, 1.6% monocytes, and 47.0% lymphocytes, a hemoglobin concentra9 tion of 11.3 g/dL, and platelet count of 153×10 /L. Serological tests revealed C-reactive protein （CRP）of 0.3 mg/dL（normally below 0.3 mg） , matrix metalloproteinase-3（MMP-3）of 63.5 ng/dL （normally 17.3 to 59.7 ng/dL）, IgA of 293 mg/dL （normally 110 to 410 mg）, IgG of 1,141 mg/dL
（normally 870 to 1,700 mg）, and IgM of 66 mg/dL （normally 46 to 260 mg） , suggesting well-controlled RA and intact humoral immunity. A bone marrow aspirate showed hypocellularity with a 9 nucleated cell count of 21.1×10 /L, in which blast cells comprised 31.1%. Some of these blast cells showed differentiation toward immature monocytes（Fig. 1A）and were positive for peroxidase and α-naphthyl butyrate esterase staining（Fig. 1B, 1C） . A diagnosis of AML-M5a according to the FAB classification was made. She had a history of tocilizumab therapy, and was thereby suggested to be in an immunocompromised state. We, therefore, employed CAG chemotherapy（low-dose cytarabine, acralubicin, and filgrastim）as remission induction therapy for AML. The clinical course of the patient is shown in Fig. 2. On day 7 after the initiation of CAG therapy, she developed anal pain due to an exacerbated hemorrhoid with fever above 38℃. The hemorrhoid was swollen, reddish, and partially erosive 9 and hemorrhagic. The WBC count was 0.5×10 /L wih 0% neutrophils. We administered tazobactam/piperacillin for the infectious hemorrhoid,
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Fig. 1．Smear preparation of a bone marrow aspirate on admission to our hospital. A: Many immature monocytes can be seen. A small number of these abnormal cells show monocytic maturation（arrow）（Wright-Giemsa staining, ×1,000） . These leukemic cells are positive for peroxidase staining（B） and α-naphthyl butyrate esterase staining（C） .
which brought about transient resolution of the fever. On day 8, we discontinued the CAG because of agranulocytosis and a clearly infectious portion of the painful hemorrhoid. On day 11, she again became febrile with a body temperature of 38℃ or higher; therefore, we added vancomycin for possible infection caused by methicillin-resistant Staphylococcus aureus. On day 12, blood culture yielded Enterococcus faecium which was
susceptible to vancomycin, while the culture of viscous fluid taken by swabbing from the erosive portion of the painful hemorrhoid yielded a negative result. On day 13, however, she became more febrile and developed frequent diarrhea with abdominal tenderness in addition to the anal pain. We, therefore, added micafungin for possible intestinal candidiasis presumably derived from the infectious hemorrhoid. On day 14, she had a
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Medical Mycology Journal Volume 55, Number 4, 2014
Anal pain Fever Peritoneal irritaon CAG
Neut −80 (%) −70
WBC (/μL) 5,000 4,000
−60 −50
3,000 2,000 WBC 1,000
䘩
Neut
−40 −30 −20 −10
CRP 40 (mg/dL) 30 20 10 5 TAZ/PIPC
10 VCM
15
17
MCFG MEPM L-AMB
Fig. 2． Clinical course of the present patient. CAG: cytarabine, acralubicin, and filgrastim; Neut: neutrophils; TAZ/PIPC: tazobactam/piperacillin; VCM: vancomycin; MCFG: micafungin; MEPM: meropenem; L-AMB: liposomal-amphotericin B.
persistently high fever with peritoneal irritation sign, and a laboratory test showed that the serum concentration of β-D-glucan had elevated to 525 pg/mL（normally below 11 pg/mL） . From this time-point, she became drowsy, with a progressive deterioration of consciousness. Although we subsequently obtained negative results from repeated blood cultures, we changed micafungin to liposomal amphotericin B and tazobactam/ piperacillin to meropenem for possible infections by micafungin-resistant fungi or multiple-drug-resistant bacteria, without improvement of her condition. She developed multiple organ failure and died on day 17. Autopsy was not performed. The day after her death, we received a report that a fungus had been grown from blood culture with a culture bottle（BACTEC Aerobic Plus, but not BACTEC Anaerobic Plus; Nippon Becton Dickinson Co., Ltd., Tokyo, Japan） , which was performed on day 13. The fungus was also grown from fecal culture performed on day 15, and blood cultures performed on days 14 and 15. Gram-stain-
ing of the pathogens from the blood culture is shown in Fig 3A. Morphologically, the fungus had mold-like features, although we could not identify the exact fungal species at that time. The growth pattern of the fungus in BD difco Potato Dextrose Agar（Nippon Becton Dickinson Co., Ltd., Tokyo, Japan）is shown in Fig. 3B. The color of the fungus colony was blackish to light brown, and it was covered with whitish filamentous organisms. On cellophane tape preparation, Scedosporium spp. was suspected because of the characteristic feature of the hyphae（Fig. 3C） . A few weeks later, this fungus was identified as S. prolificans by 6） rRNA sequence analysis , performed at the Medical Mycology Research Center, Chiba University, Chiba, Japan. An in vitro susceptibility 7） test of the isolated S. prolificans, performed at the Department of Laboratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan, showed the minimum inhibitory concentration（MIC）of amphotericin B, micafungin, voriconazole, fluconazole, itraconazole, miconazole,
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Med. Mycol. J. Vol. 55（No. 4） , 2014
Fig. 3 A: Gram-staining of the fungus grown from the blood culture, ×1,000. The smallest scale of the division is one micrometer. Morphologically, the fungus had mold-like features with developing hyphae（arrows） . B: The growth pattern of the fungus in BD difco Potato Dextrose Agar（Nippon Becton Dickinson Co., Ltd., Tokyo, Japan） . C: On cellophane tape preparation, the hyphae had a septum, and the conidium was ovum-shaped, slightly narrowing near the apex, which resulted in the formation of a small apical mass（lactophenol cotton blue staining, ×200） .
and flucytosine to be 4, ＞16, 8, ＞64, ＞8, ＞16, and ＞64μg/mL, respectively.
Discussion S. prolificans infection is rare, as previously described. However in the past 5 years, 16 cases 8−23） of S. prolificans infection have been reported . As shown in Table 2, the majority of these 16 patients were immunocompromised, having hema-
tologic diseases such as myeloid leukemia. These immunocompromised patients had a poor prognosis, while patients without hematologic or immunologic disorders had a favorable one, with 12, 23） the exception of 2 cases . Interestingly, one of these 2 patients was a drowning 5 victim in the tsunami of the Great East Japan Earthquake in 2011, indicating the presence of S. prolificans in muddy water or soil. In the present patient, we employed low-intensi-
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Table 2．Cases of Scedosporium prolificans infection in the literature during the past 5 years Case
1
Year of
Age/
report gender 2009
2
2009
3
2010
4
2010
5
2010
6
2011
7
2011
8
2011
9
2012
10
2013
11
2013
12
2013
13
2013
14
2011
15
2010
16
2012
present case
35, male 62, female
Clinical background
Fungal infection
Antifungal agents
nonspecific
epidural abscess
terbinafine,
nonspecific
female leukemia 50,
rheumatic fever in
male
childhood
29,
acute lymphoblastic
female leukemia 70, acute myeloid leukemia
55,
nonspecific female 83, myelodysplastic 10, male 35,
syndrome nonspecific acute myeloblastic
female leukemia 70,
intervertebral disc
post-lung
fungemia
voriconazole
58,
MGUS
female 71,
9
improvement
10
death
11
amphotericin B
death
12
liposomal amphotericin B improvement posaconazole, death caspofungin
fungemia
debridement,
keratitis
death
16
marked improvement
17
death
18
death
19
well-controlled
20
death
21
micafungin
death
22
fosfluconazole
death
23
voriconazole voriconazole,
fungemia
terbinafine
pericarditis, aortic
14 15
micafungin
osteomyelitis
13
cure
ketoconazole voriconazole,
fungemia
death after partial
voriconazole, terbinafine, and caspofungin voriconazole,
angioinvasion
terbinafine itraconazole,
lung
liposomal amphotericin B, voliconazole
acute myeloid
female leukemia 33,
cure
voriconazole,
multiple focal
male
8
fungemia
44,
58,
transient improvement
endocarditis,
aneurysm
lung cancer
terbinafine liposomal
fungemia
female transplantation
male
No.
and voriconazole
voriconazole, post-cardiac ocular and fungemia terbinafine female transplantation 28, acute undifferentiated pseudoaneurysm, voriconazole,
male
Ref.
caspofungin,
38,
male
Outcome
administered
fungemia lung: Tsunami
nonspecific
following Japan Earthquake
acute myeloid
female leukemia
micafungin,
fungemia
liposomal amphotericin B
death
MGUS: Monoclonal gammopathy with undetermined significance.
ty chemotherapy（CAG chemotherapy）under the assumption that she was potentially immunocompromised because of her history of tocilizumub therapy for RA. Nevertheless, she became agranulocytic on day 7 after the initiation of CAG chemotherapy, and subsequently developed bacteremia with Enterococcus faecium and finally fungemia with S. prolificans. This clinical course is quite exceptional with induction chemotherapy for AML with a low-intensity protocol. Regarding tocilizumab therapy for RA, a large cohort study in 24） Japan was published . In this report, the most
common adverse events were infections, including bacterial pneumonia, sepsis, and viral infection, indicating that RA patients treated with tocilizumab have a risk of infections. Furthermore, 3 risk factors were identified: a history of lung disease, prednisolone administration at 5 mg/day or more, and an age of 65 or older. Although the present patient had 2 of these 3 risk factors, it is difficult to fully explain her unfavorable clinical course with the risk of infection by tocilizumab. We performed antibiotic and antifungal therapies according to guidelines for febrile neut-
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Med. Mycol. J. Vol. 55（No. 4） , 2014
Table 3．In vivo activity of antifungal agents against Scedosporium spp. S. prolificans
Drug
In vivo activity Amphotericin B − Miconazole − Fluconazole − Itraconazole − Voriconazole ± Posaconazole − Ravuconazole − Albaconazole ± Terbinafine − Micafungin Caspofungin −
S. apiospermum
MIC（90％） ＞16（16-＞16）
In vivo activity − ＞16-64 − ＞16 − ＞16（＞16-＞32） − 4（4-16） + ＞8-16 + ＞8-16 + 2-4 + 16-32 − ＞32 − NA −
MIC（90％） 16（16-＞16） 1（0.5-2） 32（＞16-＞64） 4（1-＞16） 0.5（0.125-2） 2（0.25-2） 4（0.125-＞8） 1-2 ＞32-＞16 ＞16 NA
Susceptibility of Scedosporium spp. to antifungal agents is shown as + to -. Data were collected from the literature on Scedosporium spp. infection. MIC: minimum inhibitory concentration. NA: not available. Each MIC value is indicated in mg/ml and was cited from the article of reference No.26.
25）
ropenia（FN）treatment . However, the timing of the β-D-glucan test may have been too late（on day 14）,although we had already started micafungin on day 13. The test of β-D-glucan is useful to predict fungal infection and determine the timing of antifungal treatment. Indeed, a high serum concentration of β-D-glucan was reported in 3 16,21,23） cases of S. prolificans infection , as well as in the present patient. Regarding the route or origin of S. prolificans infection in the present patient, the infectious hemorrhoid is a possibility because the anal pain persisted throughout the course with fever, although S. prolificans was not detected on culture of the swollen and erosive hemorrhoid. Aside from the origin of S. prolificans infection, S. prolificans might have emerged as a microbial substitute after the treatment for bacteremia with vancomycin-susceptible Enterococcus faecium. As for the treatment of S. prolificans infection, few effective anti-fungal agents are currently available when compared to those for S. apiospermumas, as shown in Table 3. However, voriconazole may be useful in some cases of S. prolificans infection based on its minimum inhibitory concentration（MIC）against S. prolificans. Furthermore, the combination of voriconazole and terbinafine has been widely used and brought about favorable outcomes for immunocompetent but not immunocompromised patients, as shown in Table 2. Indeed, in an in vitro study, the combination of terbinafine and azole antifungal agents or that of amphotericin B and pentamidine exhibited some
26）
activities against S. prolificans . Therefore, the identification of an effective combination of antifungal agents using a checkerboard titration 26） method may be useful. Furthermore, the early diagnosis of S. prolificans infection and prompt initiation of effective antifungal treatment including voriconazole, either as monotherapy or combination therapy, appear to be crucial for immunocompromised patients.
Disclosure The authors have no conflict of interest to disclose.
References 1）Malloch D, Salkin IF: A new species of Scedosporium associated with osteomyelitis in humans. Mycotaxon 21: 247-255, 1984. 2）Lamaris GA, Chamilos G, Lewis RE, Safdar A, Raad II, Kontoyiannis DP: Scedosporium Infection in a Tertiary Care Cancer Center: A Review of 25 Cases from 1989-2006. Clin Infect Dis 43: 1580-1584, 2006. 3）Maertens J, Lagrou K, Deweerdt H, Surmont I, Verhoef GE, Verhaegen J, Boogaerts MA: Disseminated infection by Scedosporium prolificans: an emerging fatality among haematology patients. Case report and review. Ann Hematol 79: 340-344, 2000. 4）Wilson CM, O> Rourke EJ, McGinnis MR, Salkin IF: Scedosporium inflatum: clinical spectrum of a newly recognized pathogen. J Infect Dis 161: 102107, 1990.
E 70 5）Rodriguez-Tudela JL, Berenguer J, Guarro J, Kantarcioglu AS, Horre R, de Hoog GS, CuencaEstrella M: Epidemiology and outcome of Scedosporium prolificans infection, a review of 162 cases. Med Mycol 47: 359-370, 2009. 6）Wedde M, Müller D, Tintelnot K, De Hoog GS, Stahl U: PCR-based identification of clinically relevant Pseudallescheria/Scedosporium strains. Med Mycol 36: 61-67, 1998. 7）National committee for clinical laboratory standards: In Reference method for broth dilution antifungal susceptibility testing of filamentous fungi: Approved standard M38-A2, Vol. 28, CLSI, Wayne, 2008. 8）Carod-Artal FJ, Ferreira-Coral L, Mauro-Couto J, Gomes-E, de Agassiz-Vasques M: Chronic spinal epidural abscess caused by Scedosporium prolificans in an immunocompetent patient. Spine（Phila Pa 1976）34: E330-332, 2009. 9）Garcia-Vidal C, Cabellos C, Ayats J, Font F, Ferran E, Fernandez-Viladrich P: Fungal postoperative spondylodiscitis due to Scedosporium prolificans. Spine J 9: e1-7, 2009. 10）O> Hearn TM, Geiseler PJ, Bhatti RA, Dean E: Control of disseminated Scedosporium prolificans Infection and endophthalmitis. Retinal Cases & Brief Reports 4: 18-19, 2010. 11）Spanevello M, Morris KL, Kennedy GA: Pseudoaneurysm formation by Scedosporium prolificans infection in acute leukaemia. Intern Med J 40: 793, 2010. 12）Ahmad S, Zia S, Sarwari AR: Scedosporium prolificans Endocarditis: Case report and review of literature. W V Med J 106: 24-26, 2010. 13）Fernandez Guerrero ML, Askari E, Prieto E, Gadea I, Román A: Emerging infectious endocarditis due to Scedosporium prolificans: a model of therapeutic complexity. Eur J Clin Microbiol Infect Dis 30: 1321-1324, 2011. 14）Rivier A, Perny J, Debourgogne A, Thivillier C, Lévy B, Gérard A, Machouart M: Fatal disseminated infection due to Scedosporium prolificans in a patient with acute myeloid leukemia and posaconazole prophylaxis. Leuk Lymphoma 52: 1607-1610, 2011. 15）Chandel LR, Sood A, Chauhan S, Thakur K: Need to suspect fungal etiology in presumed bacterial karatitis−A case report of keratitis due to Scedosporium prolificans. Asian Journal of Medical Sciences 2: 28-30, 2011. 16）Nishio H, Utsumi T, Nakamura Y, Suzuki T, Kamei K, Saitoh T: Fungemia caused by Scedosporium prolificans in myelodysplasstic syndrome. The Journal of the Japanese Association for Infectious Diseases 86: 22-26, 2012. 17）Matlani M, Kaur R, Shweta: A case of Scedosporium prolificans osteomyelitis in an immunocompetent child, misdiagnosed as tubercular osteomyelitis. Indian J Dermatol 58: 80-81, 2013. 18）Reinoso R, Carreño E, Hileeto D, Corell A, Pastor
Medical Mycology Journal Volume 55, Number 4, 2014
JC, Cabrero M, Vázquez L, Calonge M: Fatal disseminated Scedosporium prolificans infection initiated by ophthalmic involvement in a patient with acute myeloblastic leukemia. Diagn Microbiol Infect Dis 76: 375-378, 2013. 19）Sayah DM, Schwartz BS, Kukreja J, Singer JP, Golden JA, Leard LE: Scedosporium prolificans pericarditis and mycotic aortic aneurysm in a lung transplant recipient receiving voriconazole prophylaxis. Transpl Infect Dis 15: E70-74, 2013. 20）Holmes NE, Trevillyan JM, Kidd SE, Leong TY.-M: Locally extensive angio-invasive Scedosporium prolificans infection following resection for squamous cell lung carcinoma. Medical Mycology Case Report 2: 98-102, 2013. 21）Ohashi R, Kato M, Katsura Y, Takekawa H, Hoshika Y, Sugawara T, Yoshimi K, Togo S, Nagaoka T, Seyama K, Takahashi K, Tsuchiya K, Misawa S, Kikuchi K: Breakthrough lung Scedosporium prolificans infection with multiple cavity lesions in a patient receiving voriconazole for probable invasive aspergillosis associated with monoclonal gammopathy of undetermined significance（MGUS） . Med Mycol J 52: 33-38, 2011. 22）Kimura M, Maenishi O, Ito H, Ohkusu K: Unique histological characteristics of Scedosporium that could aid in its identification. Pathol Int 60: 131-136, 2010. 23）Hatakeyama Y, Yamada Y, Furukawa K, Narita K, Ishifuji K, Kurota M, Kon H, Yarita K, Kamei K, Suwabe A: Three Cases of Tsunami Lung in which Genus Scedosporium was isolated. The Journal of Japanese Society for Clinical Microbiology 22: 289-297, 2012. 24）Koike T, Harigai M, Inokuma S, Ishiguro N, Ryu J, Takeuchi T, Takei S, Tanaka Y, Ito K, Yamanaka H: Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: interim analysis of 3881 patients. Ann Rheum Dis 70: 2148-2151, 2011. 25）Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad II, Rolston KV, Young JA, Wingard JR: Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of America. Clin Infect Dis 52: e56e93, 2011. 26）Husain S, Muñoz 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: 8999, 2005. 27）Cortez KJ, Roilides E, Quiroz-Telles F, Meletiadis J, Antachopoulos C, Knudsen T, Buchanan W, Milanovich J, Sutton DA, Fothergill A, Rinaldi MG, Shea YR, Zaoutis T, Kottilil S, Walsh TJ: Infections caused by Scedosporium spp. Clin Microbiol Rev 21: 157-197, 2008.
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Case Report
Fatal Fungemia with Scedosporium prolificans in a Patient with Acute Myeloid Leukemia ઃ
ઃ
Makoto Nishimori , Toshio Takahashi , Eiko Suzuki , Taiichi Kodaka , ઃ ઃ ઃ અ Nobuhiro Hiramoto , Kiminari Itoh , Hiroko Tsunemine , Kyoko Yarita , અ આ ઃ Katsuhiko Kamei , Hiroshi Takegawa , Takayuki Takahashi
Departments of Hematology Shinko Hospital, Kobe Laboratory Medicine, Shinko Hospital, Kobe Medical Mycology Research Center, Chiba University, Chiba # Laboratory Medicine, Kobe City Medical Center General Hospital, Kobe
ABSTRACT Scedosporium prolificans（S. prolificans）is a type of mold, which rarely affects immunocompromised people. We treated a 71-year-old woman with acute myeloid leukemia（AML-M5a）with low-dose cytarabine, acralubicin, and filgrastim as the induction therapy. On day 7 after the initiation of chemotherapy, she became febrile and agranulocytic, and developed anal pain; therefore, we discontinued the chemotherapy on day 8. Broad-spectrum antibiotics, micafungin, and then liposomal amphotericin B were ineffective. The serum concentration of β-D-glucan was 525 pg/mL. She died of multiple organ failure on day 17. S. prolificans was detected from the blood culture on day 13. Physicians should consider Scedosporium spp. infection when principal antifungal agents are ineffective and fungal infection is strongly suspected. Key words：Scedosporium prolificans, acute myeloid leukemia, β-D-glucan, mold
Introduction Scedosporium species（spp.）are ubiquitous fungi, distributed in living environments such as polluted water and soil, and classified as ascomy1） cota in a group of molds . Scedosporium spp. consist of 2 species: Scedosporium prolificans（S. proloficans）and S. apiospermum. S. prolificans was first revealed to be pathogenic in 1984, although the incidence of infection is very low, with 1.33 affected cases per 100,000 people in the 1,2） United States . S. prolificans mostly affects immunocompromised people, such as patients 3） with hematologic diseases . Human infection often results from the inhalation of spores present in the environment into the lungs or paranasal Address for correspondence : Takayuki Takahashi Department of Hematology, Shinko Hospital Received : 30, December 2013, Accepted : 19, August 2014 [email protected]
sinuses, or through direct inoculation, such as in 4） skin puncture . S. prolificans-affected body regions include the blood, lungs, bones, and soft tissue, and S. prolificans disseminates to multiple organs in many cases. Although rare, S. prolificans infection often causes fatal disease; disseminated disease is particularly associated with a 5） high mortality rate of 87.5% , because active antifungal agents against S. prolificans are currently not available. Here, we report a patient with acute myeloid leukemia（AML）who developed fatal fungemia with S. prolificans during induction chemotherapy for AML.
Case report A 71-year-old woman with leukopenia was
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Medical Mycology Journal Volume 55, Number 4, 2014
Table 1．Laboratory findings on admission WBC Neu Eos Bas Mon Lym Blast RBC Hb Ht Plt Reti Fib PT aPTT D-dimer CRP MMP-3 IgA IgG IgM
Hematology 1.8×109/L 46.8% 0.0% 0.8% 1.6% 47.0% 2.8% 3,250×109/L 11.3 g/dL 32.6% 153×109/L 1.0% Coagulation 304 mg/dL 106% 32.3 sec 0.4μg/mL Serology 0.3 mg/dL 63.5 ng/mL 293 mg/dL 1,141 mg/dL 66 mg/dL
Chemistry TP Alb LDH
7.1 g/dL 4.2 g/dL 232 IU/L
AST ALT ALP T-bil BUN
26 IU/L 43 IU/L 191 IU/L 0.9 mg/dL 10.5 mg/dL 0.6 mg/dL
Cre UA Na K Cl
4.5 mg/dL 143 mEq/L 4.2 mEq/L 109 mEq/L
Bone marrow 2.2×104/mL Ncc Megakaryocytes Decreased M/E ratio 4.55 Blasts 31.3% POX （＋） ASD （−） α-NB （+） Karyotype 46, XX
MMP-3: matrix metalloproteinase-3（normally 17.3 to 59.7 ng/dL） ; POX: peroxidase staining; ASD: naphthol AS-D chloroacetate esterase staining; α-NB: α-naphthyl butyrate esterase staining.
admitted to our hospital because of suspected AML. Three years before admission, she had been diagnosed with rheumatoid arthritis（RA）and Sjögren> s syndrome. Two years before admission, she had been treated with tocilizumab（8 mg/kg, weekly）for the acute exacerbation of RA, with improvement of the disease. Two months before admission, she had developed leukopenia（white 9 cell count: 1.8×10 /L） . Therefore, tocilizumab was discontinued with persistent leukopenia, and a bone marrow aspirate led to suspected AML. Thus, she was referred to our hospital. Physical and physiological examinations on admission were unremarkable. Laboratory findings on admission are shown in Table 1. The white 9 blood cell（WBC）count was 1.8×10 /L, with 2.8% blast cells, 46.8% neutrophils, 1.6% monocytes, and 47.0% lymphocytes, a hemoglobin concentra9 tion of 11.3 g/dL, and platelet count of 153×10 /L. Serological tests revealed C-reactive protein （CRP）of 0.3 mg/dL（normally below 0.3 mg） , matrix metalloproteinase-3（MMP-3）of 63.5 ng/dL （normally 17.3 to 59.7 ng/dL）, IgA of 293 mg/dL （normally 110 to 410 mg）, IgG of 1,141 mg/dL
（normally 870 to 1,700 mg）, and IgM of 66 mg/dL （normally 46 to 260 mg） , suggesting well-controlled RA and intact humoral immunity. A bone marrow aspirate showed hypocellularity with a 9 nucleated cell count of 21.1×10 /L, in which blast cells comprised 31.1%. Some of these blast cells showed differentiation toward immature monocytes（Fig. 1A）and were positive for peroxidase and α-naphthyl butyrate esterase staining（Fig. 1B, 1C） . A diagnosis of AML-M5a according to the FAB classification was made. She had a history of tocilizumab therapy, and was thereby suggested to be in an immunocompromised state. We, therefore, employed CAG chemotherapy（low-dose cytarabine, acralubicin, and filgrastim）as remission induction therapy for AML. The clinical course of the patient is shown in Fig. 2. On day 7 after the initiation of CAG therapy, she developed anal pain due to an exacerbated hemorrhoid with fever above 38℃. The hemorrhoid was swollen, reddish, and partially erosive 9 and hemorrhagic. The WBC count was 0.5×10 /L wih 0% neutrophils. We administered tazobactam/piperacillin for the infectious hemorrhoid,
Med. Mycol. J. Vol. 55（No. 4） , 2014
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Fig. 1．Smear preparation of a bone marrow aspirate on admission to our hospital. A: Many immature monocytes can be seen. A small number of these abnormal cells show monocytic maturation（arrow）（Wright-Giemsa staining, ×1,000） . These leukemic cells are positive for peroxidase staining（B） and α-naphthyl butyrate esterase staining（C） .
which brought about transient resolution of the fever. On day 8, we discontinued the CAG because of agranulocytosis and a clearly infectious portion of the painful hemorrhoid. On day 11, she again became febrile with a body temperature of 38℃ or higher; therefore, we added vancomycin for possible infection caused by methicillin-resistant Staphylococcus aureus. On day 12, blood culture yielded Enterococcus faecium which was
susceptible to vancomycin, while the culture of viscous fluid taken by swabbing from the erosive portion of the painful hemorrhoid yielded a negative result. On day 13, however, she became more febrile and developed frequent diarrhea with abdominal tenderness in addition to the anal pain. We, therefore, added micafungin for possible intestinal candidiasis presumably derived from the infectious hemorrhoid. On day 14, she had a
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Anal pain Fever Peritoneal irritaon CAG
Neut −80 (%) −70
WBC (/μL) 5,000 4,000
−60 −50
3,000 2,000 WBC 1,000
䘩
Neut
−40 −30 −20 −10
CRP 40 (mg/dL) 30 20 10 5 TAZ/PIPC
10 VCM
15
17
MCFG MEPM L-AMB
Fig. 2． Clinical course of the present patient. CAG: cytarabine, acralubicin, and filgrastim; Neut: neutrophils; TAZ/PIPC: tazobactam/piperacillin; VCM: vancomycin; MCFG: micafungin; MEPM: meropenem; L-AMB: liposomal-amphotericin B.
persistently high fever with peritoneal irritation sign, and a laboratory test showed that the serum concentration of β-D-glucan had elevated to 525 pg/mL（normally below 11 pg/mL） . From this time-point, she became drowsy, with a progressive deterioration of consciousness. Although we subsequently obtained negative results from repeated blood cultures, we changed micafungin to liposomal amphotericin B and tazobactam/ piperacillin to meropenem for possible infections by micafungin-resistant fungi or multiple-drug-resistant bacteria, without improvement of her condition. She developed multiple organ failure and died on day 17. Autopsy was not performed. The day after her death, we received a report that a fungus had been grown from blood culture with a culture bottle（BACTEC Aerobic Plus, but not BACTEC Anaerobic Plus; Nippon Becton Dickinson Co., Ltd., Tokyo, Japan） , which was performed on day 13. The fungus was also grown from fecal culture performed on day 15, and blood cultures performed on days 14 and 15. Gram-stain-
ing of the pathogens from the blood culture is shown in Fig 3A. Morphologically, the fungus had mold-like features, although we could not identify the exact fungal species at that time. The growth pattern of the fungus in BD difco Potato Dextrose Agar（Nippon Becton Dickinson Co., Ltd., Tokyo, Japan）is shown in Fig. 3B. The color of the fungus colony was blackish to light brown, and it was covered with whitish filamentous organisms. On cellophane tape preparation, Scedosporium spp. was suspected because of the characteristic feature of the hyphae（Fig. 3C） . A few weeks later, this fungus was identified as S. prolificans by 6） rRNA sequence analysis , performed at the Medical Mycology Research Center, Chiba University, Chiba, Japan. An in vitro susceptibility 7） test of the isolated S. prolificans, performed at the Department of Laboratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan, showed the minimum inhibitory concentration（MIC）of amphotericin B, micafungin, voriconazole, fluconazole, itraconazole, miconazole,
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Fig. 3 A: Gram-staining of the fungus grown from the blood culture, ×1,000. The smallest scale of the division is one micrometer. Morphologically, the fungus had mold-like features with developing hyphae（arrows） . B: The growth pattern of the fungus in BD difco Potato Dextrose Agar（Nippon Becton Dickinson Co., Ltd., Tokyo, Japan） . C: On cellophane tape preparation, the hyphae had a septum, and the conidium was ovum-shaped, slightly narrowing near the apex, which resulted in the formation of a small apical mass（lactophenol cotton blue staining, ×200） .
and flucytosine to be 4, ＞16, 8, ＞64, ＞8, ＞16, and ＞64μg/mL, respectively.
Discussion S. prolificans infection is rare, as previously described. However in the past 5 years, 16 cases 8−23） of S. prolificans infection have been reported . As shown in Table 2, the majority of these 16 patients were immunocompromised, having hema-
tologic diseases such as myeloid leukemia. These immunocompromised patients had a poor prognosis, while patients without hematologic or immunologic disorders had a favorable one, with 12, 23） the exception of 2 cases . Interestingly, one of these 2 patients was a drowning 5 victim in the tsunami of the Great East Japan Earthquake in 2011, indicating the presence of S. prolificans in muddy water or soil. In the present patient, we employed low-intensi-
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Table 2．Cases of Scedosporium prolificans infection in the literature during the past 5 years Case
1
Year of
Age/
report gender 2009
2
2009
3
2010
4
2010
5
2010
6
2011
7
2011
8
2011
9
2012
10
2013
11
2013
12
2013
13
2013
14
2011
15
2010
16
2012
present case
35, male 62, female
Clinical background
Fungal infection
Antifungal agents
nonspecific
epidural abscess
terbinafine,
nonspecific
female leukemia 50,
rheumatic fever in
male
childhood
29,
acute lymphoblastic
female leukemia 70, acute myeloid leukemia
55,
nonspecific female 83, myelodysplastic 10, male 35,
syndrome nonspecific acute myeloblastic
female leukemia 70,
intervertebral disc
post-lung
fungemia
voriconazole
58,
MGUS
female 71,
9
improvement
10
death
11
amphotericin B
death
12
liposomal amphotericin B improvement posaconazole, death caspofungin
fungemia
debridement,
keratitis
death
16
marked improvement
17
death
18
death
19
well-controlled
20
death
21
micafungin
death
22
fosfluconazole
death
23
voriconazole voriconazole,
fungemia
terbinafine
pericarditis, aortic
14 15
micafungin
osteomyelitis
13
cure
ketoconazole voriconazole,
fungemia
death after partial
voriconazole, terbinafine, and caspofungin voriconazole,
angioinvasion
terbinafine itraconazole,
lung
liposomal amphotericin B, voliconazole
acute myeloid
female leukemia 33,
cure
voriconazole,
multiple focal
male
8
fungemia
44,
58,
transient improvement
endocarditis,
aneurysm
lung cancer
terbinafine liposomal
fungemia
female transplantation
male
No.
and voriconazole
voriconazole, post-cardiac ocular and fungemia terbinafine female transplantation 28, acute undifferentiated pseudoaneurysm, voriconazole,
male
Ref.
caspofungin,
38,
male
Outcome
administered
fungemia lung: Tsunami
nonspecific
following Japan Earthquake
acute myeloid
female leukemia
micafungin,
fungemia
liposomal amphotericin B
death
MGUS: Monoclonal gammopathy with undetermined significance.
ty chemotherapy（CAG chemotherapy）under the assumption that she was potentially immunocompromised because of her history of tocilizumub therapy for RA. Nevertheless, she became agranulocytic on day 7 after the initiation of CAG chemotherapy, and subsequently developed bacteremia with Enterococcus faecium and finally fungemia with S. prolificans. This clinical course is quite exceptional with induction chemotherapy for AML with a low-intensity protocol. Regarding tocilizumab therapy for RA, a large cohort study in 24） Japan was published . In this report, the most
common adverse events were infections, including bacterial pneumonia, sepsis, and viral infection, indicating that RA patients treated with tocilizumab have a risk of infections. Furthermore, 3 risk factors were identified: a history of lung disease, prednisolone administration at 5 mg/day or more, and an age of 65 or older. Although the present patient had 2 of these 3 risk factors, it is difficult to fully explain her unfavorable clinical course with the risk of infection by tocilizumab. We performed antibiotic and antifungal therapies according to guidelines for febrile neut-
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Table 3．In vivo activity of antifungal agents against Scedosporium spp. S. prolificans
Drug
In vivo activity Amphotericin B − Miconazole − Fluconazole − Itraconazole − Voriconazole ± Posaconazole − Ravuconazole − Albaconazole ± Terbinafine − Micafungin Caspofungin −
S. apiospermum
MIC（90％） ＞16（16-＞16）
In vivo activity − ＞16-64 − ＞16 − ＞16（＞16-＞32） − 4（4-16） + ＞8-16 + ＞8-16 + 2-4 + 16-32 − ＞32 − NA −
MIC（90％） 16（16-＞16） 1（0.5-2） 32（＞16-＞64） 4（1-＞16） 0.5（0.125-2） 2（0.25-2） 4（0.125-＞8） 1-2 ＞32-＞16 ＞16 NA
Susceptibility of Scedosporium spp. to antifungal agents is shown as + to -. Data were collected from the literature on Scedosporium spp. infection. MIC: minimum inhibitory concentration. NA: not available. Each MIC value is indicated in mg/ml and was cited from the article of reference No.26.
25）
ropenia（FN）treatment . However, the timing of the β-D-glucan test may have been too late（on day 14）,although we had already started micafungin on day 13. The test of β-D-glucan is useful to predict fungal infection and determine the timing of antifungal treatment. Indeed, a high serum concentration of β-D-glucan was reported in 3 16,21,23） cases of S. prolificans infection , as well as in the present patient. Regarding the route or origin of S. prolificans infection in the present patient, the infectious hemorrhoid is a possibility because the anal pain persisted throughout the course with fever, although S. prolificans was not detected on culture of the swollen and erosive hemorrhoid. Aside from the origin of S. prolificans infection, S. prolificans might have emerged as a microbial substitute after the treatment for bacteremia with vancomycin-susceptible Enterococcus faecium. As for the treatment of S. prolificans infection, few effective anti-fungal agents are currently available when compared to those for S. apiospermumas, as shown in Table 3. However, voriconazole may be useful in some cases of S. prolificans infection based on its minimum inhibitory concentration（MIC）against S. prolificans. Furthermore, the combination of voriconazole and terbinafine has been widely used and brought about favorable outcomes for immunocompetent but not immunocompromised patients, as shown in Table 2. Indeed, in an in vitro study, the combination of terbinafine and azole antifungal agents or that of amphotericin B and pentamidine exhibited some
26）
activities against S. prolificans . Therefore, the identification of an effective combination of antifungal agents using a checkerboard titration 26） method may be useful. Furthermore, the early diagnosis of S. prolificans infection and prompt initiation of effective antifungal treatment including voriconazole, either as monotherapy or combination therapy, appear to be crucial for immunocompromised patients.
Disclosure The authors have no conflict of interest to disclose.
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