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  1. 1. □ CASE REPORT □ Deep Skin Infection of Scedosporium apiospermum in a Patient with Refractory Idiopathic Thrombocytopenic Purpura Makoto Takeuchi 1, Chikamasa Yoshida 1, Yusuke Ota 2 and Yutaka Fujiwara 3 Abstract Infection of Scedosporium apiospermum is very rare but is now emerging as an important cause of both localized and disseminated infections in immunocompromised patients. A 62-year-old woman, who had un- dergone steroid therapy for refractory idiopathic thrombocytopenic purpura and had a history of diffuse large B cell lymphoma, developed a deep skin ulcer complicated with lymphangitis. After culture study demon- strated the presence of S. apiospermum, voriconazole (VRCZ) was administered and prompt improvement was observed. Because it is difficult to distinguish S. apiospermum from Aspergillus by histopathology and S. apiospermum is resistant to amphotericin B, VRCZ should be selected as the first choice of antifungal agent when mold is considered to be the causative organism. Key words: Scedosporium apiospermum, deep skin infection, voriconazole, idiopathic thrombocytopenic pur- pura, steroid (Intern Med 50: 1339-1343, 2011) (DOI: 10.2169/internalmedicine.50.4890) disregarded as a pathogen. Introduction We report deep skin infection of S. apiospermum extend- ing lymphangitis which developed in a patient with refrac- Scedosporium apiospermum is the asexual anamorph of tory idiopathic thrombocytopenic purpura (ITP) complicatedthe cosmopolitan fungus Pseudallescheria boydii. The or- with remission state of diffuse large B cell lymphomaganism is ubiquitous and has been isolated from a variety of (DLBCL). The infection developed after autologous periph-natural substances such as farm soil and stream water (1). eral blood stem cell transplantation (PBSCT) and was suc-Although the incidence of infection of S. apiospermum is cessfully treated with voriconazole (VRCZ) before the de-very low, it had been recognized as a pathogen of localized velopment of disseminated infection.deep skin infection (mycetoma) after injury. Most reportedpatients were in an immunocompromised state but some Case Reportcases that developed in immunocompetent patients have alsobeen described (2, 3). Recently, the infection of S. apiosper- A 62-year-old woman was admitted because of deteriorat-mum has emerged as an important cause of disseminated in- ing bleeding tendency due to refractory and recurrent ITP infection in severely immunocompromised patients, especially August 2009. She had a history of recurrent ITP andorgan transplant recipients, and the prognosis of these inva- DLBCL. Her onset of ITP was in 1996. After the diagnosissive infections is poor (4-6). Furthermore, deep organ infec- of ITP, she underwent steroid therapy, resulting in remission.tions in immunologically normal patients have also been re- However, she experienced several relapses thereafter. Inported (7, 8), indicating that this organism should not be 2006, she underwent a splenectomy, which resulted in re-1 Division of Hematology, National Hospital Organization Minami-Okayama Medical Center, Japan, 2Division of Orthopedics, National HospitalOrganization Minami-Okayama Medical Center, Japan and 3Division of Dermatology, National Hospital Organization Minami-Okayama MedicalCenter, JapanReceived for publication November 23, 2010; Accepted for publication January 19, 2011Correspondence to Dr. Makoto Takeuchi, takeuchim@s-okayama.hosp.go.jp 1339
  2. 2. Intern Med 50: 1339-1343, 2011 DOI: 10.2169/internalmedicine.50.4890 Figure 1. A. At the onset of skin lesion. B. Before administration of voriconazole (VRCZ). C. 4 weeks after administration of VRCZ. D. 6 weeks after administration of VRCZmission. In November 2007, systemic lymphadenopathy de- was 3,999/μL (neutrophil 72%, lymphocyte 19% and mono-veloped. She was diagnosed as DLBCL stage III; IPI, high cyte 9%), platelet count was 1.0×104/μL and mild liver dam-intermediate risk. She received 6 cycles of R-CHOP [Rituxi- age (asparate aminotransferase 55 IU/L, alanine aminotrans-mab, cyclophosphamide, adriamycin, vincristine, predniso- ferase 158 IU/L) was observed. C-reactive protein was 0.06lone (PSL)] regimen followed by high-dose chemotherapy mg/dL and the titer of beta-D-glucan was 116 pg/mL. Aswith autologous PBSCT in June 2008, resulting in complete mold was found in the smear of the exudate from the lesion,remission. oral Itraconazol (ITCZ) (200 mg/day) was applied. However, In June 2009, ITP relapsed. Her platelet count was below the lesion worsened and a nodular lymphangitic pattern of1×104/μL. She received oral PSL (0.5 mg/kg daily), which spread was observed in the flexor side of the right upperresulted in no response. In August 2009, Rituximab was ad- limb, suggesting lymphangitic extension. Skin biopsy speci-ministered with a dose of 375 mg/m2 weekly 4 times. How- men demonstrated mold with separate and branching hyphaeever, no response was observed. Furthermore, thrombocy- in the subcutaneous lesion (Fig. 2).topenia did not respond to high-dose gamma globulin ther- Gray colonies of mould grew upon the culture examina-apy. Then, she was treated again with PSL (1 mg/m2) and tion of the exudate and we identified the pathogen as Sce-danazol. During the above period, she suffered from gastro- dosporium apiospermum by morphological characterizationintestinal bleeding and Pneumocystis jiroveci pneumonia and (Fig. 3). Then, we administered oral VRCZ with a dailyrequired insulin therapy owing to steroid-induced hypergly- dose of 400 mg with a loading dose of 600 mg on the in-cemia. itial day and performed pus drainage by finger compression In October, erythema with pustules was observed on the twice every day. Promptly, decreased discharge was noted.dorsal surface of her right first finger. Although she had a Formation of regenerating epidermis was observed after 2history of a slight injury at the site 4 months previously on weeks of VRCZ administration. Normal epidermis recovereda farm, the abnormality of the site was not recognized until within 2 months (Fig. 1C, D). Furthermore, probably be-then. This lesion deteriorated rapidly and deep ulceration de- cause of the effect of danazol, her platelet counts were ele-veloped in spite of antibiotics therapy (Fig. 1A, B). At that vated to a normal level. VRCZ was continued for 2 monthstime, she did not have a fever. Her white blood cell count and her skin lesion became covered with normal epidermis 1340
  3. 3. Intern Med 50: 1339-1343, 2011 DOI: 10.2169/internalmedicine.50.4890 Figure 2. Periodic acid-Schiff (PAS)-stained skin biopsy section (A ×200, B ×1000). Mold with ob- vious septate and branching hyphae was observed subcutaneously. Figure 3. Culture examination. A. CHROMagar candida culture (left); blood-agar culture (right). Cultures for fungus of fluid from skin ulcer were performed and yielded white cottony colonies. B. ×400 Lactophenol cotton-blue stain. Mold with cylindrical conidia and adjacent hyphae character- ized by thin, separate branches at acute angles. The hyphae bear an ovoid annelloconidium of scedo- sporium type.without recurrence. Italy. They collected a total of 542 proven/probable mold in- fections among 8,633 patients with acute leukemia. Among Discussion all mold infections, only 5 cases (0.9%) of proven sce- dosporiosis were diagnosed, with an incidence of 0.08% in In a surveillance study in Australia (9), 180 identified all acute leukemia patients. S. apiospermum was responsiblecases of Scedosporium were collected. Among them, 41% for all 5 cases. All patients had chemotherapy-induced se-were S. prolificans and 59% were S. apiospurmum, and vere neutropenia at the onset of the infection. Disseminated65.6% were colonization and 34.4% were infection. Predis- disease was the most common clinical presentation. Theposing factors included chronic lung disease (37.8%) and lung, sinuses, skin and orbit were the affected sites. All ofmalignancies (21.7%). Hematopoietic stem cell transplanta- these patients died within a short period.tion (HSCT), leukemia and diabetes mellitus were the pre- In the diagnosis of this infection, it is important to recog-dictors of invasive disease. In another survey of 80 sce- nize that S. apiospermum resembles Aspergillus spp. clini-dosporiosis cases in transplant recipients, disseminated ex- cally and histopathologically. Both fungi display thin, deli-tension was observed in 69% of the infections in HCST re- cate, septate hyphae branching at acute angles. It should becipients and 53% of the infections in organ transplant recipi- emphasized that they cannot be differentiated except on fun-ents (10). gal cultures (12). Rapid identification is essential because Concerning the incidence of scedosporiosis among a cer- this organism is resistant to amphotericin B. Diagnostic con-tain disease status, Caira et al (11) reported the incidence of fusion with Aspergillus spp. and uncertain therapy compli-Scedosporium infections in patients with acute leukemia in cate the management of this rare entity (13, 14). 1341
  4. 4. Intern Med 50: 1339-1343, 2011 DOI: 10.2169/internalmedicine.50.4890 Amphotericin B has historically been proven to be inef- selected as the first choice of antifungal agent when mold isfective in the treatment of S. apiospermum infection, and considered to be the causative organism.most isolates exhibit resistance in vitro (15-17). Intravenousmiconazole has been used despite limited efficacy. In addi- The authors state that they have no Conflict of Interest (COI).tion, in spite of some case reports demonstrating successfuloutcomes for localized infections, there are fewer published Referencesreports describing successful outcomes with ITCZ for thetreatment of disseminated disease in immunocompromised 1. Tadro TS, Workowski KA, Siegel RJ, et al. Pathology of hyalohy-hosts (2, 18). VRCZ has a broad spectrum of antifungal ac- phomycosis caused by Scedosporium apiospermum (Pseudalleshe-tivity in vitro, including S. apiospermum, Aspergillus spp. ria boydii): an emerging mycosis. Hum Pathol 29: 1266-1272, 1998.and Fusarium spp., but generally shows poor activity against 2. Lavigne C, Maillot F, de Muret A, Therizol-Ferly M, Lamisse F,the class Zygomycetes (15, 17, 19, 20). The successful use Machet L. Cutaneous infection with Scedosporium apiospermumof VRCZ has been reported in localized subcutaneous infec- in apatient treated with corticosteroid. Acta Derm Venereol 79:tions (21), deep organ infections and disseminated diseases 402-403, 1999.in immunocompromised adults (22-25) and chil- 3. Uenotsuchi T, Moroi Y, Urabe K, et al. Cutaneous infection in an immunocompromised patient and a review of the literature. Actadren (26, 27). Derm Venereol 85: 156-159, 2005. Troke et al (28) analyzed 107 cases of Scedosporium in- 4. Reimann D, Büssemaker E, Gross P. Successful treatment due tofections including S. apiospermum (65%) and S. prolificans Scedosporium apiospermum vacuum seal technique of a severe(35%), treated with voriconazole. Solid organ transplantation skin infection in a renal transplant recipient. Nephrol Dial Trans-(22%), hematological malignancy (21%), surgery/trauma plant 19: 245-248, 2004. 5. Raj R, Frost AE. Scedosporium apiospermum fungemia in a lung(15%), HSCT (9%) and high-dose steroid use (9%) were the transplant recipient. Chest 121: 1714-1716, 2002.predominant underlying conditions. Principal infection sites 6. Ochiai N, Shimazaki C, Uchida R, et al. Disseminated infectionwere the lungs/sinuses (24%), central nervous system (CNS) due to Scedosporium apiospermum in a patient with acute myelo-(20%) and bone (18%), while 21% of patients had dissemi- genous leukemia. Leuk Lymphoma 44: 369-372, 2003.nated infection. A successful therapeutic response was 7. Acharya A, Ghimire A, Khanal B, Bhattacharya S, Kumari N, Kanungo R. Brain abscess due to Scedosporium apiospermum in aachieved in 57% of patients treated with VRCZ. Differences non immunocompromised child. Indian J Medical Microbiologyof response rate among infection sites were seen for skin/ 24: 231-232, 2006.subcutaneous (91%) and bone (79%) infections, and the 8. Shanker S, Biswas J, Gopel L, Bagyalakshmi R, Therese L, Borselowest was for CNS infections (43%). In all, 43 (40%) pa- NJ. Anterior chamber exudative mass due to Scedosporium apio-tients died, 73% due to scedosporiosis. In addition, in trans- spermum in an immunocompetent individual. Indian J Medical Microbiology 55: 226-227, 2007.plant recipients, VRCZ has been reported to have a superior 9. Heath CH, Slavin MA, Sorrell TC, et al. Australian Scedosporiumclinical effect for scedosporiosis over other antifungal Study Group. Population-based surveillance for scedosporiosis inagents (10). Australia: epidemiology, disease manifestations and emergence of The present case is considered as an immunocom- Scedosporium aurantiacum infection. Clin Microbiol Infect 15:promised patient because she had received high-dose steroid 689-693, 2009. 10. Husain S, Munoz P, Forrest G, et al. Infections due to Scedospo-therapy, had been in the state of hyperglycemia due to high- rium apiospermum and Scedosporium prolificans in transplant re-dose steroid, had received Rituximab infusion for refractory cipients: clinical characertistics and impact of antifungal agentITP 3 months before the onset of this infection and had re- therapy on outcome. Clin Infect Dis 40: 89-99, 2005.ceived chemotherapy and autologous PBSCT 12 months be- 11. Caira M, Girmenia C, Valentini CG, et al. Scedosporiosis in a pa-fore the onset of this infection. Also, our patient had an epi- tient with acute leukemia: retrospective muticenter report. Haema- tologica 93: 104-110, 2008.sode of a slight injury on a farm 4 months before the onset 12. Travis LB, Roberts GD, Willson WR. Clinical significance ofof the skin lesion. In addition to potential exposure due to Pseudallescheria boydii: a review of 10 years’ experience. Mayoinjury, the impact of the patient’s augmented immunosup- Clin Proc 60: 531-537, 1985.pression is thought to be that the pathogenesis contributed to 13. Shinohara MM, George E. Scedosporium apiospermum: an emerg-the development of deep skin infection and lymphangitic ex- ing opportunistic pathogen that must be distinguished from Asper-tension. Although ITCZ was ineffective, VRCZ showed a gillus and other hyalohyphomycetes. J Cutan Pathol 36 (Suppl1): 39-41, 2009.striking effect on this infection. The skin lesion had almost 14. Tadros TS, Workowski KA, Siegel RJ, Hunter S, Schwartz DA.healed within 2 months and dissemination was stopped. Pathology of hyalohyphomycosis caused by cedosporium apio- Because Aspergillus spp. and S. apiospermum are often spermum (Pseudallescheria boydii): an emerging mycosis. Humdifficult to distinguish by histopathology, the fact that most Pathol 29: 1179-1180, 1998.isolates of S. apiospermum are resistant to amphotericin B is 15. Cunenca-Estrella M, Ruiz-Diez B, Martinez-Suarez JV, Monzon A, Rodriguez-Tudela JL. Comparative in-vitro activity of vori-a critical consideration to select an antifungal agent prior to conazole (UK-109,496) and six other antifungal agents againstfinal species identification. We emphasize the importance of clinical isolates of Scedosporium prolificans and Scedosporiumavoiding mistaken assumptions regarding the identity of fun- apiospermum. J Antimicrob Chemother 43: 149-151, 1999.gal isolates on the basis of the histopathology or early cul- 16. Ellis D. Amphotericin B: spectrum and resistance. J Antimicrob.tures, especially in an acutely ill patient. VRCZ should be Chemother 49 (suppl 1): 7-10, 2002. 1342
  5. 5. Intern Med 50: 1339-1343, 2011 DOI: 10.2169/internalmedicine.50.489017. Espinel-Ingroff A. In vitro fungicidal activities of voriconazole, 1501, 2000. itraconazol, and amphotericin B against opportunistic monili- 24. Nesky MA, McDougal EC, Peacock JE Jr. Pseudoallesheria boy- aceous and dematiaceous fungi. J Clin Microbiol 39: 954-958, dii brain abscess successfully treated with voriconazole and surgi- 2001. cal drainage: case report and literature review of central nervous18. Barbaric D, Shaw PJ. Scedosporium infection in immunocom- system pseudoallescheriasis. Clin Infect Dis 31: 673-677, 2000. promised patients: successful use of liposomal amphotericin B and 25. Rogasi PG, Zanazzi M, Nocentini J, et al. Disseminated Scedospo- itraconazole. Med Pediatr Oncol 37: 122-125, 2001. rium apiospermum infection in renal transplant recipient: long-19. Johnson LB, Kauffman CA. Voriconazole: a new triazole antifun- term successful treatment with voriconazole: a case report. Trans- gal agent. Clin Infect Dis 36: 630-637, 2003. plant Proc 39: 2033-2035, 2007.20. Kappe R. Antifungal activity of the new azole UK-109,496 (vori- 26. Walsh TJ, Lutstar I, Driscoll T, et al. Voriconazole in the treatment conazole). Mycoses 42: 83-86, 1999. of aspergillosis, scedesporiosis and other invasive fungal infections21. Bosma F, Voss A, van Hamersvelt HW, et al. Two cases of subcu- in children. Pediatr Infect Dis J 21: 240-248, 2002. taneous Scedosporium apiospermum infection treated with vori- 27. Klopfenstein K, Rosselet JR, Turmuhlen A, Powell D. Successful conazole. Clin Microbiol Infect 9: 750-753, 2003. treatment of Scedosporium pneumonia with voriconazole during22. Girmenia C, Luzi G, Monaco M, Martino P. Use of voriconzole in AML therapy and bone marrow transplantation. Med Pediatr On- treatment of Scedosporium apiospermum infection: case report. J col 41: 494-495, 2003. Clin Microbiol 36: 1436-1438, 1998. 28. Troke P, Aguirrebengoa K, Arteaga C, et al. Grobal Scedosporium23. Munoz P, Marin M, Tornero P, Marine Rabadan P, Rodriguez- Study Group. Treatment of Scedosporiosis with voriconazole: Creixems M, Bouza E. Successful outcome of Scedosporium apio- clinical experience with 107 patients. Antimicrob Agents Che- spermum disseminated infection treated with voriconazole in a pa- mother 52: 1743-1750, 2008. tient receiving corticosteroid therapy. Clin Infect Dis 31: 1499- Ⓒ 2011 The Japanese Society of Internal Medicine http://www.naika.or.jp/imindex.html 1343