Ann Hematol (2002) 81:593Ð596 DOI 10.1007/s00277-002-0511-2

CASE REPORT

K. Nakai á Y. Kanda á S. Mineishi á A. Hori A. Chizuka á H. Niiya á T. Tanimoto á M. Ohnishi M. Kami á A. Makimoto á R. Tanosaki á Y. Matsuno N. Yamazaki á K. Tobinai á Y. Takaue Primary cutaneous aspergillosis caused by Aspergillus ustus following reduced-intensity stem cell transplantation

Received: 10 December 2001 / Accepted: 4 July 2002 / Published online: 24 September 2002 © Springer-Verlag 2002

Abstract A 19-year-old woman with myelodysplastic merase chain reaction identified Aspergillus ustus. Al- syndrome underwent reduced-intensity stem cell trans- though this is an extremely rare complication after trans- plantation [RIST: (cladribine 0.11 mg/kg for 6 days, bu- plantation, this case highlights that we should pay more sulfan 4 mg/kg for 2 days, and rabbit antithymocyte attention to primary cutaneous aspergillosis in severely globulin)] from her one HLA-mismatched mother. Pro- immunosuppressed patients. phylaxis against graft-versus-host disease (GVHD) was performed with cyclosporine A (CSA) alone. Severe Keywords Primary cutaneous aspergillosis á Aspergillus acute GVHD in the skin, gut, and liver developed con- ustus á Reduced-intensity stem cell transplantation á currently with stable engraftment, and methylpredniso- Steroid lone was administered (1Ð2 mg/kg per day, then pulse therapy with 1 g/day for 3 days) until day 40 of trans- plant, when a necrotic lesion of 10 mm in diameter Introduction appeared on the right cheek. The initial skin biopsy of the affected area showed a nonspecific inflammatory Allogeneic hematopoietic stem cell transplantation (HSCT) change. Routine X-ray and computed tomography exam- has been developed as a curative therapeutic procedure inations of the sinuses, chest, and abdomen disclosed no for various hematologic malignancies and other disor- particular abnormalities. Despite intensive antibiotic ders. Although supportive care has been greatly im- therapy, the lesion rapidly extended to form an ulcer. A proved over the past two decades, infection after HSCT second biopsy specimen obtained from the lesion is still a life-threatening issue. Most importantly, inva- showed massive septa hyphae, suggesting mold infec- sive aspergillosis can often be fatal in severely immuno- tion. Although we immediately started amphotericin B, compromised patients [1]. Among Aspergillus species, she died of multiorgan failure on day 68. Postmortem A. fumigatus and A. flavus are the most common patho- DNA sequence analysis of the specimen using the poly- gens. They frequently colonize the sinuses and the route of infection is usually the upper airway [2, 3]. Therefore, routine chest computed tomography (CT) plays an im- K. Nakai á Y. Kanda á S. Mineishi á A. Hori á A. Chizuka portant role in the early detection of aspergillosis [4]. On H. Niiya á T. Tanimoto á M. Ohnishi á M. Kami á A. Makimoto R. Tanosaki á Y. Takaue (✉) the other hand, primary cutaneous aspergillosis has been Hematopoietic Stem Cell Transplant Unit, only recently reported in high-risk patients including National Cancer Center Hospital, 1Ð1 Tsukiji 5-chome, HIV-infected patients, burn victims, neonates, cancer Chuo-ku, Tokyo, 105Ð0045, Japan patients, solid-organ transplant recipients, and HSCT re- e-mail: [email protected] cipients [5, 6]. We describe here the first patient who de- Fax: +81-3-35423815 veloped primary cutaneous infection from A. ustus fol- Y. Matsuno lowed by systemic dissemination after HSCT using a re- Pathology Division, National Cancer Center Hospital, Tokyo, Japan duced-intensity conditioning regimen that included anti- thymocyte globulin (ATG). N. Yamazaki Dermatology Division, National Cancer Center Hospital, Tokyo, Japan Case report K. Tobinai Hematology Division, National Cancer Center Hospital, The patient was a 19-year-old woman who was diagnosed with Tokyo, Japan myelodysplastic syndrome of refractory anemia subtype in 594

Fig. 2 Skin biopsy revealed massive mycelia in the dermis. (Grocott-Gomori stain, original magnification ×400)

Fig. 1 Isolated cutaneous necrotic lesion that appeared on the pa- tient’s cheek on day 40 after transplantation. This subsequently lactomannan antigen and plasma (1Ð3)-beta-D-glucan became pos- spread to form an ulcer itive. We immediately changed fluconazole to amphotericin B at a dose of 1.5 mg/kg per day, but the skin lesions progressed rapidly and she died of multiorgan failure on day 68. Permission for au- topsy was not granted. September, 1996. She had been treated with conservative medica- We performed the polymerase chain reaction (PCR) analysis to tions, but she subsequently became dependent on frequent transfu- identify the causative agent on samples taken from the right cheek sions because of progressing pancytopenia. She then underwent and right leg using universal fungal primers, followed by species- reduced-intensity stem cell transplantation (RIST) from her one specific primers [9]. Finally, the amplified products were electro- HLA-mismatched mother. The conditioning regimen consisted of phoretically separated, cut off, and directly sequenced. The 437-bp cladribine (0.11 mg/kg for 6 days), busulfan (4 mg/kg for 2 days), sequence showed complete homology with A. ustus DNA. and rabbit ATG (1.25 mg/kg for 4 days). Prophylaxis against graft-versus-host disease (GVHD) consisted of cyclosporine A (CSA) alone. On day 11, neutrophil engraftment was achieved, but this was associated with the simultaneous appearance of high- Discussion grade fever and a systemic skin rash. The histopathologic findings by skin biopsy were compatible with acute GVHD. Methylpred- We experienced a fatal fungal infection after HSCT. Al- nisolone (mPSL) at 1 mg/kg was ineffective and the dose was in- though we could not detect the causative agent by cul- creased to 2 mg/kg followed by pulse therapy (1 g/day for 3 days) because of the worsening of diarrhea of over 500 ml/day. Concur- ture, microscopic identification of mold infection on the rently, hyperbilirubinemia and massive ascites developed, and ve- second lesion and the detection of A. ustus DNA on the no-occlusive disease of the liver was suggested. On day 37, she same specimen strongly supported the diagnosis of A. developed clonic-tonic seizure. Although a brain magnetic reso- ustus infection. A. ustus is a rare pathogen that can nance imaging examination disclosed no abnormalities, our inabil- ity to exclude the possibility of encephalopathy forced us to dis- cause invasive infection in immunocompromised pa- continue CSA and to continue mPSL alone for the treatment of tients. To the best of our knowledge, only nine cases of GVHD. On day 40, necrotic skin tissue of approximately 10 mm A. ustus infection have been described in the literature in diameter appeared on her right cheek (Fig. 1), where no skin since 1973: four with pulmonary aspergillosis, four with GVHD lesion was observed. Frequent blood culture detected only Staphylococcus epidermidis and a skin biopsy of the affected area primary cutaneous aspergillosis, and one with infective revealed nonspecific inflammatory change. Serum levels of Asper- endocarditis [10, 11]. Among the four with pulmonary gillus galactomannan antigen (Platelia Aspergillus, Diagnostic aspergillosis, the underlying diseases were three he- Pasteur, France) [7] and plasma (1Ð3)-beta-D-glucan (Fungi-tec, matological malignancies undergoing HSCT and one Seikagaku Corporation, Japan) [8] were both negative. Routine cardiac surgery for mitral valve replacement with a tri- X-ray and CT examinations of the sinuses, chest, and abdomen disclosed no particular abnormalities except for the presence of as- ple coronary artery bypass procedure. Among the four cites. At the time, she had been receiving combined antimicrobial with primary cutaneous aspergillosis, the underlying therapy including meropenem, vancomycin, and fluconazole. De- diseases were endstage hepatitis C-induced cirrhosis un- spite the immediate tapering of mPSL, the necrotic lesion contin- dergoing liver transplantation, chronic obstructive pul- ued to extend to form an ulcer of 20 mm in diameter, and small necrotic lesions then appeared on her legs. She complained of vi- monary disease receiving steroid, skin burn, and skin sual disturbance in her left eye on day 53, which was clinically di- erosion following an accident. The other case with en- agnosed as necrotic retinitis based on ophthalmoscopic findings, docarditis had had prosthetic valve replacement. Thus, without identification of any causative pathogens. A second skin with regard to HSCT recipients, few reports have been biopsy was then performed from two different lesions, right cheek and right leg, and the histopathological examination this time de- published on invasive aspergillosis caused by A. ustus, tected the presence of massive septa hyphae, suggesting mold in- and none have shown primary cutaneous involvement. fection (Fig. 2). Simultaneously, serum levels of Aspergillus ga- Since four of the nine reported cases were classified as 595 primary cutaneous aspergillosis, which is a rare form of diagnosis of involved skin biopsy was negative for evi- invasive aspergillosis, the skin may be the primary site dence of fungal infection, in hindsight we should have of infection by A. ustus. Several fungal pathogens, in- started a therapeutic dose of amphotericin B immediately cluding Aspergillus, Candida, and Fusarium, can cause after the appearance of a small skin lesion in such a pro- primary cutaneous infection in the presence of skin le- foundly immunosuppressed patient. Surgical resection of sions. Therefore, in the setting of allogeneic HSCT, the the localized skin lesion is an alternative treatment for development of skin erosion secondary to GVHD can be cutaneous fungal infection, especially with fusariosis, as a risk factor for cutaneous aspergillosis, although this recently described by Sampathkumar and Paya [19]. was not the case in our patient. Invasive aspergillosis However, our experience leads us to view this concept caused by A. ustus is associated with a high mortality with caution. Before the development of a more sensitive rate. Of the nine reported cases, only two patients were and specific method for the early diagnosis of Aspergil- cured by amphotericin B with flucytosine or topical lus species, every skin lesion in immunocompromised terbinafine. patients should be carefully examined for the possibility HSCT recipients are highly immunosuppressed as a of lethal infections. consequence of neutropenia and intense immunosuppres- sive therapy to facilitate the engraftment of donor cells Acknowledgement This study was supported by a Grant-in-Aid or prophylaxis/treatment of GVHD. Invasive aspergillo- for Scientific Research from the Ministry of Health, Labor and Welfare. sis occurs in a biphasic distribution after allogeneic HSCT, in the first 40 days during neutropenia, and in a later post-engraftment period complicated with GVHD [1]. In the latter phase, fever as an early sign of fungal References infection is frequently masked by the use of corticoste- 1. 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Heussel CP, Kauczor HU, Heussel GE, et al (1999) Pneumonia have shown that the use of ATG influenced immune re- in febrile neutropenic patients and in bone marrow and blood covery after HSCT [12, 13, 14]. This hypothesis should stem-cell transplant recipients: use of high-resolution comput- be tested in a large-scale study. ed tomography. J Clin Oncol 17:796Ð805 Fluconazole is widely used for antifungal prophylaxis 5. Burik J, Colven R, Spach D (1998) Cutaneous aspergillosis. after HSCT since it has been shown to be beneficial in J Clin Microbiol 36:3115Ð3121 6. Schimmelpfennig C, Naumann R, Zuberbier T, et al (2001) well-designed randomized controlled trials [15, 16, 17]. Skin involvement as the first manifestation of systemic asper- Wolff et al. [18] showed that fluconazole was as effec- gillosis in patients after allogeneic hematopoietic cell trans- tive as low-dose intravenous amphotericin B (0.2 mg/kg plantation. 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