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necrosis surrounded by a fibrous encapsulation and normal subcutaneous fat tissue. Figure 2 Tissue infiltration. Infiltration of subcutaneous tissue by hyphae.
Bone Marrow Transplantation (2001) 28, 899–901  2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00

Case report A novel type of metastatically spreading subcutaneous aspergillosis without epidermal lesions following allogeneic stem cell transplantation OA Cornely1, H Pels1, U Bethe1, M Seibold3, K Toepelt1, D Soehngen1 and A Ritzkowsky2 1

Department I of Internal Medicine, Hematology, Oncology and Infectious Diseases, University of Cologne, Cologne, Germany; Department of Dermatology and Venereal Diseases, University of Cologne, Cologne, Germany; and 3Robert Koch-Institute, Berlin, Germany


Summary: Systemic mycosis is among the most feared opportunistic infections in the immunocompromised host. Difficulty and delay in diagnosis and treatment often result in poor outcomes. In this communication a metastatically spreading form of subcutaneous aspergillosis developed in a patient with a history of allogeneic stem cell transplantation for relapsed Hodgkin’s lymphoma. Strikingly, necrotizing cutaneous papules or ulcerating lesions were absent. Diagnosis was accomplished after excision of a clinically non-suggestive subcutaneous nodule. Despite prompt initiation of antimycotic therapy the outcome was fatal; dosage of conventional and liposomal amphotericin B was limited due to treatmentrelated toxicities. This case report describes a novel form of aspergillosis and underlines the need for an aggressive diagnostic approach in severely immunocompromised patients. Bone Marrow Transplantation (2001) 28, 899–901. Keywords: aspergillosis; allogeneic transplantation; invasive fungal infection; mycosis; skin

Aspergillosis is an opportunistic infection in hemato-oncological patients that is particularly difficult to diagnose. The mortality rate is high and may reach up to 60%.1 Patients with uncontrolled underlying disease and those undergoing allogeneic bone marrow transplantation are especially prone to developing invasive aspergillosis. They are referred to as a high risk population.2 Organs involved comprise the lung, the brain and – after hematogenic spread – potentially all other organs.3 When involvement of the skin due to aspergillus is addressed, necrotizing cutaneous papules or ulcerating lesions secondary to embolization and skin infarcts are the commonly known clinical pictures.4,5 We report a severely immunosuppressed patient with a clinically non-suggestive and metastatically spreading form Correspondence: Dr OA Cornely, Universita¨tsklinikum Ko¨ln, Klinik I fu¨r Innere Medizin, 50924 Ko¨ln, Germany Received 5 February 2001; accepted 23 August 2001

of subcutaneous aspergillosis, that has not been described before. Case report A 39-year-old male patient was admitted because of dyspnea, night sweats and a non-productive cough. Auscultation of the lungs was unremarkable. Generalized xerosis cutis and two mildly tender subcutaneous nodules on the left thigh were the only findings of note on physical examination. Renal and liver function tests and the white blood count were within normal limits. Chest X-ray showed interstitial infiltrates in both lower lobes. The patient had been diagnosed with nodular sclerosing Hodgkin’s disease clinical stage III BE 10 years prior to the current admission. Having survived five relapses of his underlying disease, he showed a history of extensive antineoplastic treatment: three cycles of COPP/ABVD with extended field radiotherapy (mantle field, mediastinum, inversed Y) of up to 40 Gy, two cycles of DexaBEAM chemotherapy followed by autologous stem cell transplant for the first relapse, gemcitabine/dexamethasone after the second relapse and CVB (cyclophosphamide, etoposide, BCNU) for the third recurrence. Treatment for the fourth relapse consisted of an allogeneic stem cell transplant from his HLA-identical brother that was completed 9 months prior to the current presentation. The fifth and most recent relapse had been diagnosed from a transbronchial biopsy 6 months after the allogeneic transplant. Treatment comprised donor lymphocyte infusions and reduction of the immunosuppressants to monotherapy with hydrocortisone 25 mg once daily p.o. in order to induce a graft-versusHodgkin’s reaction. Except for short episodes of neutropenic fever, no major infectious complications had occurred during these years of therapy and there was no history of any other serious illness. On the current admission empiric antibiotic treatment was initiated with erythromycin, ceftriaxone and gentamicin. When bronchoalveolar lavage yielded Pneumocystis carinii pneumonia, the antibiotic treatment was adjusted. One of the slightly tender but otherwise unremarkable subcutaneous nodules was excised for diagnostic evaluation.

Subcutaneous aspergillosis OA Cornely et al


Figure 1 Excised subcutaneous nodule. Yellow and green central necrosis surrounded by a fibrous encapsulation and normal subcutaneous fat tissue.

Figure 2 Tissue infiltration. Infiltration of subcutaneous tissue by hyphae displaying a typical dichotomous branching angle (hematoxylin eosin stain, approximately ×100).

the extent of the disease. A helical CT scan showed nodular and partially confluent lung opacities. These were nonspecific and therefore consistent with both aspergillus pneumonia and recurrent Hodgkin’s disease. Both bronchoalveolar lavage and transbronchial biopsy were nondiagnostic. At the time of the CT scan, pneumonia due to Klebsiella pneumoniae isolated from sputum complicated the clinical course. Low-density liver lesions were found by another CT study; needle biopsy yielded no pathological finding. Involvement of the nasal sinuses and heart valves was excluded by negative CT scan, transesophageal echocardiography and nasal swab cultures, respectively. Magnetic resonance scans and extensive ultrasound examinations of the skin failed to detect any further lesions. However, before the results of the histology became available several new thigh nodules developed bilaterally. The diagnosis of invasive aspergillosis resulted in prompt initiation of conventional amphotericin B at a dose of 1 mg/kg once daily i.v. The aspergillus isolate underwent susceptibility testing at the German Reference Laboratory (Robert Koch-Institute, Berlin, Germany; isolate identification M768/99) giving promising minimal inhibitory and fungicidal concentrations (see Table 1). Although saline loading was instituted to prevent amphotericin B nephrotoxicity, the serum creatinine level doubled after 3 weeks of therapy. Conventional amphotericin B was switched to the liposomal formulation (Ambisome; Nexstar Pharmaceuticals, Munich, Germany) at a daily dose of 3 mg/kg i.v. No new nodules appeared and after a week a decrease in tenderness and softening of the remaining nodes indicated gradual improvement. However, due to deteriorating liver function and newly developing cholestasis the liposomal amphotericin B dose had to be reduced to 1.5 mg/kg. Immediately after dose reduction, a new nodule measuring 1.5 cm in diameter appeared in the left pectoral region. In view of the deteriorating liver and kidney function itraconazole, voriconazole and terbinafine were not considered. The patient’s condition deteriorated rapidly and 10 weeks after initiation of antifungal therapy he died from respiratory failure. Discussion Among the approximately 175 Aspergillus sp. that have been described so far about 20 species are pathogens in humans. Among these, Aspergillus fumigatus is found predominantly as an opportunistic pathogen in immunocompromised patients.3

Table 1 Figure 3 Aspergillus fumigatus. After successful culturing on Sabouraud’s dextrose agar typical aspergillus spores grew (lactophenole cotton blue, approximately ×250).

It was covered by normal coloured skin. The macroscopic appearance of the nodule is described in Figure 1. Microscopically a fungus was found (Figure 2) that was morphologically identified as Aspergillus fumigatus (Figure 3). Different imaging techniques were applied to determine Bone Marrow Transplantation

Results of the susceptibility testing (protocol NCCLS M38-P)

Antifungal Amphotericin B Itraconazole Voriconazole Terbinafine

MIC (␮g/ml)

MFC (␮g/ml)

1.0 0.25 0.125 0.5–1.0

1.0 ND ND ND

MIC = minimal inhibitory concentration; MFC = minimal fungicidal concentration; ND = not done.

Subcutaneous aspergillosis OA Cornely et al

Findlay et al6 attempted to distinguish five appearances of disseminated aspergillosis: solitary necrotizing dermal plaque, subcutaneous granuloma or abscess, persistent eruptive dermal maculopapules, transient erythema and generalized rash and, as an entity in immunocompetent hosts, progressive confluent granuloma.6 A recent comprehensive review describes the different appearances of cutaneous aspergillosis and classifies primary and secondary lesions,7 the latter occurring as hematogenously disseminated embolic lesions. The morphology of the lesion in our patient does not exactly fit any of the categories discussed and may represent yet another possible manifestation unique for its lack of epidermal lesions. The differential diagnosis encompasses candidemia, presenting with red pinpoint maculae in approximately 10% of patients8 and fusariosis metastatically involving the skin in the majority of cases. Fusarial lesions might present as subcutaneous nodules.9 Cryptococcal and nocardial disease were considered in the light of simultaneous pulmonary and skin lesions. In this patient, the daily dose of 1.5 mg/kg i.v. liposomal amphotericin B was ineffective. This may have been due to unsatisfactory tissue penetration. However, a recommendation of a higher dose cannot be based on this single experience. A dose increase has to be evaluated for each individual patient. It is unclear whether the combination of amphotericin B with intravenous 5-flucytosine as the only approved agent at that time would have resulted in further improvement.3 Itraconazole and voriconazole might turn out to be alternative options, but at the moment published data are sparse. Recently, the first echinocandin caspofungin was approved for refractory aspergillosis. The candins are well tolerated and thus represent a promising alternative even in patients with multisystem compromise. With regard to the extensive immunosuppressive treatment our patient had undergone, he might well have been even more profoundly immunocompromised than the majority of patients described in the literature, undergoing, for example, leukemia induction therapy. Neutropenia, the most important risk factor for invasive mycosis, was not present in our patient.7,10 The patient’s next of kin did not give consent for autopsy, so the exact etiology of the fatal respiratory failure could not be determined. Pneumocystis carinii and Klebsiella pneumoniae were clinically cured. Thus, pulmonary Hodgkin’s disease and invasive aspergillus pneumonia were the most likely causes for the clinical deterioration observed.

Diagnosis was accomplished only after excision of a clinically non-suggestive nodule. As described above, this nodule was a sign of disseminated mycosis. We therefore recommend an aggressive diagnostic approach whenever tender nodules of the skin occur in the immunocompromised host.


Acknowledgements We wish to express our thanks to Miriam J Baron, MD, Brigham and Women’s Hospital, Boston, MA for her thorough review of the manuscript.

References 1 Denning DW. Invasive aspergillosis. Clin Infect Dis 1998; 26: 781–805. 2 Bo¨ hme A, Karthaus M, Einsele H et al. Diagnosis of systemic fungal infections in hematology. Standard recommendations of the Working Group for Infections in Hematology and Oncology of the German Association for Hematology and Oncology. Deutsche Med Wochenschr 1999; 124: S24–30. 3 Stevens DA, Kan VL, Judson MA et al. Practice Guidelines for Diseases Caused by Aspergillus. Clin Infect Dis 2000; 30: 696–709. 4 Isaac M. Cutaneous aspergillosis. Dermatol Clin 1996; 14: 137–40. 5 Sakaria AM, Chavaz P, Hauser C. Metastatische Aspergilluspannikulitis bei blastischer Transformation eines myelodysplastischen Syndromes und Agranulozytose. Hautarzt 1995; 46: 579–581. 6 Findlay GH, Roux HF, Simson IW. Skin manifestations in disseminated aspergillosis. Br J Dermatol 1971; 85: 94–97. 7 van Burik JA, Colven R, Spach DH. Cutaneous aspergillosis. J Clin Microbiol 1998; 36: 3115–3121. 8 Viscoli C, Girmenia C, Marinus A et al. Candidemia in cancer patients: a prospective, multicenter surveillance study by the Invasive Fungal Infection Group (IFIG) of the European Organization for Research and Treatment of Cancer (EORTC). Clin Infect Dis 1999; 28: 1071–1079. 9 Boutati EI, Anaissie EJ. Fusarium, a significant emerging pathogen in patients with hematologic malignancy: Ten years’ experience at a cancer center and implications for management. Blood 1997; 90: 999–1008. 10 Ascioglu S, de Pauw B, Bennett JE et al. Analysis of definitions used in clinical research on invasive fungal infections (IFI): consensus proposal for new, standardized definitions. 39th Intersc Conf Antimicrob Agents Chemoth, San Francisco, USA, September 1999 (Abstr.).

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