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Acute invasive Aspergillus rhinosinusitis

Acute invasive Aspergillus sinonasal infections occurs almost exclusively in the immunocompromised host. This infective complication is mainly observed in patients with acute leukaemia submitted to intensive chemotherapy, in patients with severe aplastic anemia and in those undergoing allogeneic blood stem cell transplant (Voillier et al, 1986; Talbot et al, 1991; Shubert et al 1986; Drakos et al, 1993; Morrison et al, 1993; Choi et al, 1985; Singh & Paterson, 2005). In these patients the disease is aggressive and is frequently complicated by skin, palate, ocular and intracerebral extension. Other underlying conditions such as solid organ transplant, uncontrolled HIV infection, prolonged steroid therapy, solid tumours and ketoacidotic diabetes are more commonly associated with a chronic presentation of the disease (Singh & Paterson, 2005).

According to EORTC/MSG definitions of invasive mycoses (Ascioglu et al, 2002), proven fungal sinonasal infection is defined by the histopathologic examination showing hyphae from a biopsy specimen. However considering that the histopathologic features of Aspergillus and other mold infections (Fusarium spp, Scedosporium spp, Alternaria spp) are usually indistinguishable from each other, proven Aspergillus infection also requires the microbiologic isolation of the pathogen. Probable invasive sinonasal infection is defined by the association of at least 1 host factor criterion (i.e. neutropenia, graft versus host disease, prolonged use of corticosteroids, persisting fever) plus 1 microbiological criterion (positive culture from nose or sinus aspirate or Aspergillus antigen from blood) plus 1 major clinical criterion (radiologic evidence of erosion of sinus walls or extension of infection to neighboring structures, extensive skull base destruction) or 2 minor criteria (nasal discharge, stuffiness, nose ulceration or eschar of nasal mucosa, epistaxis, periorbital swelling, maxillary tenderness, black necrotic lesions or perforation of hard palade). Possible Aspergillus sinonasal infection is defined by the association of at least 1 of the above host criterion plus 1 microbiological or 1 major (or 2 minor) clinical criteria. Although these definitions are intended for use in the context of clinical and/or epidemiological research, and not for clinical decision making, they represent a useful tool to homogenize the diagnostic criteria of invasive fungal infections, including sinonasal aspergillosis. Biopsy with culture are the key tools to obtain a proven diagnosis of invasive aspergillosis, but also to exclude other fungal infections, such as zygomycosis, which may require alternative antifungal drugs. However, biopsy may not be feasible in profoundly thrombocytopenic patients; therefore in most of cases encountered in clinical practice the diagnosis of sinonasal aspergillosis is not proven but made on the basis of clinical, microbiological and radiological features.

Mortality is high, ranging from 20% in leukaemia in remission, to up to 100% in patients with relapsed leukaemia or with refractory aplastic anaemia, in those undergoing allogeneic blood stem cell transplantation and in immunosuppressive therapy for graft versus host disease or in the context of a disseminated disease (Denning, 1996; Lin et al 2001, Singh & Paterson, 2005).

According to the IDSA practice guidelines for diseases caused by Aspergillus (Stevens et al, 2000) treatment should combine medical with surgical approaches. However, extensive surgery does not seem to offer any overall benefit (Kennedy et al, 1997) or may even increase mortality among neutropenic patients (Denning & Stevens, 1990). The general caution for this invasive approach is also suggested by the lack of recent literature supporting radical surgery in the treatment of sinonasal fungal infections in severely immunocompromised patients. Amphotericin B deoxycholate at maximum tolerated doses (e.g., 1-1.5 mg/kg/d) is considered the drug of first choice and lipid formulations of amphotericin B are indicated for patients with impaired renal function or intolerant to amphotericin B deoxycholate (Stevens et al, 2000). Oral itraconazole (400 mg daily) is attractive for continuing therapy.

Recent literature underlines the crucial role of the new drugs voriconazole and caspofungin in the primary and salvage therapy of invasive aspergillosis, respectively (Denning et al, 2002; Herbrecht et al, 2002; Maertens et al, 2002). However, these experiences included very few cases of sinonasal Aspergillus infection and therefore, the role of these drugs is not well delineated. However, preliminary data from a retrospective recent single-centre experience (Girmenia et al, 2005) seem to show the promising role of voriconazole without surgery in the treatment of acute invasive Aspergillus rhinosinusitis in patients with haematological malignancies or aplastic anemia. First line treatment with voriconazole was associated with better responses at day 7 of therapy (62% versus 24%), a higher rate of complete and partial response, improved 3-month survival rate (69% versus 38%) and fewer severe side effects in 13 voriconazole treated patients compared to an historical group of 21 patients treated with amphotericin B or itraconazole, with or without combined radical surgery. The use of voriconazole in the first line treatment of sinonasal invasive aspergillosis appears appropriate.

Prepared by Dr C Girmenia,
Dipartimento di Biotecnologie Cellulari ed Ematologia,
University 'La Sapienza',
Via Benevento 6,
00161,
Rome, Italy.

October 2005