In this large retrospective study, we estimated IFS occurred in 1.77% of hospitalized patients with hematological disorders. IFS caused significantly higher mortality in AML patients with prolonged neutropenia (> 10 days). We identified surgical debridement is an independent factor associated with good outcome.
IFS developed more frequently in patients with AML, myelodysplastic syndrome, and aplastic anemia, but not at all in patients with lymphoma/myeloma. In the literature review, most patients with lymphoma who developed IFS are recipients of myeloablative allogeneic stem cell transplants [14–18]. Compared with other subtypes of hematological malignancy, patients with AML had significantly higher risk of IFS. The risk of developing IFS in AML relates to neutropenia (p < 0.001) and less to the intensity of chemotherapy regimens. The mortality of patients with AML was also much greater than non-AML patients.
Prolonged neutropenia in patients with myeloid malignancies may contribute to underlying disease, intensity and dosage of chemotherapy, colony-stimulating factor, and concurrent medication. Invasive mold infection often occurs when a large burden of spores from an environmental source is deposited on mucosal membranes lacking an effective phagocytic host defense . Using cytokine growth factors to decrease the period of chemotherapy-associated neutropenia and using laminar air flow rooms for protection against IFS  may reduce the risk of IFS after allogeneic stem cell transplantation . In this study, we found a lower incidence and mortality of IFS in 2005-2009 than in 1994-1999.
The clinical mycological spectrum of IFS is limited in patients with stem cell transplants and hematological disease [14–18]. Aspergillus and Mucor are the main mold found in biopsy, however, the prevalence is highly variable in different geographic regions [14–18, 22, 23]. In our study, Aspergillus flavus (44%) was the most common isolate. Aspergillus flavus, with its unique ability to survive at higher temperatures, is the predominant pathogen in countries, including most of the Middle East, Africa, and Southeast Asia [24, 25]. Rare IFS in Asia and Africa were reported, the clinical response varies differently with fungal subtypes, and further epidemiology study should be investigated. Mucormycosis is an emerging cause of IFS with a rapid fatal course in patients with hematological disorders [26, 27]. In our study, all four patients with mucormycoses had received high dose antifungal therapy and aggressive surgical debridement, but three died within 6 weeks (mortality, 75%). Effective treatment for Mucormycosis should be investigated.
The symptoms and signs of paranasal sinusitis (such as nasal discharge, stuffiness, epistaxis, periorbital swelling, and maxillary tenderness) are nonspecific for IFS. Symptoms and signs such as nose ulceration, eschar of the nasal mucosa, black necrotic lesions, and perforation of the hard palate are more specific, but these findings are present only at an advanced stage. The use of CT and MRI in the diagnosis of invasive fungal sinusitis has been reported . Diagnostic radiological evidence of invasive fungal sinusitis includes erosion of sinus walls, extension of infection to neighboring structures, and extensive skull base destruction. However, most patients do not have classic findings in the early phase of invasive fungal sinusitis. Earlier diagnosis by using serial Aspergillus galactomannan antigen test in the modern medical era to detect IFS, may lead to early introduce anti-fungal agent and surgical debridement, and potentially decreased morbidity and mortality in high risk patients.
There are some limitations in this study. First, this is a retrospective time cohort study in a single university institution in Taiwan. Therefore, information of laboratory results, such as Aspergillus galactomannan antigen test, might be limited. Second, surgical approach of sinusitis were performed according to clinicians' decision, thus, the etiology of control patients were not available. Third, as IFS is not a common disease in patients with heamatological disorder, the case numbers is limited.
In conclusion, outcome of IFS is usually very poor [11, 28]. In this study, functional endoscopic sinus surgery for debridement was the only indicator of better prognosis in multivariate analysis. This result confirms previous findings indicating that sinus surgery improves outcome [28, 29]. Aggressive surgical debridement combined with antifungal therapy, should be emphasized in leukemic patients in spite of their prolonged neutropenia and bleeding tendencies. Whether the intensity of chemotherapy and allogeneic stem cell transplantation were the independent prognosis of invasive fungal infection need further investigation.