Hematopoietic stem cell transplantation has been established as a curative treatment for advanced hematologic malignancies. Transplantation with a reduced-intensity conditioning regimen has been developed. The minimal toxicity of reduced-intensity stem cell transplantation (RIST) has made transplantation available for patients of advanced age or with organ dysfunction. The response of malignant lymphoma and some solid tumors to RIST has been observed. RIST with unrelated donors and umbilical cord blood has been studied. Fungal infection is an important complication of RIST. Since the prognosis of fungal infection is poor, the management has been focused on its prophylaxis. Given recent progression in RIST management, the strategy of infectious prophylaxis has also changed. Equipment in the hospital is important for fungal infection; however, the median day of the development of fungal infection is day 100, when most patients are followed as outpatients. The focus of fungal management after RIST is oral antifungal agents rather than in-hospital equipment. Various antifungal agents have recently been developed and applied for clinical use. Many antifungals have been developed simultaneously for the first time. A major change in antifungal management will probably occur in the next several years.

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We retrospectively studied the efficacy of early presumptive therapy (EPT). Subjects and Method: Of the critically ill patients admitted from January 1998 to the end of December 2000 to Kyorin University Trauma Burn and Intensive Care Center, 77 cases were diagnosed with suspected deep fungal infection, and EPT was administered. The diagnosis of suspected deep fungal infection was made by definition. EPT (FLCZ 200 to 400mg/day×14 days) was started as soon as the diagnosis was made and continued for two weeks. Its efficacy was retrospectively studied by analyzing the clinical findings, changes in local organisms, and hematological tests. Results: After treatment, 62% of the patients showed improvement in clinical signs of infection, elimination of locally detected fungus, and improvement in the serum diagnosis test. Post-EPT detection levels of the fungus had decreased to 21%. The mean pre-EPT body temperature was 38.7°C±0.6°C, but the mean post-EPT temperature was 36.7°C±0.6°C. The mean level of blood 1, 3-β-D-glucan was 35±13pg/ml at the time the diagnosis was made, but returned to normal levels after treatment had concluded. No patients died as a direct result of the fungal infection. Conclusion: This study of early presumptive therapy in critically ill patients in the emergency and intensive care medicine fields showed the therapy in these, and in high risk patients to be efficacious.

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Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in neutropenic patients with leukemia and those undergoing hematopoietic stem cell transplant (HSCT). Two major IFIs are systemic candidiasis (including candidemia, chronic disseminated candidiasis and pneumonia) and invasive pulmonary aspergillosis. Recently, the incidence of the latter has been increasing. Three levels of diagnosis are specified in the Japanese guidelines for the diagnosis and treatment of IFIs. Proven fungal infections are diagnosed by histological/microbiological evidence of fungi at the site of infection or positive blood culture (fungemia). Clinically documented fungal infections are diagnosed by typical radiological findings such as halo sign on chest CT plus positive serological/molecular evidence of fungi such as Aspergillus galactomannan, β-glucan or fungal DNA. Possible fungal infections are diagnosed by typical radiological findings or positive serological/molecular evidence of fungi. For patients with high risk such as those undergoing HSCT, antifungal prophylaxis using oral antifungal agents is recommended. For possible fungal infections, empiric therapy with fluconazole (FLCZ) or amphotericin B (AMPH) is recommended. For patients with proven fungal infections or clinically documented fungal infections, targeted therapy is warranted. In case of candidemia, the best choice is FLCZ (400mg/day) or AMPH (0.5∼0.7mg/kg/day), and for invasive pulmonary aspergillosis, a higher dose of AMPH (1.0∼1.5mg/kg/day) is indicated. Micafungin (MCFG), recently licensed in Japan, is an active agent for both Candida and Aspergillus. This drug seems useful for empiric and targeted therapy of IFIs.

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To improve the outcome of invasive Candida infections, earlier empirical therapy before the establishment of the definitive diagnosis is considered to be necessary. However, appropriate use of empirical therapy for suspected candidiasis in febrile non-neutropenic surgical patients has not been defined. According to the guidelines from the Infectious Diseases Society of America, empirical therapy of suspected candidiasis in this setting should be limited to patients with Candida colonization of multiple sites, multiple other risk factors, and absence of any other causes of fever. A corrected colonization index which takes into account both the density and the degree of colonization of Candida spp. was shown to be the independent factors that predict subsequent candidal infection.
It may also be appropriate to commence empirical therapy on the basis of a positive serodiagnostic test. β-D glucan is a cell-wall constituent of fungi, which is assumed to be a marker of fungal sepsis. However, it has been shown that β-D-glucan can also be detected in patients without fungal infections, such as those on haemodialysis, and its positive predictive value is relatively low. The monoutilization of β-D-glucan for the assessment of fungal infection should therefore be avoided. The combined assessment of β-D-glucan and extent of colonization with Candida spp. is believed to have the advantage of lessening the likelihood of a false positive reaction of β-D-glucan.

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Invasive mycosis in solid organ transplantation is mainly caused by Candida and Aspergillus, and its risk is higher in small bowel, liver, pancreas, and lung transplantation. Although limited analyses propose not a few risk factors for invasive mycosis in respective transplanted organs, the efficacy of prophylactic use of antifungal agents or preemptive treatments based on the information is not fully supported by prospective randomized controlled clinical data. The final guideline should be helpful for tailor-made evidence-based management based on the stratification of patients by pretransplant, surgical, immunosuppressive and organ specific characteristics. The process of repeated proposals and verification in a large number of patients is necessary.

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Candida albicans is a major cause of oral and esophageal infections in elder persons with poor oral hygiene and immuncompromised patients with hyposalivation, diabetes mellitus, prolonged use of antibiotics or immunosuppressive drugs. Oral thrush is a common form of oropharyngeal candidiasis whose clinical features consist of white patches appearing as discrete lesions on the buccal mucosa, throat, tongue, and gum linings that develop into confluent pseudomembranes resembling milk curds. We recently reported a simple murine model of thrush-type oral candidiasis that mimics the natural infectionin humans and is useful for both symptomatological and mycological evaluation of the responsiveness to antifungal treatments. By using this oral candidiasis model, protective activities of oral administration of several types of herbal preparations such as teatree oil, clove preparation and bovine lactoferrin were clarified. The mechanisms of protective actions of lactoferrin against oral candidiasis were particularly elucidated to include augmentation of T-cell activities of lesional lymphoid tissues. More recent studies suggested that saliva from healthy persons also shows a protective action for this murine oral candidiasis model.

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A type of oral lesion, so-called glossodynia has been on the increase recently. Glossodynia is a kind of psychosomatic disease in which the patient experiences chronic pain on the surface of the tongue. It has never been diagnosed as coming from organic or functional pain.
Although glossodynia can be cured by antianxiety drugs, antidepressants, or autogenic training and so on, usually. These are not a desirable solution.
We initially tried to administer the antifungal drug, ITCZ, to 65 glossodynia patients. Sixty-four of them were cured of tongue pain after 1-3 weeks. The effective rate of recovery was 98.5%. Only two patients experienced reccurence of pain after 15 and 17 weeks, respectively, and Candida albicans was isolated from the surface of their tongues. The nature of the recurrent strains was investigated by MICs against 4 antifungal drugs, ITCZ, MCZ, AMPH-B, and NYS, as well as by the API 20C Auxanogram biochemically, and a molecular epidemiologic study by PFGE. Each case of Candida albicans was almost the same before and after the administration of ITCZ.
Above all, it is important to carefully inspect the candidiasis of the tongue and to initially administer antifungal drugs when the diagnosis is glossodynia.

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We describe a case of allergic fungal sinusitis (AFS) caused by Bipolaris spicifera, the first case reported in Japan. A 70-year-old man was admitted to our hospital because of diplopia following bilateral nasal obstruction and discharge. Radiological studies using computed tomographic scan showed a large soft tissue mass occupying the right frontal, bilateral ethmoid and sphenoid sinuses. He underwent drainage surgery and histopathological examination of the contents of the paranasal sinuses revealed scattered fungal hyphae within “allergic mucin”. By cytological examination, these hyphae showed septation at irregular intervals, and were swollen to various sizes. Microbiological studies identified the fungus as Bipolaris spicifera. The presence of allergic mucin and scattered fungal hyphae were very important findings in making a diagnosis of AFS histopathologically, so squash cytology of the contents of the paranasal sinuses was quite useful to observe fungal elements and identify the strain in this case.

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After several types of dermatophytes were applied to the stratum corneum obtained from a healthy human heel, we evaluated the penetration speed of fungal elements into the stratum corneum and the effect of washing its surface.
We designed the following two environments, assuming tinea pedis after applying fungal elements to the surface of the stratum corneum. The samples were incubated under conditions simulating the daily life of those who wear socks in a house: (1) 90% humidity for 8 hours, and 100% humidity for 16 hours, and those who have bare feet in a house: (2) 80% humidity for 8 hours and 100% humidity for 16 hours. We took the samples out every 24 hours and made observations by PAS stain and scanning electron microscope before and after washing them. Although fungal elements were not removable in (1), even if washed one day later, they could be removable one and two days later in (2). We suggest that fungal elements were easily removable even if dermatophytes had begun to penetrate the surface of the stratum corneum, because the soles retained a low humidity when the shoes were removed, and the soles and interdigital regions were washed every day.
Moreover, in an experiment assuming tinea corporis, fungal elements were applied to the cutting side of the stratum corneum, incubated at 80% humidity, and observed after PAS stain. The penetration of Trichophyton tonsurans to the cutting side of the stratum corneum began in 0.5 days, which was sooner than other dermatophytes. We believe this is one factor of the latest expansion of T. tonsurans infection in Japan.

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