Guidelines for the management of dermatomycosis (2019).

The "Guidelines for the management of dermatomycosis" of the Japanese Dermatological Association were first published in Japanese in 2009 and the Guidelines Committee of the Japanese Dermatological Association revised it in 2019. The first guidelines was prepared according to the opinions of the Guidelines Committee members and it was of educational value. The revised version is composed of introductory descriptions of the disease concepts, diagnosis, medical mycology and recent advances in treatment, along with clinical questions (CQ), which is intended to help in general practice for dermatologists. The CQ are limited to those involved in therapy but include some of the recently launched antifungal agents. The level of evidence and the degree of recommendation for each item were reviewed by the committee based on clinical studies published by 2018. For rare dermatomycoses, recommendations by the committee are described in the guidelines. In this field, there are still few good quality studies on treatment. Periodic revision in line with new evidence is necessary.

Identification of ketoconazole as an AhR-Nrf2 activator in cultured human keratinocytes: the basis of its anti-inflammatory effect.

Ketoconazole (KCZ) has been shown to exhibit anti-inflammatory effects in addition to its inhibitory effects against fungi; however, the underlying molecular mechanism remains poorly understood. Aryl hydrocarbon receptor (AhR), a receptor that is activated by polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons such as dioxin, is a sensor of the redox system against oxidative stress and regulates nuclear factor-erythroid 2-related factor-2 (Nrf2), a master switch of the redox machinery. To clarify whether KCZ modulates AhR-Nrf2 function leading to redox system activation, cultured human keratinocytes were treated with KCZ. Confocal microscopic analysis revealed that KCZ induced AhR nuclear translocation, resulting in the upregulation of CYP1A1 mRNA and protein expression. Furthermore, KCZ actively switched on Nrf2 nuclear translocation and quinone oxidoreductase 1 expression. Tumor necrosis factor-α- and benzo(a)pyrene (BaP)-induced reactive oxidative species (ROS) and IL-8 production were effectively inhibited by KCZ. Knockdown of either AhR or Nrf2 abolished the inhibitory capacity of KCZ on ROS and IL-8 production. In addition, KCZ-induced Nrf2 activation was canceled by AhR knockdown. Moreover, KCZ inhibited BaP-induced 8-hydroxydeoxyguanosine and IL-8 production. In conclusion, the engagement of AhR by KCZ exhibits the cytoprotective effect mediated by the Nrf2 redox system, which potently downregulates either cytokine-induced (AhR-independent) or PAH-induced (AhR-dependent) oxidative stress.

Differential induction of Th1-prone immunity by human dendritic cells activated with Sporothrix schenckii of cutaneous and visceral origins to determine their different virulence.

Sporotrichosis is caused by a thermo-dependent dimorphic fungus, Sporothrix schenckii. The major clinical manifestations occur in the skin; however, cases of visceral manifestations have also been increasingly reported with some being observed in immune compromised patients. Different virulence of individual S. schenckii strain as well as immune status of the host could contribute to form such different clinical manifestations. Thus, the purpose of the study was to investigate whether different virulence of individual S. schenckii could be a factor for such clinical difference. We investigated the interactions between human monocyte-derived dendritic cells (MoDCs) and S. schenckii, assessed by (i) morphological features, (ii) surface marker expressions, cytokine productions, (iii) signaling pathways and (iv) allostimulatory activity of the activated MoDCs. Immature MoDCs, obtained from peripheral blood monocytes supplemented with granulocyte macrophage colony-stimulating factor and IL-4, were stimulated with S. schenckii strains of both yeasts and conidia forms of different origins (cutaneous isolates: KMU4649, IFM5906 and IFM46010; visceral isolates: KMU4648, IFM41598 and ATCC26331) to be used for various assays. Through the analysis, we found that the cutaneous S. shenckii of cutaneous origins were more potent to activate MoDCs to induce strong T(h)1 response, as evidenced by abundant IFN-gamma production, while the S. shenckii of visceral origins induced only minimal dendritic cell activation and T(h)1 induction. The p38 mitogen-activated protein kinase and c-Jun N-terminal kinase signaling pathways appeared to be associated with the differential activation of the MoDCs by S. schenckii of cutaneous and the visceral origins. Overall, we concluded that the differential activation of MoDCs by S. schenckii of cutaneous and visceral origins to induce T(h)1 response, other than immune status or the host, may be a factor for their different clinical manifestations.

Concurrent double infections of the skin: phaeohyphomycosis and nocardiosis in a patient with idiopathic thrombocytopenic purpura.

We describe a case of concurrent double infection with phaeohyphomycosis and lymphocutaneous nocardiosis in an immunocompromised host. The episode occurred almost simultaneously with an incident of insect bites. Exophiala spinifera was isolated from lesions on the left arm and Nocardia asteroides was isolated from lesions on the right hand. Clinical resolution occurred within 5 months after initiation of antimicrobial treatment with oral itraconazole and minocycline. We believe that this case represents a novel episode of previously unreported concurrent infections with phaeohyphomycosis and lymphocutaneous nocardiosis in human beings.

Cutaneous alternariosis with chronic granulomatous disease.

We report here a case of dermal cutaneous alternariosis in a 69-year-old man with X-linked chronic granulomatous disease (CGD). The lesion on the back of the right hand spread and became indurated, even though oral itraconazole 100 mg daily for 12 weeks was administered. After 28 weeks of treatment with oral fluconazole at 200 mg daily, the lesion disappeared and left only slight pigmentation. Alternaria species are common saprophytes that are not usually pathogenic in humans. However, there are some reports of cutaneous alternariosis in immunocompromised patients. To our knowledge, this is the first case of cutaneous alternariosis in CGD and the response to fluconazole, a drug not usually used for this mycosis.

Cutaneous Scedosporium apiospermum infection in an immunocompromised patient and a review of the literature.

Scedosporium apiospermum (also known as Pseudallescheria boydii) is a ubiquitous filamentous fungus. This fungus is known as a cause of mycetoma, which may occur in a normally immune host following trauma. However, in an immunocompromised host, S. apiospermum may cause a life-threatening infection. We describe a case of S. apiospermum infection of the right hand in a patient who was receiving long-term immunosuppressants for adult Still's disease. We also review the cases of S. apiospermum infection with cutaneous manifestations reported between 1998 and 2003.

Dermatomyositis with tuberculous fasciitis.

A case of dermatomyositis with tuberculous fasciitis is described. A 69-year-old Japanese man treated with prednisolone for dermatomyositis developed erythema and bilateral swelling of arms and forearms. A diagnosis of tuberculous fasciitis was confirmed by the presence of acid-fast bacilli in a biopsy specimen and the growth of Mycobacterium tuberculosis from tissue cultures. The unusual presenting clinical features resulted in delayed diagnosis. We emphasize that tuberculous fasciitis should be considered in an immunocompromised patient who is treated with steroids, especially if the results of initial treatment are not satisfactory.

Therapeutic approaches to subcutaneous mycoses.

Subcutaneous mycoses, which are much less common than superficial fungal infections, are characterized by a heterogeneous group of infections that often result from direct penetration of the fungus into the dermis and subcutaneous tissue through traumatic injury. The fungus spreads by local deep tissue invasion from the inoculation site. The disease usually remains localized and then slowly spreads to adjacent tissue and eventually to the lymphatics. More rarely, hematogenous dissemination is observed. There are usually various clinical features and thus a broad range of differential diagnoses. The common subcutaneous mycoses are sporotrichosis, chromoblastomycosis, phaeohyphomycosis, eumycotic mycetoma, and hyalohyphomycosis. Many subcutaneous mycoses are confined to the tropical and subtropical regions, but some, such as sporotrichosis, are also prevalent in temperate regions. Subcutaneous mycoses can occur in healthy individuals. In immunocompromised individuals, these infections can disseminate widely. Treatment usually involves use of antifungal agents and/or surgical excision. Treatment of some serious subcutaneous mycoses remains unresolved, and there have been reports of relapses or progression during therapy and problems with lack of tolerability of antifungal drugs. Identification of the etiologic agent by culture is essential for prognostic and management considerations, since some fungi are more frequently associated with dissemination. Results of antifungal susceptibility tests may provide valuable information for deciding the appropriate method of treatment. Development of new antifungal agents and combination therapies may result in improvement in the management of subcutaneous mycoses in the future.