Case of ultraviolet B‐mediated photosensitivity during the administration of voriconazole

Abstract

Dear Editor, Voriconazole (VRCZ) is a broad-spectrum triazole antifungal agent and widely used as a prophylactic measure in immunocompromised patients. Currently, the evidence regarding the association between the use of VRCZ and the risk of photosensitivity and subsequent skin cancer development is of extensive interest. We report a case of actinic keratosis (AK) during VRCZ treatment with ultraviolet (UV)-B-mediated photosensitivity. A 69-year-old Japanese man was referred to us with a 2year-history of multiple hyperkeratotic erythematous lesions on the cheeks (Fig. 1a). Histopathological examination of the lesion showed acanthosis and atypical cells increased above the basal cell layer, resulting in the diagnosis of AK (Fig. 1b). He had been an office worker, and he had no history of sunburn reaction. Additionally, no laboratory abnormality suggesting any photosensitivities was found, including RBC protoporphyrin and urinary uroporphyrin. Because he had received VRCZ treatment (basically 400 mg/day, no serum level data) for underlying invasive paranasal aspergillosis for 5.5 years after surgical operation, the association between VRCZ and AK was strongly indicated. Both UV-A-induced minimal response dose (MRD) and UV-B-induced minimal erythema dose (MED) were measured twice: during VRCZ treatment and after VRCZ discontinuation. We used a Dermaray M-DMR-100 (Terumo Clinical Supply, Tokyo, Japan) to provide UV. MRD in both were negative (range, 2–10 J/cm). In contrast, MED was reduced by VRCZ administration; MED during VRCZ treatment to 30 mJ/cm, and that after VRCZ discontinuation was 110 mJ/cm (Fig. 1c). These results were consistent with the diagnosis of VRCZ-induced UV-B photosensitivity. Topical imiquimod was introduced for the treatment, and then skin lesions disappeared. Haylett et al. reported that MRD in only four patients out of 12 patients treated with VRCZ was reduced, and MED in all 12 patients was normal, although every patient experienced some clinical symptoms after sun exposure. In contrast, our case showed normal MRD and reduced MED by VRCZ administration. Previous reports revealed some mechanisms of VRCZinduced photosensitivity and carcinogenesis. VRCZ metabolites plus UV-A generates reactive oxygen species (ROS) and resultant DNA damage, leading to initiation of cancer development. Meanwhile, the experiments using Xpa-knockout mice demonstrated that VRCZ metabolites plus UV-B has effects on significant upregulation of cytokines and the formation of ROS-induced DNA damage, indicating that UV-B may afford VRCZ-induced photosensitivity; however, this is the first clinical case of detailed photobiological assessment focused on UV-B while taking VRCZ and after discontinuation. Therefore, the direct evidence about VRCZ-induced UV-B photosensitivity is still limited. Additionally, there may be a possibility that the differences of the activities of the drug metabolizing enzymes and genetic background are associated, because there is a genetic polymorphism of CYP2C19, the metabolic enzyme of VRCZ, and over 20% of Japanese population have been genotypically identified as poor metabolizers of CYP2C19. We should be aware of photosensitivity and skin cancer development in the patients utilizing VRCZ, and if photosensitivity or subsequent skin cancer is observed in such patients, the measure of MRD/MED is recommended to check UV-A/ UV-B sensitivity while taking VRCZ and after discontinuation for adequate understanding of VRCZ-induced photosensitivity.