Photodynamic Therapy as an Adjunct Treatment in a Patient With Deep Dermatophytosis and Inherited <scp>CARD9</scp> Deficiency

A 50-year-old male showed midline destructive lesions secondary to deep dermatophytosis due to Trichophyton interdigitale in the nasal dorsum. In vitro susceptibility testing detected no antifungal resistance. However, there was progressive facial midline destruction despite terbinafine 250 mg/day for 8 weeks, itraconazole 100 mg twice a day for 8 weeks, griseofulvine 500 mg twice a day for 12 weeks, amphotericin B 4 mg/kg/day for 10 days every month during 3 months, voriconazole 200 mg every 12 h for 8 weeks, and posaconazole 300 mg/day for 10 weeks. The genetic test confirmed homozygous Q289X CARD9 (caspase recruitment domain-containing protein 9) mutation. The patient was stable with itraconazole 400 mg/day and terbinafine 125 mg/day concomitantly. However, in October 2024, the patient returned following an episode of gastroenteritis, and he presented with edema and erythema on the nasal dorsum extending to the bilateral malar region, with ulceration on the left nasal slope, adherent desquamation (Figure 1A) and pain. A skin biopsy confirmed the presence of hyphae in the dermis and granulomatous inflammation (Figure 2). Trichophyton interdigitale was isolated in Sabouraud agar and identified by MALDI-TOF. The blood showed eosinophilia 1500 μL. Computed tomography did not reveal cranial involvement. Initially, intravenous amphotericin B was started but had to be suspended due to renal failure. Therefore, it was decided to start adjuvant itraconazole 400 mg/day and terbinafine 125 mg/day and to initiate a treatment with photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA). Signed informed consent was obtained. Two sessions of red-light topical PDT were performed 14 days apart. After careful washing, BF-200 ALA (Ameluz, Biofrontera, Leverkusen, Germany) was applied to the treatment area and incubated for 3 h under occlusion. After this, illumination was performed for 10 min with BF-RhodoLED (37 J/cm2; Biofrontera, Leverkusen, Germany). The patient reported pain 3/10 on the validated visual analogue scale during illumination, and he was treated with cold water spray at a distance of 10 cm applying cold water spray laterally between the lamp and his face. The pain was relieved. One month after the last PDT, the lesion presented good evolution with resolution of the ulcer and decrease of erythema and edema (Figure 1B,C). We made a biopsy and it showed no evidence of hyphae. The patient was followed for 9 months and he is stable. However, due to his immunodeficiency in CARD9, the patient needs to maintain the antifungals treatment further. The patient is being evaluated for allogenic hematopoietic stem cell transplantation. Deep dermatophytosis is an invasive and potentially life-threatening fungal infection [1, 2]. CARD9 is an adaptor protein crucial for innate and adaptive immunity, operating downstream of pattern recognition receptors in immune cells [3], neutrophil recruitment, interleukin 17 production, and phagosome formation to kill fungal yeasts [2]. Dermatophytes are believed to invade through follicular rupture, direct skin invasion, lymphatic, or hematogenous spread [4]. Therapeutic options for CARD9-associated invasive fungal infections have not yet been established [2]. Combination of antifungal drugs, recombinant GM-CSF therapy, allogenic hematopoietic stem cell transplantation, or surgery has been used [2]. PDT has emerged as a promising alternative for managing dermatophytosis [5, 6]. Treating fungal skin infections has become increasingly complex to treat due to the survival of fungi in non-keratinized tissues, high resistance to commonly used antifungals such as terbinafine, and a higher incidence in immunocompromised patients [4, 7]. However, these treatments can be limited by factors such as prolonged duration, potential systemic side effects, and the emergence of antifungal resistance. PDT has demonstrated antimicrobial capacity and a reduction in biofilm formation [7]. It offers a rapid onset of action, minimal invasiveness, and a reduced risk of developing resistance compared to traditional antifungal agents [8]. Additionally, PDT can be combined with existing antifungal therapies, potentially enhancing therapeutic outcomes and allowing for dose reduction of systemic agents, thereby minimizing adverse effects [5, 9]. The penetration of ALA is estimated to be around 1–3mm The interaction between protoporphyrin IX, a metabolite of ALA, and the specific light source generates reactive oxygen species injures the infected cells. PDT has been used in deep persistent suppurative granulomatous perifolliculitis showed a disappearance of fungi in follicles by directly destroying the structure of fungal cells and recruiting CD4+ T cells [9]. In vitro experiments have validated T. rubrum ability to metabolize ALA into protoporphyrin IX ALA-PDT effectively inhibits the growth of T. rubrum, resulting in a reduction in both colony number and size [9]. Pain is a major drawback of PDT. Cold water spray at a distance of 10 cm is effective for pain reduction during PDT and can easily be used. In conclusion, PDT represents a viable adjunct or alternative to conventional antifungal treatments for dermatophytosis. We present the first case of deep dermatophytosis in a patient with CARD 19 deficiency treated with adjuvant PDT. All authors contributed to the design and implementation of the research, to the analysis of the results, and to the writing of the manuscript. The authors thank Dra. Iria González Vasconcellos for the help. The authors have nothing to report. Informed Consent was obtained. The authors declare no conflicts of interest. The authors have nothing to report.