The potential role for topical imiquimod in the treatment of chronic mucocutaneous candidiasis caused by gain‐of‐function mutation in STAT1: A case‐report

Dear Editor, Chronic mucocutaneous candidiasis (CMC) is a rare immunodeficiency characterized by chronic or recurrent infection of the skin, mucous membranes, and nails with candidal and non-candidal infections. Heterozygous STAT1 gain-of-function (GOF) mutations are found in approximately 50% of the cases. Long-term antifungal therapy is considered the first-line option but resistances to antifungals, particularly azoles, represent a serious concern, leading to the use of intravenous or second-line therapies such as GM-CSF, G-CSF, and JAK–STAT inhibitors. We present a case of a 9-year-old female with a heterozygous missense mutation in STAT1 (c.862A>G; p.Thr288Ala), with a longstanding, disfiguring, and recurrent skin infection by Trichophyton rubrum successfully treated with a combination of topical imiquimod, terbinafine, and ketoconazole. The lesions started when she was 4 years old. She was initially successfully treated with oral itraconazole (5 mg/kg/day) for 10 months, but it was suspended due to hepatotoxicity, with consequent progression of the lesions. Fluconazole (4 mg/kg/day) for 6 weeks resulted in some improvement but quickly relapsed after suspension and did not work when reintroduced. During this period, she maintained treatment with either topical ketoconazole, terbinafine, or ciclopirox. Physical exam showed thick erythematous-desquamative plaques at both feet plus onychodystrophy (Figure 1(A)). Skin biopsy showed an exuberant inflammatory response at the dermis, rich in polymorphonuclear cells, and fibrosis, along with hyperplasia of the epidermis permeated by fungal structures—identified as T. rubrum in the mycological exam (confirming a previous result). Itraconazole (5 mg/kg/day) for 4 months resulted in significant improvement (Figure 1(B)) but was associated with significant hepatotoxicity during follow-up. Because oral antifungal was not an option and topical antifungals resulted in quick relapse, we hypothesized that adding imiquimod to a topical fungistatic plus a fungicide antifungal could avoid disease relapse. She started topical imiquimod 5% twice a week (one sachet per week) combined with topical ketoconazole (20 mg/g) and terbinafine (20 mg/g) daily in the affected areas. Treatment for 12 months showed no adverse effects neither loss of efficacy. The initial reaction was marked by an initial inflammation that subsided after a couple of weeks with a reduction of scaling and evolution to atrophic and hypopigmented scar-like lesions. The direct mycological examination was negative. The nails and the periungual skin, where the initial lesions were thicker, kept some of the changes (Figure 1(C)). Imiquimod is a potent activator of the innate immune system and its antifungal role has been described in chromoblastomycosis and chronic tinea interdigitalis. It acts through stimulation of TLR7 and/or TLR8—a sub-family of Pattern Recognition Receptors