Efficacy and Safety of Atmospheric Pressure Cold Plasma in the Treatment of Moderate-to-severe Tinea Pedis: a Prospective, Randomized, Double-blind, Placebo-controlled Multicenter Clinical Trial

Tinea pedis, commonly known as athlete's foot, is a highly contagious dermatophytic infection of the feet, characterized by erythema, desquamation, vesicles, and sometimes thickening or fissuring of the skin. It remains one of the most prevalent skin diseases worldwide, especially in hot and humid environments, which favor fungal growth and transmission. Typical clinical manifestations include blistering, scaling, and itching between the toes, on the heels, and the lateral aspects of the foot; in severe cases, patients may experience maceration, exudation, and secondary bacterial infections.

Moderate-to-severe tinea pedis is associated with extensive skin involvement, more intense symptoms (such as severe pruritus, pain, and functional impairment), frequent recurrences, and an increased risk of complications including cellulitis and chronic wounds. These forms of the disease are not only more refractory to conventional topical therapies, but also have a significant impact on patients' quality of life and daily functioning. Persistent or extensive lesions are more likely to harbor residual fungi in anatomical niches (e.g., toe webs, heel fissures), leading to repeated treatment failures and contributing to transmission within households and the wider community. Therefore, improving the efficacy of fungal inactivation and reducing recurrence rates in moderate-to-severe tinea pedis is a key unmet need in dermatology.

Over the years, multiple approaches have been explored for superficial fungal eradication, including preventive measures, physical therapies, and chemical agents. However, current treatments face several limitations: (1) the complex anatomical structure and irregular surface of the foot make it difficult for topical agents or sterilization procedures to penetrate all affected areas, often leaving residual fungi; (2) dermatophytes have substantial survival capacity and may develop resistance, making mild or insufficient therapies less effective for complete eradication; (3) many existing treatment modalities are cumbersome, require complex procedures, or lack flexibility, limiting their widespread use and patient adherence. As a result, achieving both effective fungal eradication and practical, patient-friendly treatment options remains an important clinical challenge, especially for moderate-to-severe cases.

Atmospheric pressure cold plasma (CAP) represents an innovative fourth-state physical technology, capable of generating a high density of energetic electrons, ions, excited atoms, and reactive species (including ROS and RNS) at near-room temperature. This technology has been widely adopted for material processing, environmental protection, new energy applications, and increasingly, for biomedical purposes. In medical research, CAP-generated reactive agents, ultraviolet irradiation, and thermal effects have been shown to disrupt microbial cell structures, induce apoptosis, and promote tissue regeneration by stimulating growth factor expression and enhancing wound healing processes. Importantly, CAP offers selective cytotoxicity, enabling targeted inactivation of pathogenic microorganisms while preserving normal tissue viability through adjustable plasma parameters.

Given its potent antimicrobial effects, safety profile, and unique physical-chemical mechanisms, CAP is a highly promising candidate for the treatment of recalcitrant cutaneous infections, such as moderate-to-severe tinea pedis. Applying CAP to the management of tinea pedis could potentially address the unmet needs of deeper fungal eradication, reduced recurrence, and improved patient outcomes, particularly in those with more extensive, symptomatic, or difficult-to-treat disease.