Cryotherapy versus CO2 laser in the treatment of plantar warts: a randomized controlled trial

Background Warts are one of the most common infections in humans. Plantar warts are a subtype of non-genital warts, and several procedures and topical treatments have been used in its treatment. Cryotherapy is one of the most popular modalities, but it is time-consuming and remission rates vary in different studies. CO2 laser was the first laser used for treating warts. To date, no clinical trial has been done to compare CO2 laser with cryotherapy in the treatment of plantar warts. Patients and Methods This randomized controlled trial was performed in order to compare the efficacy and number of sessions needed to treat plantar warts in 60 patients who had received no previous treatment in the previous 3 months. They were randomly allocated to the cryotherapy or CO2 laser group. The number of sessions needed for response and the recurrence rate after a 3-month follow-up was compared in the 2 groups. Results Sixty patients with plantar warts were randomly allocated to either the CO2 laser or cryotherapy groups. Median age was 25 (range=18–53) and 27 (range= 18–75) years in the cryotherapy group and CO2 laser groups, respectively. Both groups were matched for age and sex (56% male and 44% female in the cryotherapy group and 34% male and 66% female in the CO2 laser group). The median number of sessions needed for complete resolution of the warts in the CO2 laser and cryotherapy groups were 1 (range=1–2) and 3 (range=1–12), respectively. The difference in the number of sessions was statistically significant between the 2 groups (P-value≤0.001). Recurrence rates after a 3-month follow-up was not statistically significant (P-value= 0.069). Conclusion The number of sessions needed to treat plantar warts was less using CO2 laser than cryotherapy; therefore, this modality can be a good addition to the already existing anti-wart armamentarium.

Each pass had 2 components. First, the focused mode with a spot size of 1 mm, and second, the unfocused mode that was induced with a 5 cm distance between the laser probe and the lesion(s).
Mupirocin ointment was prescribed for all the patients 2 times a day for 3 days.
Resolution of the lesions was considered as clearance of the lesion(s) on inspection and palpation and was documented by photography. Persistence of the lesion(s) after 12 weeks of treatment with cryotherapy or 3 sessions of CO 2 laser was considered as failure.
Three months after resolution of the lesions, the patients were re-evaluated for possible recurrence.

Results
Sixty patients were enrolled in the trial. Twenty-seven in the cryotherapy group and 29 in the CO 2 laser group completed

Introduction
Warts are one of the most common benign neoplasms. It is the third most common skin disease in childhood and is probably even more common in adulthood [1]. Warts are induced by over 100 types of human papillomavirus (HPVs) and can affect any race [2]. They are subdivided into genital and non-genital types. In a study from India in 2016, the ratio of non-genital warts to the genital forms was 9 to 1 [3]. Non-genital warts are subsequently subdivided into common, plane, palmoplantar, mosaic, filiform or digitate types [4]. Palmoplantar warts are one of the most common types of non-genital warts [5]. Following discovery of HPVs as the causative agent of warts, several treatment methods have been introduced. Currently, there is no specific antiviral agent against HPVs. Systemic cidofovir affects DNA viruses such as HPV, but renal toxicity limits its use [6]. No curative standard definitive oral or topical treatment exists for warts [7]. Current treatments are based on 2 mechanisms: destruction of the bulk of the neoplasm or stimulation of cellular immunity against HPVs [8,9]. Topical immunomodulators (imiquimod [10]), topical and intralesional cytotoxic agents (5-FU, podophyllin [11]), immunotherapy (diphenylcyclopropenone [12]), topical and oral retinoids [13], and systemic immunomodifiers (cimetidine, interferons [14] have been used with some success. Local destructive methods are used more often than immunomodifiers. They include cryotherapy [15], trichloroacetic acid [16], lactic acid, salicylic acid, electrosurgery, curettage, surgery with scalpel or scissors [17], photodynamic therapy [18], and various types of lasers [17].
In a Cochrane review done in 2003 by Gibbs et al [19], cryotherapy was reported to be the most commonly used therapy for warts. However, the treatment outcome with cryotherapy as compared to topical salicylic acid was not significant, and a higher morbidity was reported for cryotherapy. For bleomycin, 5FU, and intralesional interferon and photodynamic therapy, data was limited. This clinical trial challenges the use of cryotherapy in the treatment of warts. Patients treated with cryotherapy face a higher cost, as stated by Stamuli et al [20]. Ablative and non-ablative lasers have been used in order to decrease the duration of the treatment course and recurrence of warts. The first laser that was used for warts was CO 2 laser [21], followed by pulsed dye laser and Er: YAG laser [22,23]. CO 2 laser has been used for recalcitrant warts with remission rates ranging from 50% to 100%, in only a few studies [24,25].
To our knowledge, no clinical trial in the English literature has compared cryotherapy with CO 2 laser in the treatment of plantar warts [26]; hence, this study was designed to compare the efficacy of these 2 modalities in the treatment of plantar warts.
in the laser group and one in the cryotherapy group failed treatment (Figure 4). No clinical infection was detected in any of the patients.
Two episodes of moderate bleeding occurred during laser therapy, which was managed by coagulation with the CO 2 laser unfocused mode.

Discussion
There are several treatment options for treating plantar warts ranging from office-based therapy (such as cryotherapy) to treatments applied by the patient (such as salicylic acid) [27].
Various lasers have been used for this purpose with different the trial. Three patients in the cryotherapy group were lost to follow-up, and a patient in the laser group was withdrawn from the trial and had to be referred for skin biopsy because of a suspicious lesion on the plantar surface of his opposite foot that appeared to be melanoma.
Demographic characteristics of the patients are summarized in Table 1. The 2 groups were matched according to sex and age. Five patients in the laser group and 2 in the cryotherapy group had coexistent warts on their hands. Two patients in the laser group and 3 in the cryotherapy group had diabetes mellitus type 2, and a patient in the laser group had hypothyroidism.
The CO 2 laser power used was 21±4 watts, both for focused and unfocused mode. The median number of sessions needed for complete treatment with CO 2 laser was 1 (range= 1-2) while in the cryotherapy group, it was 3 (range=1-12).
The number of required sessions for the 2 groups was compared by Mann-Whitney test, and the difference was statistically significant (P-value≤ 0.001) (Figures 1-3). One patient  HPVs. Liquid nitrogen might become contaminated if direct contact devices are used; not so with spray guns [34]. The remission rate with this method in our study was 70%. In a study by Ahmed et al, the authors noted a 44% and 47% cure rate with cryotherapy using the spray gun and cotton swab, respectively [35]. This difference between our results and the aforementioned article may be due to the difference in disease chronicity and follow up.
To our knowledge, there is no study comparing CO 2 laser with cryotherapy in the English literature, although comparisons of other lasers have been undertaken. In a study by Akhyani et al, no superiority in remission rate for PDL laser was found when compared with cryotherapy. However, patients in the PDL group achieved remission sooner in the course of treatment [36]. In our study, we did not find a statistically significant difference in the recurrence rate between our 2 groups, and the P-value was 0.069.
One main concern in this study was the issue of possible In the other arm of our study we used cryotherapy. There are several studies on the efficacy of cryotherapy and the adverse effects attributed to this method, although there is limited data comparing this method with other methods in the treatment of plantar warts [31]. Liquid nitrogen with a temperature of -196˚ C was used for cryotherapy and was applied with spray gun, probe, or cotton swab. For choosing the best interval for applying cryotherapy, we did not find any difference between 1-week, 2-week, or 3-week intervals.
It seems that the number of sessions determine efficacy of  patients who later undergo aesthetic procedures using the same device. It seems that the risk of viral transmission from CO 2 laser plume after procedures on non-genital warts is not higher than the general population [37]. In our study, we did not see any clinically apparent warts in our cosmetic patients that used the same device and no warts were observed in the dermatologist performing the laser treatment in our cases.
The absence of any clinical infection in both groups can be attributed to the topical application of mupirocin ointment.
Therefore, administering a topical ointment might help to reduce post-procedural infections.

Conclusion
Overall, CO 2 laser can be an effective and timesaving treatment modality for plantar warts. However, studies with larger sample sizes and longer follow-up periods are advised in order to confirm the results of this study.