Clearance of multiple cutaneous warts by targeting a single lesion: A randomized comparative evaluation of mild local hyperthermia versus cryotherapy

To the Editor: Multiple mucocutaneous warts are common in patients due to virus spreading or self-inoculation, as exemplified by 22.2% of the patients with plantar warts having more than one lesion.1De Planell-Mas E. Martínez-Garriga B. Zalacain A.J. Vinuesa T. Viñas M. Human papillomaviruses genotyping in plantar warts.J Med Virol. 2017; 89: 902-907Google Scholar Specific immune responses against human papillomavirus-harboring lesions contribute to self-regression or treatment-mediated clearance of warts. As such, the treatment-induced immune response to one target lesion could likely initiate the immune-mediated clearance of untargeted or remote lesions in patients with multiple warts containing the same human papillomavirus types. Indeed, we have previously observed that applying local hyperthermia at 44 °C on a single lesion resolved the lesions of 59.1% (150 of 254 cases) of the patients with multiple untreated plantar warts.2Huo W. Gao Y.L. Wang H.Y. et al.Local hyperthermia versus cryotherapy for treatment of plantar warts: a prospective multi-centre non-randomized concurrent controlled clinical trial.Acta Derm Venereol. 2022; 102 (adv00655)Google Scholar There is little evidence regarding response of untreated warts to cryotherapy of a single wart.3Jean L.B. Julie V.S. Lorenzo C. Dermatology.4th ed. Elsevier, 2018Google Scholar This 2-center, evaluator-blinded randomized controlled trial evaluated the overall clearance efficacy by applying local hyperthermia or cryotherapy to a target lesion in patients with multiple warts (ClinicalTrials.gov Identifier: NCT03734003, Supplement I, available via Mendeley at https://data.mendeley.com/datasets/4yk8v93vpn/1). Patients aged 18 to 70 years who were clinically diagnosed with common warts, plantar warts, or condyloma acuminata and who had at least 2 lesions and no local or systematic treatment in the past 3 months were included (Table I). Excluded were those with systemic viral infections and/or other severe cutaneous infections, pregnant or lactating women, and patients with conditions not fit as evaluated by the researchers. Patients entered the treatment arms by the blocked randomization method at a 1:1 ratio. Target lesions were chosen as previously reported.2Huo W. Gao Y.L. Wang H.Y. et al.Local hyperthermia versus cryotherapy for treatment of plantar warts: a prospective multi-centre non-randomized concurrent controlled clinical trial.Acta Derm Venereol. 2022; 102 (adv00655)Google Scholar,4Huo W. Gao X.H. Sun X.P. et al.Local hyperthermia at 44 degrees C for the treatment of plantar warts: a randomized, patient-blinded, placebo-controlled trial.J Infect Dis. 2010; 201: 1169-1172Google Scholar Local hyperthermia at 44 ± 2 °C was accomplished by an infrared thermotherapy instrument (Liaoning Yanyang Medical Instrument Co Ltd, China; Supplement II, available via Mendeley at https://data.mendeley.com/datasets/4yk8v93vpn/1) once daily for 3 consecutive days, with each session lasting 30 min. Two weeks later, similar treatments were administered for 2 consecutive days and then once a week for 2 more weeks. In total, the hyperthermia was administered for 7 treatments. In the cryotherapy group, liquid nitrogen was applied by a cotton tipped swab 3 times with a 2-week interval in a month (Supplement III, available via Mendeley at https://data.mendeley.com/datasets/4yk8v93vpn/1). Clearance of the lesions was defined as restoration of the normal appearance of the skin of both the targeted and nontargeted lesions in a patient. Treatment responses were evaluated at 1, 2, 3, and 4 months after the first treatment (Supplement IV, available via Mendeley at https://data.mendeley.com/datasets/4yk8v93vpn/1).Table IBrief demographics and treatment response between patients receiving local hyperthermia and cryotherapy on a single target lesionHyperthermia groupCryotherapy groupRate difference (95% CI)∗The rate difference and the 95% confidence interval for the difference between 2 independent arms, calculated according to the Wilson procedure with a correction for continuity.PPatients, N4444Age, y, mean ± SD34.2 ± 12.2630.1 ± 11.51.108Sex, n (%).830 Male25 (56.8)24 (54.5) Female19 (43.2)20 (45.5)Number of lesions, n, mean ± SD15.2 ± 28.29.4 ± 10.8.205Duration of disease, mo, mean ± SD31.8 ± 36.327.1 ± 31.6.518Previous treatment, n (%)15/44 (34.1)7/44 (15.9).496Clearance of target lesions, n (%) Month 10/44 (0.0)1/44 (2.3)2.3 (−8.0 to 13.5).315 Month 26/44 (13.6)2/43 (4.7)9.0 (−5.8 to 23.9).147 Month 34/43 (9.3)7/43 (16.3)7.0 (−9.4 to 23.3).333 Month 416/44 (36.4)9/44 (20.5)15.9 (−4.5 to 34.8).098 Total26/44 (59.0)19/44 (43.1)15.9 (−6.3 to 36.2).135Clearance of nontargeted lesions along with target lesions, n (%) Month 10/44 (0.0)1/44 (2.3)2.3 (−8.0 to 13.5).315 Month 24/44 (9.1)0/43 (0.0)9.1 (−2.8 to 22.6).043 Month 37/43 (16.3)3/43 (7.0)9.3 (−6.6 to 25.2).178 Month 413/44 (29.5)8/44 (18.2)11.4 (−8.1 to 29.8).211 Total24/44 (54.5)12/44 (27.2)27.3 (5.1-46.2).0093Clearance of different warts within 4 mo, n/N (%) Verruca vulgaris4/9 (44.4)5/10 (50.0)5.6 (−38.9 to 47.3).809 Plantar warts10/17 (58.8)3/14 (21.4)37.4 (−1.7 to 64.2).036 Condyloma acuminatum6/8 (75.0)0/1 (0.0)75.0 (−27.4 to 95.6).134 Mixed types†Mixed types: patients with both diagnosed verruca vulgaris and plantar warts.4/10 (40.0)4/19 (21.1)19.0 (−17.4 to 54.5).278Recurrence rate within 1 y, n (%)1/23 (4.3)2/10 (20.0)15.7 (−10.0 to 51.7).151VAS score (mean ± SD)‡t test on the VAS scores collected during treatment at day 1, week 2, and week 4, for the 2 groups of patients.1.0±1.24.4±1.9t = −10.051<.001Other side effects, n (%) Blistering/bleeding/erosion2/44 (4.7)7/44 (16.3)11.4 (−3.7 to 26.6).157 Pigmentation/scar0/44 (0.0)4/44 (9.1)9.1 (−2.6 to 22.6).116Calculations are made on intent-to-treat populations.CI, Confidence interval; SD, standard deviation; VAS, visual analog scale.∗ The rate difference and the 95% confidence interval for the difference between 2 independent arms, calculated according to the Wilson procedure with a correction for continuity.† Mixed types: patients with both diagnosed verruca vulgaris and plantar warts.‡ t test on the VAS scores collected during treatment at day 1, week 2, and week 4, for the 2 groups of patients. Open table in a new tab Calculations are made on intent-to-treat populations. CI, Confidence interval; SD, standard deviation; VAS, visual analog scale. A total of 104 patients were screened. Eighty-eight patients entered the study, with 44 patients in each group. Four months after the initial treatment, 54.5% versus 27.2% of the patients had overall clearance of lesions in the hyperthermia and cryotherapy arms, respectively (95% confidence interval, 5.1 to 46.2; P < .01). There was no significant difference in the clearance rates of the target lesions between the hyperthermia and cryotherapy arms (59.0% vs 43.1%, respectively; P > .05). The patients experienced higher pain scores when being treated with cryotherapy than with local hyperthermia (visual analog scale score 4.35 ± 1.92 vs 0.99 ± 1.20, respectively; P < .001), (Table I, Supplement V, available via Mendeley at https://data.mendeley.com/datasets/4yk8v93vpn/1). The limitations of the study included the small patient numbers, inability to blind the participants, and the hyperthermia protocol being more time-consuming. The medical instrument for infrared thermotherapy is a patented device (Patent No: US 8,246,668 B2) owned by The First Hospital of China Medical University; Rui-Qun Qi, Xing-Hua Gao, and Hong-Duo Chen are original patent holders. The patent was transferred to and manufactured by Liaoning Yanyang Medical Instrument Co Ltd. We thank Guijiao Bi, Henan Si, Yuanyuan Liu, Quan Wen, and He Ai for serving as participating investigators. We thank Meng Li, Jianxun Mao, Yimei Du, Yangbin Wang, Zihan Wang, Shengnan Zhao, Ze Wu, Tianhua Xu, Hongjuan Li, Yang Liu, Abdulrahman A, and A. Amer collected data. We thank Yunfei Cai for providing part of the statistical analysis. We thank Prof Robert A. Schwartz of Rutgers New Jersey Medical School for manuscript corrections. Letter from the editor: Hyperthermia for cutaneous wartsJournal of the American Academy of DermatologyPreviewIn this issue of the Journal of the American Academy of Dermatology, Qi et al present data suggesting that targeted therapy of a single lesion with hyperthermia can result in the regression of multiple cutaneous warts. The treatment of cutaneous verrucae remains problematic with many modalities in use and a high rate of recurrence. Cryotherapy remains the standard therapy, but treatments can be painful. Other treatment choices range from laser and other forms of surgical ablation to topical acids, imiquimod, 5-fluoruracil, and candida antigen, attesting to the refractory nature of warts in many patients. Full-Text PDF