Many therapeutic modalities are available for common warts, including either the conventional destructive treatments, or immunotherapy, which is based on the activation of the immune system to deal with the virus and suppress its activity (13). Such therapy may be applied either topically or through intralesional injection or through systemic administration (14). However, no single therapy has been established as completely curative. Many studies have suggested the advantage of combining different wart therapies rather than using a single monotherapy (15)(16)(17).
In the present study, we examined the additive effects of combining cryotherapy with intralesional PPD in treatment of multiple common warts compared to intralesional PPD monotherapy.
In the PPD treated group, a significant response in terms of reduction in the number and size of warts was observed; 48% of the patients showed complete response and 24% showed near complete response.
Several studies have observed variable degree of therapeutic responses of warts with IL PPD treatment (18)(19)(20)(21). This may be explained by the fact that immunotherapy induces a delayed-type hypersensitivity reaction that increases the ability of the immune system to recognize and clear HPV (22) and the clearance of untreated distant warts strongly indicated the development of a widespread cell-mediated immunity against HPV as a response to intralesional antigen injection(23).
Our results in the intralesional PPD treated group are in agreement with a number of studies showing comparable response rates ( 44%:48% ) after 3-6 sessions of IL PPD treatment (12)(24)(25) .
On the contrary, some studies showed better therapeutic response compared to ours after IL PPD treatment. Saoji et al (2016) and Youssef et al. (2009) showed complete clearance in 80% of patients after four to six sessions. The higher response rate in their studies might be due to injection of multiple warts in each session and the use of large PPD dose in contrast to ours.
Singh et al (2018) showed complete response in 72% of cases after four sessions of PPD treatment. This may be due to including patients with single warts.
Wananukul et al (2009) observed complete clearance in 93% of the mother warts and 87% in distant warts after six sessions. They included single warts and the mean size of treated warts was relatively smaller (8mm) compared to our study (26mm).
On the other hand, lower cure rates after IL PPD were obtained in other studies. Rajashekar et al (2020) showed complete clearance of all warts in 35.5% of patients, using a fixed dose of 0.1ml of PPD antigen.
On comparing between the two studied groups, no significant difference was noted between IL PPD versus combined cryotherapy and PPD group regarding reduction in size or number of warts.
Luk et al (2006) showed that the combination of cryotherapy with 5-Fluorouracil (5-FU) had no additional therapeutic benefit than cryotherapy plus placebo in the treatment of common warts.
However, multiple studies reported better therapeutic response of combined cryotherapy with various types of immunotherapy for treatment of warts. Moubasher et al (2021) noted the complete clearance of genital warts in 46.7% in cryoimmunotherapy group (cryotherapy plus IL PPD) compared to 13.3% in IL PPD treated group. Also Attwa et al (2020) have noted 40% of patients showed complete clearance in cryoimmunotherapy group (cryotherapy plus IL candida antigen) versus 25% in intralesional Candida antigen group.
In our study, there was no relation between treatment response and the patient’s sex, site of lesions and PPD dose in both treatment groups. In PPD treated group there was a negative relation between the age of the patients and treatment response, where younger age was significantly associated with better response.
This was in agreement with Shaheen et al (2015) who noted a negative relation between treatment response of warts and age in the PPD-treated patients. This was explained as younger patients were more capable of producing an effective immune response than older patients.
In the present study, no relation was observed between disease duration and treatment response in both treated groups. This is consistent with the observations of Kus et al (2005) and Nimbalkar et al (2016) with IL PPD treatment. Elela et al (2011) and Abd-Elazeim et al (2014) showed better response in shorter disease duration.
The present study also showed a significant positive relation between the size of induration after tuberculin skin test and the therapeutic response in both treated groups. This may indicate that patients with larger induration of tuberculin test had more effective immune response, and therefore better response to treatment. This came in match to Kus et al (2005) and Abd-Elazeim (2014) who reported a relation between response to treatment and the size of tuberculin reaction. On the other hands, Khozeimeh et al (2017) noted no relation between the induration size and the therapeutic response.
In our study, higher rates of complete to near complete response were achieved after fewer sessions (2-3sessions) with cryotherapy plus PPD group. This finding indicates the advantage of combining cryotherapy with IL PPD to decrease the number of sessions. In the line with our results Choi et al (2011) compared the efficacy of cryotherapy plus immunotherapy using topical diphenylcyclopropenone (DPCP) versus cryotherapy plus 5FU/salicylic acid and cryotherapy alone in the treatment of periungual and plantar warts, they concluded that using cryotherapy with immunotherapy(DPCP) reduces the number of required sessions. Furthermore, we observed no recurrence in the cryotherapy plus PPD group compared to a 20% recurrence of warts in the PPD group.
Attwa et al (2020) suggested the synergistic effect of both intralesional candida antigen and cryotherapy. Intralesional antigen immunotherapy induces a strong cell-mediated immune reaction to alter the balance between TH1 and TH2 responses leading to the eradication of HPV (35). Cryotherapy causes local destruction of HPV-infected keratinocytes with a stronger exposure of HPV hidden antigens in addition to several immunological effects mediated mainly via Natural killer cells (36) and can also trigger the immunologic reaction causing secondary cell damage (37).
Patients in combined (cryotherapy and PPD) group, have experienced more pigmentary changes and blistering than PPD treated group. However, hypopigmentation after treatment resolved gradually in the majority of patients.
Similarly Attwa et al (2020) reported more erythema , blistering and hypopigmentation in combined cryotherapy and intralesional candida antigen group compared to IL candida antigen alone group. Surprisingly, they reported significantly more erythema, edema and hypopigmentation in the cryotherapy plus IL candida group compared to cryotherapy alone group.
Also Moubasher et al (2021) noted more pain and hypopigmentation in cryoimmunotherapy (cryotherapy and PPD) group than PPD alone group. Such side effects can be minimized by using less aggressive cryotherapy regimens especially when combined with other treatments to enhance therapeutic efficacy without increasing the rate of side effects.
Limitations of the study include small number of patients, shorter follow up duration, and few number of treatment sessions and lack of third group of cryotherapy alone. However, we didn’t include this group based on results of previous studies which favored the superior efficacy of IL PPD compared to cryotherapy.