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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 5  |  Issue : 1  |  Page : 54-58

Comparison of purified protein derivative and vitamin D in the treatment of recalcitrant warts


Department of Dermatology, Rajarajeswari Medical College and Hospital, Bengaluru, Karnataka, India

Date of Submission17-Feb-2020
Date of Decision15-Apr-2020
Date of Acceptance19-May-2020
Date of Web Publication19-Feb-2021

Correspondence Address:
Belliappa Pemmanda Raju
Department of Dermatology, Rajarajeswari Medical College and Hospital, Kambipura, Mysore Road, Bengaluru - 560 074, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CDR.CDR_51_20

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  Abstract 


Background: Viral warts are caused by human papillomavirus. There are various treatment modalities which cause destruction of the warts. Not all of them are very effective on difficult-to-treat warts. For the treatment of difficult-to-treat warts, new and effective treatment includes intralesional immunotherapy. Objectives: The aim was to evaluate and compare the efficacy of intralesional Vitamin D and tuberculin purified protein derivative (PPD) as immunotherapy in difficult-to-treat warts. Materials and Methods: A total of 100 patients with difficult-to-treat viral warts were enrolled in this randomized controlled study. Group A patients were injected intralesionally with 2.5 TU of tuberculin PPD (0.1 ml) and Group B patients were injected with 0.1 ml of Vitamin D3 per lesion to a maximum of ten lesions. The clinical assessment was done by photographic measurements at baseline, before each treatment session, and after the completion of the treatment every 2 weeks for a total of four sessions. Unpaired t-test was used to compare both the treatment modalities. Results: In Group A, a total of 38 (76%) patients showed complete clearance and 12 (24%) showed partial response, while in Group B, a total of 42 (84%) patients showed complete clearance, while 8 (16%) showed partial response. There was no statistically significant difference between both the modalities. Conclusions: Intralesional Vitamin D3 injection and intralesional PPD may be a treatment option for difficult-to-treat warts that are unresponsive to conventional treatments. Both are equally effective with minimal side effects.

Keywords: Recalcitrant warts, tuberculin purified protein derivative, Vitamin D3


How to cite this article:
Raveendra L, Raju BP, C Dharam KK, Kumar Yadav VM. Comparison of purified protein derivative and vitamin D in the treatment of recalcitrant warts. Clin Dermatol Rev 2021;5:54-8

How to cite this URL:
Raveendra L, Raju BP, C Dharam KK, Kumar Yadav VM. Comparison of purified protein derivative and vitamin D in the treatment of recalcitrant warts. Clin Dermatol Rev [serial online] 2021 [cited 2021 Jun 13];5:54-8. Available from: https://www.cdriadvlkn.org/text.asp?2021/5/1/54/309768




  Introduction Top


Cutaneous warts are caused by human papillomavirus. There are various treatment modalities which sometimes may not result in complete clearance of warts. Local tissue destruction in the form of electrocautery, cryotherapy, laser surgery, and application of chemical irritants is the commonly employed method of treatment.[1] However, it is not practical for multiple lesions and palmo-plantar and facial lesions because of associated scarring, pigmentation, and recurrence. With immunotherapy, warts have been found to regress without any scarring, and the recurrence rate is minimal.[2],[3],[4]

We undertook this study to evaluate the efficacy of tuberculin purified protein derivative (PPD) versus Vitamin D3 immunotherapy for the treatment of viral warts.


  Materials and Methods Top


The study was conducted between December 2017 and December 2018 at a tertiary care hospital. Institutional ethical clearance was obtained. After proper clinical history and a detailed examination, written informed consent was obtained from all patients. Consent for children below the age of 5 years was taken from their parents. A total of 100 consecutive patients with difficult-to-treat warts such as palmoplantar warts, periungual warts, facial warts (>10 lesions), verruca vulgaris (>10 lesions), and verruca plana (>10 lesions), who were untreated or were off treatment for at least 1 month were included. Patients on immunomodulatory drugs, children below 5 years of age, pregnant females, and patients with a history of active systemic infection or illness were excluded from the study. Patients were alternately divided into Group A and Group B, and they received intralesional tuberculin PPD and Vitamin D3, respectively, according to the assigned group.

  • Group A: Into each lesion, 2.5 TU of PPD was injected. In case of multiple lesions, a maximum of ten premarked representative lesions covering all the sites, a maximum of 25 TU of PPD in each session was injected
  • Group B: Into each lesion, 0.1 ml of Vitamin D3 was injected. In case of multiple lesions, a maximum of ten premarked representative lesions covering all the sites, a maximum of 1 ml of Vitamin D3 in each session was injected, and clinical photographs were taken.


A total of four sessions were done at an interval of 2 weeks irrespective of whether patients had a complete response or not. Clinical response was assessed, and photographs were taken during each visit. Patients were followed up at 1 month after the last dose. After 6 months, all the patients were called telephonically to inquire about any recurrence. The response to treatment was evaluated by observing all the warts on the injected and noninjected sites. The response was graded as complete resolution on total clearance of the lesions, and as partial resolution if there was no or partial clearance of the lesion.


  Results Top


In this study, the maximum number of patients were in the age group of 21–40 years, which was 78 (78%) followed by <20 years, which was 14 (14%) followed by >40 years, which was 8 (8%), as shown in [Table 1]. Males outnumbered females in a ratio of 1.9:1. The most common site was the hands seen in 62 patients, and the mean duration of the occurrence of warts was 7.3 months [Table 2] and [Table 3]. In Group A, the maximum number of warts was 15 seen in 8 patients and the minimum number of warts was single large palmoplantar wart seen in four patients. Similarly, in Group B, the maximum number of warts in a patient was 35, and minimum number of warts was single large palmoplantar wart seen in 4 patients.
Table 1: Distribution of patient according to age

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Table 2: Distribution of warts according to site

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Table 3: Duration of lesions

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In both the groups, palmoplantar warts were the most common seen in 28 (56%) patients in Group A and in 34 (68%) patients in Group B. The other type of wart noticed was verruca vulgaris seen in 14 (28%) patients in Group A and in 9 (18%) patients in Group B. Both palmoplantar warts and verruca vulgaris were seen in 8 (16%) patients of Group A and in 7 (14%) of Group B.

The study showed that in Group A, out of 50 patients, 38 (76%) showed complete clearance, while 12 patients (24%) showed partial clearance [Table 4] and [Figure 1]. In Group B, out of 50 patients, 42 patients (84%) showed complete response, while 8 patients (16%) showed partial response [Table 4] and [Figure 2]. Unpaired t-test was used to compare both the treatment modalities. There was no statistically significant difference between both the modalities (P > 0.05).
Table 4: Results of treatment in Group A and Group B

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Figure 1: Group A – lesions before and after treatment

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Figure 2: Group B – lesions before and after treatment

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In Group A, among patients with palmoplantar warts, complete response was seen in 20 (72%), while partial response was seen in 8 (28%) patients. In Group B, among patients with palmoplantar warts, complete response was seen in 32 (94%), while partial response was seen in 2 (6%) patients [Table 5]. We compared the response between Group A and B with Z-test for equality of proportions; palmoplantar warts responded better to Vitamin D than to tuberculin PPD, which was statistically significant (P < 0.05).
Table 5: Results of treatment of palmoplantar warts in Group A and Group B

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Similarly, in Group A, among patients with verruca vulgaris, complete response was seen in 12 (85%) and partial response was seen in 2 (15%) patients. In Group B, among patients with verruca vulgaris, complete response was seen in 7 (77%) and partial response was seen in 2 (23%) patients [Table 6]. There was no statistically significant difference in response between the two groups.
Table 6: Results of treatment of verruca vulgaris in Group A and Group B

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At the end of follow-up, recurrence was observed in two patients (4%) in Group A and four patients (8%) in Group B [Table 7]. No allergic or systemic adverse reactions and no sign or symptoms of hypervitaminosis D were observed. The patients only complained of minimal-to-moderate pain during injection, which was managed by injecting 0.2 ml lignocaine prior to injection, and postprocedural pain was managed by nonsteroidal anti-inflammatory drugs.
Table 7: Recurrence of warts in Group A and Group B

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  Discussion Top


In viral, fungal, and mycobacterial infections, cell-mediated immunity is known to play a protective role. Spontaneous regression of the warts has been noted in various trials, and also a Cochrane review found a cure rate of 22% in the placebo arm.[5],[6] Immunotherapy is a new modality to increase cell-mediated immunity, and various substances are used to either stimulate or suppress body's immune system. This form of treatment helps the body to fight against cancer, infection, and other diseases.[7] To stimulate cell-mediated immunity, various viral, fungal, or mycobacterial antigens and vaccines have been tried intralesionally such as measles mumps rubella (MMR) vaccine, Bacillus–Calmette Guerin (BCG) vaccine), Candida antigen, and Mycobacterium indicus pranii vaccine.[2],[4],[6],[8],[9],[10],[11]

We chose to induce immunotherapy in patients of warts using tuberculin PPD or Vitamin D3. PPD was chosen because positive cell-mediated immune response with PPD is easy to induce because of the high prevalence of tuberculosis infection in India. In addition, PPD does not contain any viable organism, so it has a very low risk of hypersensitivity and can be used safely.[12] Vitamin D3 was again chosen because it does not contain any viable organism and is inert.

Injection of PPD activates T helper cell 1 cytokines, interleukin (IL)-4, IL-5, IL-8, interferon-gamma (INF-gamma), and tumor necrosis factor-alpha, which can activate cytotoxic and natural killer cells.[13] It also leads to the circulation of activated T cells in the body, thereby leading to clearance of injected as well as distant warts.[3],[4],[13],[14]

Our study showed that out of 50 patients, 38 (76%) showed complete clearance and 12 patients (24%) showed partial clearance of warts when PPD was used. Similar to our study, Saoji et al. reported complete clearance in 76% of patients and 24% were nonresponders when intralesional PPD was used.[12] Elela et al. and Singh et al. noted complete clearance in 94.1% of patients and 80% of patients, respectively.[14],[15] Kus et al. noted complete clearance in five (29%) patients, partial response in ten (59%) patients, and no response in two (12%) patients while using intralesional tuberculin injection.[16]

Various studies have used different dosing schedules for injecting PPD or other injectables into the warts.[12],[13] The dose per lesion given in few studies was dependent on the induration obtained after giving an intradermal test dose of PPD prior. A dose of 0.3 ml PPD was injected if induration obtained was 5–9 mm, 0.2 ml was injected if it was 10–15 mm, and 0.1 ml was injected if induration was more than 15 mm.[17] We did not check the sensitivity to tuberculin in our patients because Indian patients are usually reactive to tuberculin due to the prevalence of tuberculosis.

In our study, we have injected PPD in up to a maximum of ten warts at a time and achieved a complete clearance in 76% of cases. Milante has compared the efficacy of injection into a single wart and injection of PPD into multiple warts and found that injecting into multiple warts at a time showed better results than injecting into a single wart. Similar results were reported by Saoji et al. and others.[3],[4],[10],[11],[17]

Vitamin D, at low concentrations, stimulates in vitro keratinocyte proliferation and differentiation, while it inhibits the same at higher concentrations. Antimicrobial peptide expression is induced on the upregulation of Vitamin D receptors (VDR) in the skin.[18] Recent experiments have shown Vitamin D to have immunomodulatory effects by inhibiting the expression of IL-6, IL-8, tumor necrosis factor-alpha, and gamma, which in turn is mediated through VDR-dependent pathway.[19]

Our study showed that out of 50 patients, 42 (84%) showed complete clearance and 8 patients (16%) showed partial clearance when Vitamin D was used. Similar results were obtained by Raghukumar et al. and Singh et al. where complete clearance was seen in 90% and 72.5% of patients, respectively. Topical form of Vitamin D3 has been used for common as well as anogenital warts, showing good results.[15],[20] Aktas et al. were the first to use intralesional Vitamin D3 in the treatment of plantar warts recalcitrant to various treatments. They noted complete resolution in 80% of patients.[21] Kavya et al. showed complete clearance of warts in 78.57% of patients treated with intralesional Vitamin D3.[19]

In our study, intralesional immunotherapy with PPD and Vitamin D showed no statistically significant difference in the results obtained. Similar results were noted by Singh et al. in their study.[4] In addition, we observed that there was clearance of warts at anatomically distant sites together with the disappearance of the injected wart with both modalities of immunotherapy. This is also called as field effect and is very helpful for situations where there are multiple warts or intractable warts.[17] Similar observation was noted by Singh et al. and Wananukul et al. in their study.[4],[15] Intralesional immunotherapy has this advantage that it not only treated warts, but due to it, the distant warts also disappeared. This is because immunotherapy enhances the host cell-mediated immunity against the virus.[22]

We observed that Vitamin D3 was better than tuberculin PPD for the treatment of palmoplantar warts, wherein complete clearance was seen in 94% and 72% of patients, respectively. In a study by Fathy et al., 70% clearance rate of palmoplantar warts was observed with intralesional Vitamin D3, and it was superior compared with intralesional injection of Candida antigen.[23] In the study by Rezai et al., 65.2% of patients observed clearance of palmoplantar warts when MMR was used as immunotherapy.[24] Observing these results, we can imply that in palmoplantar warts, Vitamin D3 immunotherapy is a good treatment option.

We observed that both Vitamin D3 and tuberculin PPD showed 85% and 77% response in patients with verruca vulgaris, respectively, and there was no statistical difference between the two treatment modalities. In a study by Nofal and Nofal, complete response was seen in 81.4% of patients with common warts when MMR was used for immunotherapy.[10] In another study by Majid and Imran in patients with recalcitrant verruca vulgaris, 56% showed complete response with intralesional injection of Candida antigen.[25]

In our study, we did not come across any major side effects except pain during and after injection. Few other studies also showed no major side effects while using intralesional Vitamin D3.[15],[19] A meta-analysis of intralesional immunotherapy for the treatment of warts showed not much side effects with PPD when compared to placebo.[1] Nodule formation at the site of injection in 25%; hyperpigmentation in 30%; and swelling, fever, blister, erythema, and induration were noted in 10% of patients in the study by Singh et al. using PPD.[15]

In a study by Garg and Baveja et al. using Mycobacterium w vaccine for the treatment of warts, many local and systemic complications such as high-grade fever, redness, swelling, induration, and ulcer formation were noted at the injection site.[26] Flu-like symptoms were noted in patients treated with MMR vaccine intralesionally.[27],[28] In a study by Singh et al. using immunotherapy with M. pranii vaccine, low-to–moderate-grade fever, nodule, ulcer, atrophic scar at the site of injection, and paraesthesia distal to the site of injection were noted in 81.8% of patients.[6]

A meta-analysis of intralesional immunotherapy for the treatment of warts showed that PPD and MMR were the most effective compared to many other agents such as trichophyton antigen, BCG, Candida antigen, M. indicus pranii, Mycobacterium w, Vitamin D, corynebacterium parvum, INF-alpha, INF-gamma, propionibacterium parvum, propionibacterium acnes, and also autoinoculation.[1]


  Conclusions Top


Overall, intralesional Vitamin D3 and intralesional PPD are effective in the treatment of difficult-to-treat warts. Intralesional Vitamin D3 injection and intralesional PPD may be treatment options for warts that are unresponsive to conventional treatments. It is a simple, well-tolerated treatment method that is easy to administer in outpatient clinics. Its advantages over conventional methods include treatment of distant warts and avoidance of scarring. One disadvantage may be the repeated sittings required for the treatment, so it may be considered only for difficult-to-treat warts.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Salman S, Ahmed MS, Ibrahim AM, Mattar OM, El-Shirbiny H, Sarsik S, et al. Intralesional immunotherapy for the treatment of warts: A network meta-analysis. J Am Acad Dermatol 2019;80:922-3.  Back to cited text no. 1
    
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Clifton MM, Johnson SM, Roberson PK, Kincannon J, Horn TD. Immunotherapy for recalcitrant warts in children using intralesional mumps or Candida antigens. Pediatr Dermatol 2003;20:268-71.  Back to cited text no. 2
    
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Eassa BI, Abou-Bakr AA, El-Khalawany MA. Intradermal injection of PPD as a novel approach of immunotherapy in anogenital warts in pregnant women. Dermatol Ther 2011;24:137-43.  Back to cited text no. 3
    
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Wananukul S, Chatproedprai S, Kittiratsacha P. Intralesional immunotherapy using tuberculin PPD in the treatment of palmoplantar and periungual warts. Asian Biomed 2009;3:739-43.  Back to cited text no. 4
    
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Gibbs S, Harvey I, Sterling JC, Stark R. Local treatments for cutaneous warts. Cochrane Database Syst Rev 2006;3:CD001781.  Back to cited text no. 5
    
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Singh S, Chouhan K, Gupta S. Intralesional immunotherapy with killed Mycobacterium indicus pranii vaccine for the treatment of extensive cutaneous warts. Indian J Dermatol Venereol Leprol 2014;80:509-14.  Back to cited text no. 6
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Nofal A, Nofal E. Intralesional immunotherapy of common warts: Successful treatment with mumps, measles and rubella vaccine. J Eur Acad Dermatol Venereol 2010;24:1166-70.  Back to cited text no. 10
    
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Horn TD, Johnson SM, Helm RM, Roberson PK. Intralesional immunotherapy of warts with mumps, Candida, and Trichophyton skin test antigens: A single-blinded, randomized, and controlled trial. Arch Dermatol 2005;141:589-94.  Back to cited text no. 11
    
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Saoji V, Lade NR, Gadegone R, Bhat A. Immunotherapy using purified protein derivative in the treatment of warts: An open uncontrolled trial. Indian J Dermatol Venereol Leprol 2016;82:42-6.  Back to cited text no. 12
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Elela IM, Elshahid AR, Mosbeh AS. Intradermal vs. intralesional purified protein derivatives in treatment of warts. Golf J Deramatol Venereol 2011;18:21-6.  Back to cited text no. 14
    
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Singh SK, Mohan A, Gupta AK, Pandey AK. A comparative study between intralesional PPD and Vitamin D3 in treatment of viral warts. Int J Res Dermatol 2018;4:197-201.  Back to cited text no. 15
    
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Milante RR, Venida-Tablizo A, King-Ismael D. Efficacy and safety of single versus multiple intralesional immunotherapy with purified protein derivative (PPD) in the treatment of multiple verruca vulgaris. Int J Dermatol 2019;58:1477-82.  Back to cited text no. 17
    
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Raghukumar S, Ravikumar BC, Vinay KN, Suresh MR, Aggarwal A, Yashovardhana DP. Intralesional Vitamin D3 injection in the treatment of recalcitrant warts: A novel proposition. J Cutan Med Surg 2017;21:320-4.  Back to cited text no. 20
    
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Rezai MS, Ghasempouri H, Asqary Marzidareh O, Yazdani Cherati J, Rahmatpour Rokni G. Intralesional injection of the Measles-Mumps-Rubella vaccine into resistant palmoplantar warts: A randomized controlled trial. Iran J Med Sci 2019;44:10-7.  Back to cited text no. 24
    
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