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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 3  |  Page : 522-528

Intralesional vitamin D3 vs purified protein derivative in treatment of recalcitrant cutaneous and venereal warts


Department of Dermatology and Venereology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt

Date of Submission16-Feb-2020
Date of Acceptance01-Mar-2020
Date of Web Publication2-Oct-2020

Correspondence Address:
MD Doaa A.E.-M.H Pessar
Assistant Professor of Dermatology and Venereology, Department of Dermatology and Venereology, Faculty of Medicine for Girls, Al-Azhar University, 125 Khalig Elmasri Street, Hadaiq Elqoba, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjamf.sjamf_24_20

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  Abstract 


Introduction Human papilloma virus (HPV) can produce a significant amount of anxiety and stress in patients. Many therapeutic options are available for treating warts. More recent and effective treatment, including intralesional immunotherapy, have been tried in the recent times with variable success rates.
Aim The aim was to compare the efficacy, safety, and the clinical response of intralesional vitamin D3 (Vit D3) vs purified protein derivative (PPD) in the treatment of recalcitrant cutaneous and venereal warts.
Patients and methods This study was carried out on 30 patients with cutaneous and venereal recalcitrant warts. Fifteen patients (11 patients with recalcitrant cutaneous warts and four patients with recalcitrant venereal warts) were subjected to intralesional injection of Vit D3 in one up to three warty lesions in every patient; the other 15 patients (11 patients with recalcitrant cutaneous warts and four patients with recalcitrant venereal warts) were subjected to intralesional injection of PPD in one up to 15 warty lesions in every patient. Assessment of the results was done by clinical evaluation, patient satisfaction, and multiple digital photographs.
Results We found that the total response rate to immune therapy was 83.3% in both groups of patients collectively. In the Vit D3-treated group, complete response was achieved in 73.3% of patients and partial response in 26.6%. However, in the PPD-treated group, complete response was achieved in 46.6% of patients, partial response in 20%, and 33.3% of the patients showed no response. The overall clinical response in Vit D3-treated group was significantly higher than in the PPD-treated group (100 vs 66.67%, respectively). We also found that the longer the duration of HPV infection, the poorer the response rate to treatment and the need for more sessions.
Conclusion Clinical efficacy and safety of intralesional injection of Vit D3 vs PPD for treatment of HPV, the high response rate, the absence of adverse effects, low cost, and the affordability of the Vit D-treated group makes it a very useful tool in the treatment of HPV and is more superior than the PPD.

Keywords: human papilloma virus, purified protein derivative, vitamin D3


How to cite this article:
Pessar DA, Mohamed AS, Galal SA. Intralesional vitamin D3 vs purified protein derivative in treatment of recalcitrant cutaneous and venereal warts. Sci J Al-Azhar Med Fac Girls 2020;4:522-8

How to cite this URL:
Pessar DA, Mohamed AS, Galal SA. Intralesional vitamin D3 vs purified protein derivative in treatment of recalcitrant cutaneous and venereal warts. Sci J Al-Azhar Med Fac Girls [serial online] 2020 [cited 2020 Oct 26];4:522-8. Available from: http://www.sjamf.eg.net/text.asp?2020/4/3/522/296930




  Introduction Top


Human papilloma virus (HPV) is a type of infection that has no single therapy proven to be effective. There is a constant circular argument about the best treatment because of lack of sound scientific evidence to support any particular treatment. However, balancing the adverse effects with efficacy must always be considered [1].

Immunotherapies are agents that modulate the immune response to enhance or positively alter general or local immunity. Immunotherapy has many advantages over other modalities of treatment such as lack of need to treat all lesions, lack of scarring, time and cost effectiveness, less recurrence rates, and less painful [2].

Our aim was to compare the efficacy, safety, and the clinical response of intralesional injection of vitamin D3 (Vit D3) vs purified protein derivative (PPD) in the treatment of recalcitrant cutaneous and venereal HPV infection.


  Patients and methods Top


This study was carried out on 30 patients with recalcitrant cutaneous and venereal warts recruited from the outpatient Dermatology Clinics in Dallah Hospital, Riadh, KSA, from July 2018 to July 2019.

Inclusion criteria

Any adult patient aged above 16 years old, of either sex, who presents with more than 2 calcitrant cutaneous or venereal HPV lesions with absence of concurrent systemic or topical treatment of HPV was included in our study.

Exclusion criteria

Any patients with fever or any signs of inflammation or infection, pregnant or lactating women, or immunocompromised patients were excluded from this study.

The study was approved by the Local Institutional Ethics Committee of Dallah Hospital, Riyadh, KSA. All participants were informed about the nature of the study, and written informed consent was obtained.

All patients underwent detailed history taking with special reference to the presence of any systemic disease, tuberculosis, atopy, diabetes mellitus, duration, site and number of warty papules, and history of previous treatment. General and dermatological examination of type, site, size, and number of warty lesions was done.

Treatment protocols

The patients were divided into two groups.
  1. Group 1: it included 15 patients subjected to intralesional injection of Vit D3 in one up to three warty lesions. Vit D3 is a clear, colorless, sterile solution available in vials containing 600 000 IU of cholecalciferol in 1 ml (15 mg). The selected warts were injected with 0.2 ml of Vit D3 (15 mg/ml) slowly into the base of each wart with a 27- G insulin syringe.
    • The injections were repeated every 2 weeks for a maximum of four injections. If complete clearance was achieved before four injections, the treatment was stopped, and patient was followed up for recurrence. Patients were evaluated for treatment efficacy and adverse reactions every 2 weeks for first 2 months and monthly thereafter to record for any recurrence for 6 months.
  2. Group 2: it included 15 patients subjected to intralesional injection of tuberculin PPD in one up to 15 warty lesions for every patient.


PPD is a clear, colorless, sterile solution; every 0.1 ml contains 5 tuberculin units. The bottle is valid for one month from the first use.

Injection was done at 2-week interval until complete clearance or for a maximum of four injections whichever was nearer.

Primary test injection dose was done before immune therapy as follows:
  1. For Vit D3, this was done by applying a small drop of Vit D3 followed by scratching the skin by an insulin syringe and was read after 15 min (presence of erythema or wheal means a positive test) [3].
  2. PPD patients were tested for immunity by intradermal injection of 0.1 ml of tuberculin PPD containing 5 tuberculin units in the skin of the forearm. The test was read at 48–72 h after administration, and sensitivity was indicated by induration with or without erythema. The test was considered positive when the induration was greater than or equal to 5 mm in diameter [4],[5].
  3. The clinical response to treatment was evaluated by photographic comparison, patients’ satisfaction, and the decrease in size and number of warts.


The response of the treated wart was considered as follows:
  1. Complete resolution (if disappearance of the lesion was complete and appearance of normal skin).
  2. Partial resolution (>5% reduction in number and regression in size).
  3. No response (persistent lesions without any reduction noticed).


Assessment of the results was done depending on both clinical observations and multiple digital photographs.

Statistical analysis

Patients’ data were presented as frequency and percentage for categorical variables, and mean (median) and SD for numerical variables [11]. Groups were compared by independent samples Student’s t-test and χ2-test for numerical and categorical data, respectively. Pearson’s correlation coefficient test was used for measuring association between two quantitative variables. All data and statistical analyses were handled by statistical package for the social sciences (SPSS, IBM; SPSS Inc., Chicago, USA) computer package version 18.


  Results Top


Demographic, duration of lesions, and pretreatment clinical data of the two studied groups are shown in [Table 1]. Their ages ranged between 16 and 50 years, with average (mean±SD) of 39.60±9.71 and 38.80±7.14 for Vit D3-treated and PPD-treated groups, respectively ([Table 1] and [Figure 1]).
Table 1 Pretreatment clinical data in both studied groups of patients

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Figure 1 A 39-year-old male patient presented with multiple resistant warts. (a) Before PPD injection, (b) after first session of PPD injection and (c) after 3 sessions of PPD injection. A 43-year-old male patient with genital warts: (d) before PPD injection, (e) after 2 sessions of PPD injection, and (f) after three sessions of PPD injection. A 41-year-old female patient with multiple recalcitrant warts of the hands: (g) before Vit D3 injection, (h) after first session of Vit D3 injection, and (i) after two sessions of Vit D3 injection. PPD, purified protein derivative.

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Regarding treatment response, there was significant improvement in vit D3-treated group, where 11 (73.3%) of 15 patients achieved complete response and four (26.6%) patients achieved partial response. However, in the PPD-treated group, seven (46.6%) of 15 patients achieved complete response, three (20%) patients achieved partial response, and five (33.3%) patients showed no response (P<0.05) ([Table 1]).

Patients who had complete response after first, second, and third sessions in Vit D3-treated group were more than PPD-treated group (13.3 vs 13.3%, 33.33 vs 13.3%, and 26.6 vs 20% in Vit D3- and PPD-treated groups, respectively) ([Table 2]).
Table 2 Relation between the response to treatment and the number of sessions

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[Table 3] reveals the maximum response and mean duration of both studied groups. In Vit D3-treated group, patients with complete response showed maximum response at session 2.18±0.75, and the mean duration of their warty papules was 4.29±2.49 months, and patients with partial response showed maximum response at the third session, and the mean duration of warty papules was 12.25±8.22 months.
Table 3 Maximum response and mean duration in both studied groups of patients

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However, in the PPD-treated group; patients with complete response showed maximum response at session 2.14±0.89, and the mean duration of their warty papules was 3±1.73 months, and patients with partial response showed maximum response at the third session, and the mean duration of warty papules was 8.66±3.05 months ([Table 3]).

There was a high significant correlation between the duration of HPV and the number of sessions needed for response (the longer the duration of HPV infection, the more the number of sessions needed for resolution) ([Table 4]).
Table 4 Correlation between duration of illness and the number of sessions

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No statistically significant correlation was found between the sex of the patient and the response to treatment in Vit D3-treated and PPD-treated groups (P>0.05) ([Table 5]). Moreover, no statistically significant correlation was found between the number of lesions and the response to treatment in Vit D3-treated and PPD-treated groups (P>0.05) ([Table 6]).
Table 5 Comparison between patient groups regarding the response to treatment in relation to the sex of the patients

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Table 6 Comparison between patients’ groups regarding the response to treatment in relation to the number of the lesions

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On comparing the adverse effects in Vit D3-treated and PPD-treated groups, no statistically significant difference was found between the two groups (P>0.05) ([Table 7]).
Table 7 Comparison between patients’ groups regarding the adverse effects of treatment

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  Discussion Top


HPV can create a significant amount of anxiety in patients as a result of their persistence and because of the social stigma that remains attached to their presence4. In addition, there is no right single approach to a patient with HPV because of lack of sound scientific evidence to support any particular treatment [1].

Our study compared the clinical efficacy and safety of intralesional injection of Vit D3 vs PPD for treatment of HPV; the total response rate in our study was 83.33% in both groups of patients collectively. In the Vit D3-treated group, complete response was achieved in 73.3% of patients and partial response in 26.6%. However, in the PPD-treated group, complete response was achieved in 46.6% of patients, partial response in 20%, and 33.3% of the patients showed no response. The response was subdivided into complete and partial responses. Complete response in PPD was achieved in nine (60%) patients, with disappearance of all lesions, even those that were not injected directly with PPD, and partial response was achieved in four (26.66%) patients, whereas two (13.33%) patients showed no response. In the Vit D3-treated group, complete response was achieved in 73.33% of patients, and partial response in 26.67%. None of the Vit D3-treated patient showed no response.

Regarding the response in Vit D3-treated group, our results agreed with and were superior to those of Kavya et al. [2], who reported complete clearance was seen in 82.60% of patients with verruca vulgaris. Adverse effects were seen in 80% of the patients, but all were minor with no life-threatening complications. Swelling at the site of injection was the most common adverse effect seen in 78.57% of patients, which resolved without any treatment in 4 weeks. Dyspigmentation was seen in one patient. Recurrence was observed in one patient with palmoplantar wart during 6-month follow-up period. Moreover, Aktas et al. [3] reported close results to those of Kavya et al. [2], where 80% of the patients showed complete resolution of their warts at the 2-month follow-up. At the 6-month follow-up, no recurrences were observed. The overall cure rate was 80%, and the patients were very satisfied with the results. In our work, none of the patients experienced adverse effects such as erythema, swelling, itching, dyspigmentation, ulcer, or scar formation. No allergic or systemic adverse reactions and no sign or symptoms of hypervitaminosis D were observed. The only patient complaints were of minimal to moderate pain during injection. The better response in our study could be attributed to the different treatment protocol of the studies. In our work, we injected Vit D3 every 2 weeks, whereas in the studies by Kavya et al. [2] and Aktas et al. [3],the average number of days between sessions was 21 and 30 days, respectively.

The exact mechanism of Vit D activity against warts remains to be elucidated; however, it controls cell proliferation and differentiation and has immunoregulatory activities. Its effects are mediated via the vitamin D receptor, which is present in keratinocytes, melanocytes, fibroblasts, and immune system cells of the skin.

The exact mechanism of PPD in the resolution of HPV infection may be owing to generation of strong cytokines and T-cell responses.

Minimal or no response to PPD may be owing to either lack of a memory T-cell population capable of targeting the virus or that lymphocytes fail to expand clonally with appropriate stimulation or unable to traffic to the sites of viral infection. Another explanation is that lymphocytes are weak effectors in terms of elaboration of necessary cytokines and/or recruitment of additional effector cells [6].

So, the previous mechanisms may also explain the weaker response of PPD in comparison with Vit D3 that was observed in our study.

Regarding the number of sessions needed for response, we found that patients who had complete response after first, seocnd, and third sessions in Vit D3-treated group were more than PPD-treated group (13.3 vs 13.3%, 33.3 vs 13.3%, and 26.6 vs 20% in Vit D3- and PPD-treated groups, respectively).

We also found that there is a direct proportional relationship between the duration of HPV infection and the number of sessions needed for response (r=0.46, P=0.01). This implies that early treatment of HPV is better and that waiting for spontaneous resolution sometimes makes the condition difficult to treat. The results of Kavya et al. [2] were in accordance with our findings. In their study, the mean duration of warts was 10.2 months and 10.6 months in patients with complete and partial response, respectively, whereas in patients with no response, the mean duration of warts was 15 months.

In the Vit D3-treated group, the mean duration of warts was 4.29±2.49 and 12.25±8.22 months in patients with complete and partial response, respectively. However, in the PPD-treated group, the mean duration of warts was 3±1.73 and 8.66±3.05 months in patients with complete and partial response, respectively, and the mean duration in patients with no response was 13.40±4.33 months.

This denotes that the longer the duration of HPV, the less response to treatment in both groups.

Regarding the effect of clinical variables on the treatment response, the age, sex, and number of lesions did not show a significant effect on the treatment response with both Vit D3- and PPD-treated groups.

Regarding the adverse effects, no serious adverse effects were reported in the patients included in our study with both Vit D3 and PPD treatment. Only insignificant local reactions in the form of swelling and erythema were seen. Similar reactions were reported by Kavya et al. [2] and Aktas et al. [3]. Only two patients in PPD-treated group had postinflammatory hyperpigmentation in our study.

Saoji et al. [7] evaluated PPD for treatment of palmoplantar and periungual warts and reported that complete resolution at the third session was 67%, whereas after the sixth session, complete resolution reached 93%. They injected PPD into the largest wart every 14 days until the lesion disappeared or for a maximum of six treatments. This regimen was different from our protocol of treatment as we injected PPD every 2 weeks in one up to 15 lesions in the same patient.Eassa et al. [8] and Wanaukul et al. [9] also used different regimen via weekly intradermal injection of PPD in pregnant women with anogenital warts. Overall, 47.5% of their patients demonstrated complete clearance, 37.5% had partial response, and 15% did not respond to treatment.

In our study, cutaneous warts showed better response than venereal warts. Overall, two cases from four of venereal warts showed no response with PPD group and one case from four venereal wart cases showed partial response with Vit D3 group.

Saoji et al. [7] evaluated PPD for treatment of venereal warts and reported complete resolution in 60% of cases.

Akula et al. [10] evaluated Vit D3 and PPD in cutaneous warts, not in venereal warts, and they reported complete clearance was observed in 90.9% of patients who received PPD and 83.3% of patients achieved complete clearance who received Vit D3.


  Conclusion Top


We conclude that both Vit D3 and PPD are safe and effective immunotherapeutic agents for the treatment of recalcitrant cutaneous and venereal HPV especially if the lesions are disseminated, resistant to treatment, and in sensitive areas, with many advantages over other modalities of treatment, such as lack of need to treat all lesions, lack of scarring, time and cost effectiveness, and less painful. Moreover, Vit D3 is superior to PPD in treatment of HPV owing to its better results, less adverse effects, cheaper, and easily stored.

Recommendations

A further prospective study on a large population is recommended and long-term follow-up is mandatory to detect recurrences after both modalities.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Garg S, Baveja S. Intralesional immunotherapy for difficult to treat warts with Mycobacterium w vaccine. J Cutan Aesthet Surg 2014; 7:203–208.  Back to cited text no. 1
    
2.
Kavya M, Shashikumar BM, Harish MR, Shweta BP. Safety and efficacy of intralesional vitamin D3 in CUTANEOUS WARTS: AN OPEN UNCONTROLLED TRIAL. J Cutan Aesthet Surg 2017; 10:90–94.  Back to cited text no. 2
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3.
Aktas H, Ergin C, Demir B, Ekiz O. Intralesional vitamin D injection may be an effective treatment option for warts. J Cutan Med Surg 2016; 20:118–122.  Back to cited text no. 3
    
4.
Kus S, Ergun T, Gun D, Akin O. Intralesional Tuberculin for treatment of refractory warts. J Eur Acad Dermatol Venereol 2005; 19:515–516.  Back to cited text no. 4
    
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Smolinski KN, Yan AC. How and when to treat molluscum contagiosum and warts in children. Pediatr Ann 2005; 34:211–221.  Back to cited text no. 5
    
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Shaheen MA, Salem SA, Fouad DA, El-Fatah AA. Intralesional tuberculin (PPD) versus measles, mumps, rubella (MMR) vaccine in treatment of multiple warts: a comparative clinical and immunological study. Dermatol Ther 2015; 28:194–200.  Back to cited text no. 6
    
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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; 82:42–46.  Back to cited text no. 7
    
8.
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; 24:137–143.  Back to cited text no. 8
    
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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; 3:739–743.  Back to cited text no. 9
    
10.
Akula ML, Shetty M, Shetty V, Patel P, Basil A. Comparative study of therapeutic efficacy of intralesional vitamin D3 versus intralesional purified protein derivative in the treatment of warts. Indian J Clin Exp Dermatol 2018; 4:226–231.  Back to cited text no. 10
    
11.
Sokal RR, Rohlf FJ. The principles and practice of statistics in biological research. In: Sokal RR, Rohlf FJ, editors. Text Book of Biometry, 3rd ed. New York, NY: Freeman WH; 1995; 313–314  Back to cited text no. 11
    


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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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