|Year : 2022 | Volume
| Issue : 1 | Page : 26-30
|Intralesional purified protein derivative of tuberculin versus intralesional mycobacterium W vaccine in treatment of recalcitrant extragenital warts: A randomized, single-blinded, comparative study
Alpana Mohta1, Suresh Kumar Jain2, Rajesh Dutt Mehta1, Aakanksha Arora1
1 Department of Dermatology, Venereology and Leprosy, Sardar Patel Medical College, Bikaner, Rajasthan, India
2 Department of Dermatology, Venereology and Leprosy, Government Medical College, Kota, Rajasthan, India
|Date of Web Publication||19-Apr-2022|
Department of Dermatology, Venereology and Leprosy, Sardar Patel Medical College, Bikaner - 334 001, Rajasthan; Postal Address: 4 E, 155-156, Jai Narayan Vyas Colony, Bikaner - 334 002, Rajasthan
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Introduction: Of late, immunotherapy has emerged as a promising therapeutic modality for the treatment of recalcitrant and difficult to treat warts. Purified protein derivative of tuberculin (PDD) and mycobacterium w (Mw) vaccine hold promising prospects for the treatment of verruca, especially in a country like ours where a majority of the population is already sensitized to mycobacterium tuberculosis both due to disease endemicity and Bacillus Calmette-Guérin (BCG) vaccination. Aims and Objectives: We aimed at evaluating the treatment outcome of intralesional PPD tuberculin and Mw vaccine in the treatment of recalcitrant extragenital warts in immunocompetent subjects. Materials and Methods: The patients included immunocompetent subjects between the ages of 16 and 65 years with two or more extragenital warts. The patients were randomized into two groups, namely A (PPD Tuberculin) and B (Mw vaccine). In both groups, 0.1 mL of active intralesional immunogen was injected at the base of the largest wart. The doses were repeated at 4 weeks' intervals for a maximum of 5 injections. Additionally, the improvement in quality of life was measured using the Hindi-validated version of the Dermatology Quality of Life Index (DLQI) questionnaire. Results: Ninety-seven patients completed the study, with 46 in group A and 51 in group B. In group A, 24 (52.17%) patients had complete clearance in all warts, and in group B, 32 (62.75%) (P = 0.38). The most common adverse event in patients of group A was transient injection site erythema and swelling, whereas that in group B was mild transient fever. None of the patients showed any signs of recurrence in the ensuing follow-up period. There was a statistically significant improvement in the mean DLQI scores after treatment in both groups (P < 0.0001). Conclusion: Both PPD Tuberculin and Mw vaccine are effective in the treatment of recalcitrant warts with minimal recurrence rate. The safety profile of PPD is superior to Mw vaccine. We suggest both to be used as first-line therapy in the treatment of difficult to treat warts.
Keywords: Immunotherapy, Mw vaccine, PPD tuberculin, recalcitrant warts, warts
|How to cite this article:|
Mohta A, Jain SK, Mehta RD, Arora A. Intralesional purified protein derivative of tuberculin versus intralesional mycobacterium W vaccine in treatment of recalcitrant extragenital warts: A randomized, single-blinded, comparative study. Indian J Dermatol 2022;67:26-30
|How to cite this URL:|
Mohta A, Jain SK, Mehta RD, Arora A. Intralesional purified protein derivative of tuberculin versus intralesional mycobacterium W vaccine in treatment of recalcitrant extragenital warts: A randomized, single-blinded, comparative study. Indian J Dermatol [serial online] 2022 [cited 2023 May 29];67:26-30. Available from: https://www.e-ijd.org/text.asp?2022/67/1/26/343278
| Introduction|| |
Extra genital warts are benign tumors arising from keratinocytes infected with human papilloma virus (HPV). While most warts either resolve on their own or with conventional treatment options, some warts over the course of time tend to become recurrent and recalcitrant. Of lately, various immunogens have been tried for the treatment of such warts with an excellent rate of response. Antigens such as measles, mumps, and rubella (MMR) vaccine, candida antigen, trichophyton antigen, Bacillus Calmette-Guérin (BCG) vaccine, Propionibacterium parvum, Mycobacterium w (Mw) vaccine, and purified protein derivative of tuberculin (PPD) have been utilized for the same.
Both Mw vaccine and PPD are antigens based on the Mycobacterium genus. Mw vaccine consists of the Mycobacterium inducus pranii, a multipurpose vaccine being used for myriad diseases for a long time but only recently approved for leprosy patients. Purified protein derivative (PPD), an antigen used for testing any prior exposure to the tuberculin protein, is extracted from Mycobacterium tuberculosis. Both the above-mentioned immunogens hold promising prospects for the treatment of verruca, especially in a country like ours where a majority of the population is already sensitized to mycobacterium tuberculosis both due to disease endemicity and BCG vaccination at birth as part of the national immunization program.
These immunogens rely on the induction of Th1-mediated immune response by upregulation of interleukin-2 (IL-2), IL-4, IL-5, and interferon-γ (IFN-γ).
This study was aimed at evaluating the efficacy and safety of intralesional Mw vaccine and intralesional PPD in the treatment of patients with recalcitrant extragenital warts in immunocompetent subjects and changes in quality of life in study subjects.
| Method|| |
This prospective, randomized interventional study was initiated after obtaining due approval from the institutional ethical board and conducted between the months of September 2019 and September 2020. The patients included immunocompetent subjects between the ages of 16 and 65 years with two or more extragenital warts. Only patients with recalcitrant warts, off all other concurrent treatment options for the last 1 month, were chosen for the study. Patients with warts failing to respond after five treatments over a period of 6 months were considered as having recalcitrant warts.
Lactating females, patients with both genital and extragenital warts, patients with any sort of immunosuppression, or those with any history of prior hypersensitivity reaction to any of the immunogens or their components were excluded from the study.
All the patients gave their written informed consent before being enrolled in the study. The patients were randomly divided into two groups A (PPD) and B (Mw vaccine). In order to minimize the bias and maximize the result validity, our study was blinded. However, our trial could only be single-blinded, considering the limited number of the researchers involved and the practical aspects of dose adjustment while keeping in mind some potential specific side effects of each immunogen. The patients were randomized in an unstratified manner by utilizing an open list of computer-generated random number table.
In group A, the patients were treated with 0.1 mL of intralesional injection of PPD tuberculin using an insulin syringe, injected in the largest wart. Similarly, in group B, injection Mw vaccine was administered in the largest wart in the dose of 0.1 mL. In both groups, injections were repeated every fourth week, till there was complete clearance of all warts or a maximum of 5 injections. Any adverse events during or after treatment were noted on follow-up visits. Post-treatment follow-up was done every month for at least 3 months after the completion of therapy.
Response to treatment
Response to treatment in injected warts was graded as: Complete response (CR) if 100% clearance was seen with reappearance of normal skin markings, partial response (PR) if 99%–50% reduction in size was seen, and inadequate or no response (NR) if <50% reduction was observed. Similarly, for uninjected warts, CR was labeled as complete clearance of all uninjected warts (including distant warts), PR was ≥50% reduction in size/number of uninjected warts, and <50% reduction in size/number was labeled as NR.
Evaluation of quality of life
A Hindi-validated version of prof Andrew Y Finlay's Dermatology Quality of Life Index (DLQI) was used for the evaluation of the quality of life (QOL) after obtaining due approval from the creator. The patients were asked to fill the questionnaire before initiation of treatment and after completion of follow-up. The QOL was assessed before initiation of treatment and at the end of follow-up period.
The outcome was assessed according to the clearance of warts and improvement in QOL.
The sample size for each group was calculated using the probability of 95% with a significant result considered at 5%, giving the sample size to be 42 per group. However, we targeted to keep the sample size to be 45 per group in order to avoid any further reduction in size due to possible dropouts.
Simple random sampling was done. The randomization was done using an open list of computer-generated random number tables. This unstratified randomization involved patients choosing a random number that was mentioned on the patient's prescription for further visits. Allocation concealment was done using sequentially numbered, opaque, and sealed envelopes. Numbers were assinged to the envelopes beforehand, and the investigators opened the envelopes sequentially, only after the participant's name was being written on the envelope.
Statistical analysis of continuous and categorical variables were calculated using mean, standard, absolute numbers, and percentage. Continuous variables between two groups were compared using an unpaired t-test and within a group using the paired t-test. The Chi-square test was used in order to compare the nominal categorical data between the groups.
| Results|| |
Ninety-seven patients completed the study with 46 in group A and 51 in group B. The mean age of the patient in group A was 31.3 ± 5.7 years, whereas that in group B was 33.6 ± 6.1 years. The male to female ratio was 2.1:1 and 1.9:1 in groups A and B, respectively. In group A, amongst the injected warts, CR was seen in 29 (63%) patients, PR in 8 (17.4%), and NR in 9 (19.6%) patients [Figure 1] and [Figure 2]. Whereas amongst patients in group B, as far as injected warts were concerned, 39 (76.5%) had complete resolution in their warts, 7 (13.7%) had PR, and only 5 (9.8%) had NR [Figure 3] and [Figure 4]. However, the response rate in both groups was comparable, and statistically insignificant difference was observed (P = 0.29) [Table 1].
|Figure 1: (a) Multiple interdigital warts. (b) Complete resolution after 3 doses of PPD Tuberculin|
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|Figure 2: (a) Multiple verruca vulgaris on the dorsum of the right hand. (b) Complete resolution after 4 doses of PPD Tuberculin|
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|Figure 3: (a) Multiple periungual warts on the thumb (b) Complete resolution after 3rd dose of Mw vaccine|
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|Figure 4: (a) filiform wart on the elbow. (b) Complete resolution of warts with post-inflammatory hyperpigmentation after 4th dose of Mw vaccine|
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As the immunogens were injected only into one largest wart of each patient, we also had to assess the overall rate of response in all warts (including both injected and uninjected warts) in each patient. We observed that 24 (52.17%) patients in group A had complete clearance in all warts, 10 (21.74%) had partial clearance in size/number, and 12 (26.09%) had minimal or no response. Similarly, in group B, 32 (62.75%) had complete, 6 (11.76%) had partial, and 13 (25.49%) had minimal to no reduction in all warts. On statistical analysis, this difference in response rate between the two groups was statistically insignificant (P = 0.38) [Table 1].
Additionally, we also assessed the difference in response between the “injected” and “uninjected” warts in both groups. There was a statistically insignificant difference in the response rate between “injected” and “uninjected” warts in both group A (P-value = 0.57) and group B (P-value = 0.11).
In group A, adverse events were encountered in a total of 29 patients, whereas in group B, 43 patients experienced adverse events, and the difference was statistically significant (P-value = 0.017). Some patients had a constellation of more than one adverse events. The most common adverse event in patients of group A was transient injection site erythema and swelling seen in 29 (63.04%) patients. Other side effects included mild localized pruritus (n = 21, 45.65%), mild fever (resolving on its own in 1–2 days) in 11 (23.91%) patients, and generalized urticaria seen in 1 (2.17%) patient after 3rd dose of PPD.
In group B, 28 (54.90%) patients developed mild fever within 24 h of each injection which resolved on its own in the next 1–2 days. In 11 (21.57%) patients, a painful indurated nodule over the injection site was seen, most commonly at 2–3 weeks after the first dose. However, with repeated dosing, the size of the nodule stayed the same in these patients and at the final follow- up visit done on 12th week, the nodule had regressed in 3 (5.88%) patients with no scarring, in 7 (13.72%) with minimal scarring, and with hypertrophic scar in 1 (1.96%) patient. In 2 (3.92%) patients, we also observed an injection site ulceration, which was managed by administering atypical mycobacterial drug therapy until resolution of ulcer (seen at 6 weeks). Other minor side effects included injection site erythema and pruritus observed in 14 (27.45%) and 11 (21.57%) patients, respectively, which resolved on their own within a week.
Interestingly, in both the groups, in patients reporting lesional pruritus over the injected wart, there was a rapid clearance of warts.
The mean DLQI score of patients before the initiation of therapy in group A was 7.24 ± 0.96. However, after the completion of the treatment and follow-up period, the score reduced to 3.65 ± 0.83 (P < 0.0001). Similarly, in group B, the mean score pretreatment was 8.03 ± 1.09, which reduced to 1.97 ± 0.72 (P < 0.0001) after completion of treatment and follow-up visits. The rate of reduction was highly statistically significant in both groups.
| Discussion|| |
Even though, in 60%–65% patients, warts spontaneously resolve within 2 years, in the remaining patients they could become recurrent or recalcitrant to treatment. Additionally, some variants of warts such as palmoplanatar, subungual, and fissured warts can become exceptionally painful and discomforting. Similarly, patients with warts on exposed sites such as the face or dorsum of hands also seek treatment for cosmetic concerns., The conventional medical treatment options for warts include salicylic acid, fluorouracil, bleomycin, podophyllin, to name a few. Various other modalities such as radiotherapy, cryotherapy, electrocautery, photodynamic therapy, and surgical excision all rely on the principles of destructive therapy.,
However, as all these modalities have a low rate of success and high scarring and recurrence rates (up to 30%), of late the concept of immunotherapy has emerged to overcome these lacunae. It stimulated cellular immune response and, therefore, clears both manifest and subclinical warts. Similarly, by upregulation of immunity throughout the body, it is also a lucrative tool for the clearance of warts on inaccessible sites (periungual or subungual warts), sensitive sites (facial/perianal/genital), and multiple warts.,
In our study, we observed a significant reduction in the size and number of warts in both groups with minimal rates of recurrence during the 3 months' follow-up period. Our results were in accordance with the various studies conducted in the past using the same immunogens. Although there was a quicker resolution of warts in group B compared to group A, at the end of follow-up, it was statistically insignificant, further emphasizing the fact that the immunotherapy has a sustained response. However, in our study, the safety profile of patients was better with PPD compared to Mw. Severe adverse events such as injection site ulceration and scarring were encountered only with Mw vaccine.
The pioneering study utilizing PPD as an immunogen was conducted by Kus et al. in 2005 for the treatment of refractory warts with 13 patients having a total of 17 warts. They demonstrated complete clearance in 5 (29.4%) warts with an excellent safety profile. Various studies in the past have demonstrated success rates ranging from 48.5% to 96%.,,,
Of these, apart from Kus et al., only two studies were conducted on patients similar to the ones included in our study with recalcitrant or difficult to treat warts. These studies carried out by Amirnia et al. and Saoj et al. reported clearance rates of 77.1% and 76%, respectively. Our findings were also in close approximation with them both (63%).
The forerunner study using Mw vaccine was done by Gupta et al. in 2008 for anogenital warts with an outstanding success rate of 88.9%. The success rate of Mw vaccine against extragenital warts has been reported to be between 54.5% and 93.3%.,,,,
Interestingly, we observed that during the 3 months' follow up, three patients in group A and four in group B, who had reported only partial clearance in their warts after the last injection, developed complete clearance of warts in an average of 6.5 weeks, suggesting an although delayed but sustained response in such patients. We, therefore, suggest that after the completion of immunotherapy protocol, the patients should be advised to wait for at least 3 months before switching to a different therapy option.
Apart from us, only one other study carried out by Chandra et al. has done a head-to-head comparison of these two immunogens and reported results similar to ours.
While comparing the DLQI, we observed that there was a statistically significant improvement in QOL in both groups after completion of therapy (P < 0.0001). However, the mean reduction was greater in patients treated with the Mw vaccine than those with PPD tuberculin.
Our study had various limitations such as a small sample size, a short follow-up period, absence of analysis in genital warts, and no immunological profile assessment.
| Conclusion|| |
Immunotherapy utilizing Mw vaccine and PPD tuberculin have excellent efficacy in the treatment of multiple, recalcitrant warts, or warts on difficult-to-treat sites with minimal recurrence rates. We, therefore, suggest both these immunogens be utilized as first-line agents for the management of warts. However, the safety profile is better with PPD. Although the Mw vaccine is slightly superior with a faster onset of action, it is associated with a higher rate of adverse events.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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