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   Table of Contents     
ORIGINAL ARTICLE  
Year : 2014  |  Volume : 7  |  Issue : 4  |  Page : 203-208
Intralesional immunotherapy for difficult to treat warts with Mycobacterium w vaccine


Department of Dermatology, Army College of Medical Sciences, Base Hospital, Delhi Cantonment, New Delhi, India

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Date of Web Publication4-Feb-2015
 

   Abstract 

Background: Immunotherapy is an evolving therapeutic modality for the treatment of warts. We conducted a study to assess the efficacy and safety of intralesional Mycobacterium w vaccine for the treatment of warts at sites that were difficult to treat. Materials and Methods: Thirty patients with at least one wart present on either the plantar surface of their feet, palms, volar aspect of their fingers, or periungual or subungual region, were treated with 0.1 ml of killed Mycobacterium w vaccine given intralesionally in a single wart, without any prior sensitisation dose. Thereafter, a single injection of 0.1 ml of vaccine was given at intervals of four weeks in a single wart till there was complete resolution of the warts or a maximum of 10 injections. Treatment was stopped if there was no response after three injections. The patients were followed up for at least six months. Results: Out of the 30 patients, 28 (93.33%) patients had complete resolution of their warts, both at the injected and distant sites. The mean (SD) time for complete clearance of warts was 43.71(32.82) days and the mean (SD) dose of vaccine that was required for complete clearance of warts was 0.186 ml (0.101). Four patients (14.28%) had a recurrence of warts. The treatment was well-tolerated and the side effects were reversible in the majority of the patients. Conclusion: In comparison to the earlier studies using Mycobacterium w vaccine for the treatment of warts, our study was different in the following aspects: No sensitisation dose was given, only a single wart was injected at a time and the duration between the period of injections was increased to four weeks. With all these changes we eliminated the complications due to the sensitisation dose and achieved good results. This study provides new insight into the dose and schedule of treatment of this evolving therapeutic modality.

Keywords: Warts, immunotherapy, Mycobacterium w vaccine, intralesional

How to cite this article:
Garg S, Baveja S. Intralesional immunotherapy for difficult to treat warts with Mycobacterium w vaccine. J Cutan Aesthet Surg 2014;7:203-8

How to cite this URL:
Garg S, Baveja S. Intralesional immunotherapy for difficult to treat warts with Mycobacterium w vaccine. J Cutan Aesthet Surg [serial online] 2014 [cited 2019 Oct 22];7:203-8. Available from: http://www.jcasonline.com/text.asp?2014/7/4/203/150740





   Introduction Top


Warts are common viral infections caused by the human papilloma virus (HPV). Management of warts over the subungual and periungual region, palms, volar surface of the fingers and plantar surface of the feet are especially challenging and frustrating for the physician. Immunotherapy for warts has been performed using diphenylcyclopropenone, squaric acid dibutyl ester (SADBE), imiquimod, tuberculin jelly, interferon alpha and gamma (IFN-gamma), skin test antigens like Candida, [1],[2] mumps, [3],[4] Trichophyton[3] and tuberculin. [5],[6] Vaccines that have been used for immunotherapy of warts include Bacillus Calmette-Guérin (BCG) vaccine, [7] mumps measles rubella vaccine, [8]Mycobacterium w vaccine [9],[10],[11],[12] and autologous vaccine. [13]

The exact mechanism of action of the Mycobacterium w vaccine (MWV) in the clearance of warts is not known. The intralesional MWV initiates a strong proinflammatory delayed-type of hypersensitivity response against Mycobacterium w (Mw), which attracts the antigen-presenting cells, leads to the production of helper T-cell type I cytokines (IL-2, IL-4, IL-5, IFN-ɣ) and causes activation of the natural killer and cytotoxic T cells. These antigen processing cells may recognise and process the HPV particles in the infected tissue. This strong adaptive immune response, which is not only against Mw, but also against HPV, leads to the clearance of warts both at the site of injection as well as the distant sites. [9],[10],[14]

The Mycobacterium w vaccine contains a heat-killed suspension of Mw, which is a nonpathogenic, cultivable, atypical mycobacterium belonging to the Runyan group IV class of mycobacteria. It is now renamed as Mycobacterium indicus pranii. [15] It is available in India in a 0.6 ml vial, with each dose of 0.1 ml containing 0.5 × 10 9 cells of heat-killed Mw, 0.9% w/v of sodium chloride and 0.01% w/v of Thimerosal. It has been found to be useful in the treatment of tuberculosis, [16] leprosy, [17],[18] human immunodeficiency virus infection [19] and cancer of the head, neck, bladder and lung. [10],[20],[21] It stimulates T-cell response and production of cytokines like IL-2, IL-4, IL-5 and IFN-γ. [22]

Most of the studies on the use of MWV [9],[10],[11],[12] in the treatment of warts have used the initial sensitising dose by injecting 0.1 ml of MWV in each deltoid region. Also in these studies, after the sensitisation dose, intralesional injections of MWV were given in at least two to five warts at a time and the dose was repeated either at weekly or bi-weekly intervals. We undertook a study to evaluate the efficacy and safety of intralesional MWV in an open-label study for the treatment of warts at difficult-to-treat sites such as palms, volar surface of fingers, plantar surface of feet and the subungual and periungual regions. Our study differed from the previous studies, as we did not use any prior sensitisation dose, injected only a single wart at a time and repeated the dose at four weekly intervals.


   Materials and Methods Top


A prospective, uncontrolled, open-label, interventional study was performed with 30 patients. The inclusion criteria were: Patients who were clinically diagnosed with single or multiple warts, with at least one wart present on either the plantar surface of the feet, palms, volar surface of the fingers, periungual or subungual regions, with no prior history of treatment for the same. Patients under five years and over 60 years of age were excluded from the study. Patients who were immunocompromised, pregnant or lactating and patients with a history of hypersensitivity or allergy to vaccines were also excluded from the study. Approval was obtained from the Ethical Committee and written informed consent was obtained from all the patients. No sensitisation dose was given to the patients. The patients were treated with 0.1 ml of intralesional injection of MWV using an insulin syringe, which was given in a single wart, and repeated at intervals of four weeks, till there was complete clearance of all warts, or a maximum of 10 injections. The treatment was stopped if there was no response after three injections of vaccine. In case of multiple warts, the largest wart was chosen for injecting the vaccine and the injections were repeated at the same site. The lesion count of both the injected as well as the uninjected warts was recorded on each visit. Complete clearance of all the warts, both at the treated as well as distant sites was taken as a clinical cure. Adverse effects were noted. Patients were followed up every two months for at least six months after completion of treatment.

Statistical analysis

Data is described in terms of Mean ± Standard Deviation (SD). The Student t-test was applied. A value of p < 0.05 was considered as statistically significant.


   Results Top


Out of 30 patients, there were 19 males and 11 females in the age group of six to forty-five years and a mean (SD) age of 22.57 years (11.106). The number of warts in the patients ranged from 1-15 in number, with the site of involvement of warts in the upper limb being the palm, volar surface of finger, periungual area of the fingernail, subungual area of the fingernails and dorsum of the finger and in the lower limb, the plantar surface of the toes, soles, dorsum of the feet and periungual region of the toes and legs. Out of the 30 patients, 28 (93.33%) patients had complete resolution of the warts, both at the injected as well as the distant sites [Figure 1] and [Figure 2]. In two (6.67%) patients the warts did not resolve. The mean (SD) time to complete clearance of the warts was 43.71 (32.82) days, with the warts on the upper limb clearing in 52.78 (40.71) days and those on the lower limb clearing in a mean time of 41.69 (28.98) days (p 0.217). The mean (SD) dose of MWV that was required for complete clearance of the warts was 0.186 ml (0.101), with a mean dose of 0.211 ml (0.078) required to clear warts on the upper limb and 0.181 ml (0.117) required to clear warts on the lower limb (p 0.227). Patients with a single wart required a mean (SD) dose of 0.182 ml (0.087) of MWV for complete clearance of warts, patients with two to five warts required 0.15 ml (0.071), those with six to ten warts required 0.167 ml (0.115) and patients with >10 warts required a mean dose of 0.333 ml (0.153), for complete clearance of the warts. There was no statistically significant difference between the mean dose of MWV required to clear one wart in comparison to that required to clear >10 warts (p 0.111). The mean (SD) number of the injection sessions required for complete clearance of warts was 1.86 (1.01). The mean (SD) time of follow-up was 11 months (2.83), with a range of six to seventeen months. Out of 28 patients who had complete resolution of the warts, four (14.28%) patients had recurrence of warts at a site different from those previously involved. The time of recurrence was six months in two patients, seven months in one and eleven months in one patient. The systemic side effects experienced by the patient were fever in 20 (66.67%) patients, myalgia in seven (23.33%) patients, headache in three (10%) patients and vomiting in two (6.67%) patients. The local side effects at the site of injection were redness, swelling and induration in 10 (33.33%) patients and spontaneous ulceration in two (6.67%) patients.
Figure 1: (a) Multiple plantar warts before treatment, (b) warts after two injections of MWV showing slight resolution, (c) complete resolution of warts after four injections of MWV

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Figure 2: (a) Subungual wart before treatment, (b) resolution of wart after single injection of MWV, (c) periungual wart before treatment, (d) resolution of wart after single injection of MWV

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Twenty (66.67%) patients experienced high-grade fever between 101 ° F and 104 ° F, in some cases associated with chills and rigors, beginning on the day of injection, which subsided with paracetamol tablets. Out of 10 patients who had local complications at the site of injection in the form of redness, swelling and induration, the site of injection was the periungual area of the fingernails in three (30%) patients, palms in two (20%), subungual area of fingernail in one (10%), volar surface of the finger in one (10%) and the sole in three (30%) patients. Hence, out of 10 patients who experienced redness, swelling and induration at the site of injection, seven (70%) patients received their injection on the hands as compared to three (30%) patients who received the injection on the feet. The swelling usually developed within a week's time of having the injection and was associated with mild pain and tenderness. In most of the patients the swelling subsided within a month's time. All the patients were treated with Capsule Amoxicillin and Clavulanic acid for seven days and Tablet Ibuprofen for 10 days for the swelling. In all these 10 patients, X-ray of the involved parts were taken and none of them had any underlying bony involvement. Out of two patients who experienced spontaneous ulceration, the site of injection was the palm in one (50%) patient and the plantar surface of the great toe in one (50%) patient. Three patients underwent incision and drainage for their swelling. Their site of injection was the palm in one patient (33.33%), volar surface of finger in one (33.33%) and the plantar surface of toe in one (33.33%) patient. Only a single patient, whose site of injection was the plantar surface of the toe, underwent debridement of the swelling in the Surgery Department.


   Discussion Top


In our study complete clearance of both the treated and untreated distant warts was seen in 28 (93.33%) patients. The mean (SD) time to complete clearance was 43.71 (32.82) days. Although the warts on the lower limb subsided earlier as compared to those on the upper limb, the difference was not found to be statistically significant (p 0.218). The mean (SD) dose of MWV required for complete resolution of the warts was 0.186 (0.101) ml. Hence, the treatment was cost-effective to the patient, as one vial of MWV containing 0.6 ml of vaccine costs approximately Rupees 450. The dose required for clearance of warts on the lower limb was less as compared to the upper limbs, although the difference was not statistically significant (p 0.227). The total dose required to clear a single wart was less as compared to that required for a patient having more than 10 warts, although the difference was not statistically significant (p 0.111). The mean (SD) number of injection sessions required for complete clearance of warts was 1.86 (1.01), hence, the number of hospital visits was less for the patient. The mean (SD) duration of follow-up was 11 months (2.83), with a range of 6-17 months, during which the recurrence of warts was seen in four (14.28%) patients. The systemic side effects were transient in nature and could be easily managed with medication. The incidence of local side effects in the form of redness, swelling, and induration at the site of injection was more in case of injections given on the hands as compared to the feet, with maximum complications occurring if the site of injection was the distal digit of fingers, especially in the periungual region. In patients who underwent incision and drainage, there was no frank drainage of pus discharge from the lesion. The reason why these complications were more at the injection site given on the distal digit may be due to the closed compartment and limited space for the local reaction that can normally occur after injection of MWV. The complications occurred in spite of the fact that the injections were kept superficial. The swelling subsided in a month's time.

In a study by Meena et al., [10] using MWV for the treatment of multiple warts, a sensitisation dose of 0.1 ml was given in each deltoid region at the baseline. After two weeks, subsequent injections were given at an interval of one week intralesionally into three to five lesions at a time. Complete clearance of the warts at the site of injection was seen in 33 (83%) patients with 23 (70%) of the 33 patients showing resolution of the distant untreated warts. The mean (SD) time to complete clearance was 9.7 (2.6) weeks. Recurrence was seen in three patients during a follow-up period of 4.48 (1.32) months. The side effects reported were tender erythematous papules healing with a scar at the deltoid region in all patients, erythema at the site of the warts in 25 (70%) patients, swelling in six (16%), and superficial ulceration in one patient. Two patients had low-grade fever and two patients had tenderness and swelling of the submandibular lymph node.

Hence, in comparison to this study, the mode of administration of MWV in our study showed a higher rate of clearance of the warts, both at the injected as well as the distant sites. Also the warts resolved earlier, with fewer treatment sessions in our study. In our study, as no sensitisation dose was given, no side effects like nodule and scar formation were seen at the deltoid region. Although the recurrence rate in the study was slightly less as compared to ours, this could also be because of the long follow-up period of mean of 11 months in our study in comparison to 4.48 months in the study by Meena et al.

In another study by Gupta et al. [10] in which killed MWV was used for the treatment of anogenital warts, a sensitisation dose of 0.1 ml was given in each deltoid and intralesional injections were given in ≤3 warts at a time, which were repeated at weekly intervals.There was complete clearance of the warts in eight out of the nine patients (88.9%) who were treated. All the patients showed an immunological reaction at the site of sensitisation in the deltoids. Adverse effects were seen in four patients. No recurrence was seen after a mean follow-up of 5.1 months.

In a study by Singh et al., [11] retrospective analysis was done to evaluate the efficacy and safety of MWV in the treatment of extensive extragenital cutaneous warts in 44 patients. The patients were sensitised with 0.1 ml of MWV injected vaccine injected intradermally over each deltoid region. In the sensitised individuals, ≤0.1 ml of the vaccine was injected intralesionally in two to four warts after two weeks. The injections were repeated at intervals of two weeks. Complete clearance of the warts was seen in 24 (54.5%) patients, with a mean of 3.4 ± 1.1 injections. Resolution of the warts at distant sites was seen in 38 (86.3%) patients. Adverse effects were present in 36 (81.8%) patients, with the presence of nodule formation at the site of sensitisation. In two patients the nodule progressed to form an ulcer, which healed leaving an atrophic scar. In the remaining 34 patients it subsided spontaneously in two to three weeks, without any residual changes. Nodule formation was present in 19 (43.1%) patients at the site of the injected wart and three such nodules healed with atrophic scars. Owing to lack of the sensitisation dose given in our study, the incidence of complications due to sensitisation was not seen.

In a double-blind randomized clinical trial, which was conducted by Kumar et al., [12] the efficacy and safety of intralesional MWV was compared with that of imiquimod 5% cream, in the treatment of anogenital warts, along with changes in the HPV-6 and HPV-11 viral loads. Fifty nine percent (n = 26) of the patients in the imiquimod group and 67% (n = 30) of those in the MWV group had complete resolution (p = 0.52). There was a significant decline in the mean viral loads of HPV-6 ( p = 0.003) and HPV-11 ( p = 0.03) after treatment in the MWV group, but only in the viral load of HPV-6 (p = 0.01) in the imiquimod group. The study concluded that both imiquimod 5%, and the MWV were equally effective in achieving clinical and virological clearance for HPV-6, whereas, only MWV resulted in a significant decline in the HPV-11 viral load.

The clearance rate for cutaneous extragenital warts with immunotherapy, using various skin test antigens and vaccines other than MWV ranged from 39.7 to 87%. [1],[2],[3],[7],[8],[23],[24] Hence, the clearance of warts using MWV with our mode of administration was similar to other skin test antigens and vaccines for the treatment of warts. Further head-to-head studies would be needed to directly compare the efficacies between various intralesional immunotherapy options, their schedules and doses.

In our study, no test dose was given. A test dose is given to check the immunological response to the vaccine and to sensitise those who are not. For the following reasons we did not perform the test dose before starting the treatment:

  1. In India most of the patients have a latent infection with Mycobacterium tuberculosis, which has antigenic similarity with Mw. Thus, there are high chances of a good immunological response to MWV injection without prior sensitisation. Therefore, there is no need to unnecessarily subject the patient to multiple painful injections.
  2. The test dose injection which is given intradermally over both deltoid regions would have led to nodule formation, ulceration, scarring, and other complications at the deltoid region. To manage these unwarranted scars (some of which might become hypertrophic or may lead to keloid formation) the patient would have to undergo many different procedures including surgical scar management, and that would lead to increased cost and increased morbidity for the patient. Even in cases where sensitisation would have been required, an intralesional injection at the wart site could have done the same, without any scarring and local complication at the site not having the wart.
  3. It also reduced the total dose of vaccine given to each patient, which never exceeded 0.1 ml at any session in our study.
  4. We also gave repeat injections at an interval of four weeks to reduce the chances and severity of local side-effects of the vaccine injection.
  5. We also injected the vaccine intralesionally into a single wart each time, and hence, multiple painful pricks were not required during each session.


The dose was standardized to 0.1 ml as recommended by manufacturers and the same dose of vaccine was used for treating warts of all the patients recruited for this study.

It is well-known that any kind of trauma including the trauma due to intralesional injection can lead to development of a non-specific immune response against the wart antigens, resulting in resolution of the traumatized wart. However, owing to the high 93.33 percentage of patients, who showed complete resolution after intralesional immunotherapy by MWV, there seems to be a definite role of this test antigen in the resolution of warts. Also the resolution of warts at both the injected as well as the distant sites goes in favour of a systemic immune response against the wart antigen rather than wart clearing only due to trauma.


   Conclusion Top


Treatment of warts at difficult-to-treat sites, using immunotherapy with MWV, given without any prior sensitisation dose in a single wart, at four weekly intervals, has shown high cure rates, both at the injected as well as distant sites, with low recurrence rates. The treatment is cost-effective and requires only few treatment sessions. Patients with warts on the feet and who were given injections on the feet responded early. They required a lesser dose of vaccine and experienced lesser local complications as compared to those with warts on the hands, although the difference was not statistically significant. The systemic side effects could be treated easily.

This study provides a new insight into the dose and schedule for the treatment of this evolving therapeutic modality. Its role in the treatment of warts needs further evaluation in randomized controlled trials.

 
   References Top

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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. 3
    
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Correspondence Address:
Dr. Shilpa Garg
22/11 Geeta Mandir Marg, New Rajinder Nagar, New Delhi - 110 060
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0974-2077.150740

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