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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 24  |  Issue : 2  |  Page : 110-115

Intralesional measles, mumps, and rubella vaccine versus cryotherapy in treatment of warts: A prospective study


Department of Dermatology, Venereology and Leprosy, Mandya Institute of Medical Sciences, Mandya, Karnataka, India

Date of Submission03-Jun-2020
Date of Acceptance05-Aug-2020
Date of Web Publication10-Nov-2020

Correspondence Address:
Dr. Deepadarshan Kalegowda
No-13, OPD Block, Department of Dermatology, Venereology and Leprosy, Mandya Institute of Medical Sciences, BM Road, Mandya - 571 401, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jdds.jdds_60_20

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  Abstract 


Background: Warts are benign tumors caused by infection of keratinocytes with human papillomavirus. Various modalities are available for the treatment of cutaneous warts such as destructive procedures, surgical methods, and immunotherapy. Recently, immunotherapy with intralesional antigens/vaccines is emerging as a novel method with encouraging results. Purpose: The study aimed to compare the efficacy of intralesional mumps, measles, and rubella (MMR) vaccine versus cryotherapy in the treatment of cutaneous warts. Methods: In this prospective study, 60 clinically diagnosed cases of cutaneous warts were enrolled and randomly divided into two groups of 30 each. Patients of Group A received 0.5 ml of reconstituted MMR vaccine, which was injected into the largest wart. The dose was repeated at 3-week intervals until complete clearance or for a maximum of 3 doses. In Group B, patients received cryotherapy with liquid nitrogen at weekly intervals for a maximum of 9 sessions. Patients of both the groups were followed up at the 3rd, 6th, and 9th weeks to evaluate clinical outcome on the Visual Analog Scale. Statistical analysis was done by the Chi-square test using SPSS software. Results: Out of 30 patients, 63.3% (19) of the patients of Group A showed complete clearance of warts compared with 33.3% (10) of the patients of Group B at the end of 9 weeks. Adverse effects were more with cryotherapy including pain, blistering, and depigmentation, whereas immunotherapy was well-tolerated except for the pain during injection. Conclusion: Intralesional MMR vaccine immunotherapy was more effective, with an added advantage of regression of distant warts, fewer sessions, and no serious side effects.

Keywords: Cryotherapy, immunotherapy, mumps, measles, and rubella, warts


How to cite this article:
Rajegowda HM, Kalegowda D, Madegowda SK, Palanayak JK. Intralesional measles, mumps, and rubella vaccine versus cryotherapy in treatment of warts: A prospective study. J Dermatol Dermatol Surg 2020;24:110-5

How to cite this URL:
Rajegowda HM, Kalegowda D, Madegowda SK, Palanayak JK. Intralesional measles, mumps, and rubella vaccine versus cryotherapy in treatment of warts: A prospective study. J Dermatol Dermatol Surg [serial online] 2020 [cited 2020 Dec 4];24:110-5. Available from: https://www.jddsjournal.org/text.asp?2020/24/2/110/300393




  Introduction Top


Warts are benign tumors, well-defined hyperkeratotic papillomas, caused by multiple strains of human papillomaviruses (HPVs).[1] Although warts resolve spontaneously in 65%–78% of the patients, many seek treatment because they can be unsightly, tender, or painful.[2]

The treatment of warts depends on two main therapeutic options: conventional destruction and immunotherapy.[3] Management is often challenging due to unpredictable clinical course. Selecting the most appropriate treatment is usually difficult because of the various therapeutic lines available and immune status of the patients.

Conventional destructive modalities are painful and often cause scarring, with high frequency of relapse.[2] Hence, the efficacy and safety of immunotherapy is compared with cryotherapy.


  Methods Top


Sixty clinically diagnosed cases of cutaneous warts, on the basis of history and typical clinical features, fulfilling the inclusion of having multiple cutaneous warts, age more than 12 years, with no concurrent systemic, or topical treatment of warts within the past 4 weeks were included in the study after clearly explaining the nature of the study and obtaining written informed consent. Patients with fever or any signs of inflammation or infection, children <12 years, pregnant and lactating females, immunocompromised patients, patients having anogenital/facial warts, and patients having history of asthma, allergic skin disorders, meningitis, or convulsions were excluded.

The study was conducted over a period of 18 weeks from May 2019 to January 2020, in the outpatient department of dermatology at our institute, after obtaining ethical clearance from the institutional review board (IRB).

Procedure

Demographic and clinical details for number, size of warts, and sites involved were recorded. The detailed cutaneous examination was conducted in good light, and appropriate digital photographs were taken. Every alternate patient was divided into two groups (Group A and Group B). The group receiving intralesional mumps, measles, and rubella (MMR) vaccine was designated as Group A, and the other group receiving cryotherapy was designated as Group B. Patients were advised not to use any other wart treatment during the study period.

Treatment protocol

In Group A, a single-dose vial of freeze-dried MMR vaccine (Tresivac, marketed by Serum Institute of India Ltd., India) was reconstituted with 0.5 ml of provided diluent (distilled water for injection) as per manufacturer's instructions just before intralesional use. The reconstituted MMR vaccine 0.5 ml was injected in one largest wart using a 30G insulin syringe (one dose) and repeated at every 3-week interval until complete clearance or for a maximum of three doses.

In Group B, all patients received cryotherapy once a week until complete clearance of warts or for a maximum of nine sessions. In each session, cryotherapy was done with liquid nitrogen using cryotherapy gun; each application was done until a frozen halo of 2 mm around the base of the wart appeared (usually after 2–10 s). After thawing, the second cycle was also performed in the same way in each session.

Outcome evaluation

The patients were evaluated clinically and by comparing with baseline clinical photographic records at each treatment session for resolution of treated wart and distant warts, reduced size and number of warts, and any immediate or late adverse effects, if any. Adverse reactions in both the groups were recorded as well. The clinical improvement was rated as complete clearance, excellent response, good response, or unsatisfactory response by the patient and physician global assessment using the Visual Analog Scale (VAS) score at each visit taking baseline clinical photograph as controls.

The clinical improvement was evaluated as follows:

  • Grade 4 = Complete clearance (VAS score = 100%) – Complete disappearance of treated warts and skin texture at the site is restored to normal
  • Grade 3 = Excellent response (VAS score = 75% 99%) – Reduction in size and number of treated warts, few residual warts still visible
  • Grade 2 = Good response (VAS score = 50%-74%) – Some reduction in size only but no decrease in number of warts
  • Grade 1 = Poor response (VAS score ≤ 50%) – No significant change in size and number of warts
  • Recurrence = Recurrence during the study period.


After completion of treatment period, the patients were also followed up similarly every 4-week interval for another 8 weeks(final visit).

Statistical analysis

Data were analyzed with the help of the SPSS version 20 software IBM Company, Chicago. Data were expressed as mean ± standard deviation for quantitative variables and number and percentage for qualitative ones. Chi-square test and t-test were used to compare the efficacy of two therapies. P < 0.05 was considered statistically significant.


  Results Top


Sixty patients with 434 warts were enrolled in this study. There were 17 males and 13 females in Group A, whose mean age was 28.35 years and 25.31 years, and 18 males and 12 females in Group B with a mean age of 25 years and 24.33 years, respectively. The baseline parameters (age, sex, and subdistribution of warts) between the two groups were statistically comparable, and no significant statistical difference was observed.

At the end of the 3rd week ( first follow-up visit), grade of response in the MMR group compared with the cryotherapy group was Grade 1 response in 63% versus 17%, respectively, Grade 2 response in 30% versus 63%, and Grade 3 response in 2% versus 20%, respectively. None of the groups showed Grade 4 response at the end of 3rd week. A summary of response at each visit is depicted in [Table 1].
Table 1: The therapeutic response in the two groups at the end of treatment

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After the end of 6 weeks (second visit), Grade 1 response was seen in a similar number of patients, 13% in both the groups. Grade 2 response was seen in 20% versus 53%, respectively, and Grade 3 response seen in 50% versus 30%, respectively, whereas Grade 4 response was observed in 17% of the MMR-treated group compared with 3% of the cryotherapy group.

At the end of 9 weeks (third visit), Grade 1 response was found in 7% versus 10%, Grade 2 response in 17% versus 50%, and Grade 3 response seen in 20% versus 13%, whereas Grade 4 response was observed in 57% versus 27% patients of the MMR and cryotherapy groups, respectively.

With regard to the response of warts to the treatment at final visit, the MMR-treated group had better results compared with the cryotherapy group and higher rates of complete response (63.33% vs. 33.33%, respectively). Grade 3 response was 20% versus 16.67%, respectively, whereas Grade 2 response was observed in 10% versus 40%, respectively, and no response in 6.67% versus 10%, respectively [Figure 1], [Figure 2], [Figure 3], [Figure 4] and [Graph 1].
Figure 1: Multiple plantar warts (a) at presentation, (b) Grade 2 response at 6 weeks, (c) Grade 3 response at 9 weeks, and (d) complete clearance of treated warts after three doses

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Figure 2: Multiple palmar warts (a) at presentation, (b) Grade 2 response at 3 weeks, (c) Grade 3 response of treated and distant warts at 9 weeks, (d) persistent Grade 3 response after three doses

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Figure 3: Multiple common warts over dorsal feet (a) at presentation, (b) Grade 2 response at 3 weeks, (c) Grade 3 response at 9 weeks, and (d) complete clearance of treated warts at 9 weeks of cryotherapy

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Figure 4: Periungual wart (a) at presentation, (b) Grade 2 response at 6 weeks, and (c) Grade 3 response at 9 weeks, (d) Grade 3 response after 9 sessions of cryotherapy

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Most of the patients in both the groups experienced mild-to-moderate pain during injection that was of short duration and similar in both the groups, whereas erythema, swelling, and pigmentary changes were seen mostly in the cryotherapy group.


  Discussion Top


Viral warts are a common problem affecting approximately 10% of the population. Warts are usually common in the pediatric age group and immunosuppressed patients, although it can affect anyone and can present at any age.[4]

They can appear in various forms which include verruca vulgaris, plane, plantar, myrmecia, coalesced mosaic, filiform or digitate, and periungual warts. It can occur at any age mostly seen in children and young adults, occurring with equal frequency both in males and females. They are frustrating for both patients and clinicians because of their inconsistent outcome which affects a patient's quality of life, thereby causing embarrassment due to their unsightly appearance, and fear of negative appraisal by others.

The prognosis of warts is variable with some patients showing spontaneous resolution, whereas others show persistence and progression with spreading to other body sites, leading to physical and emotional distress to the patients.

Immune mechanisms may explain the spontaneous resolution of warts.[5] The immune response elicited by HPV includes the production of specific antibodies and cell-mediated immunity with activation of Th-1 lymphocytes.[6] Th2-secreted interleukin (IL)-4 helps in antibody secretion, while IL-12 is one of the pro-inflammatory cytokines characteristic of Th-1-based immune response.[5]

Destructive procedures, such as chemical cauterization with salicylic acid, podophyllotoxin, trichloroacetic acid, formaldehyde, 5-fluorouracil, and photodynamic therapy, or surgical methods, such as cryosurgery, laser ablation, electrocautery, and excision, are used invariably to treat warts. Treatment with contact sensitizers, imiquimod, intralesional interferons and oral levamisole, cimetidine, or zinc sulfate has been tried with variable success.[2]

Most of the current therapeutic options result in the clearing of wart within 1–6 months, but in 20%–30% of the patients, they do relapse, and new lesions may appear as a result of failure of the cellular immune system to detect and remove the lesions completely.[4] Furthermore, these available destructive modalities may be painful, ineffective, costly, and may be associated with disfigurement, scarring, and high recurrence rates.

The multitude of therapies available for the treatment of warts reflects that no single treatment has proven 100% efficacy, and most of them remain unsatisfactory.

Recently, immunotherapy with intralesional antigens (autogenous vaccine, Candida antigen, mumps antigen, trichophyton skin test antigen, and tuberculin) or vaccines (Bacillus Calmette–Guérin vaccine, measles, mumps, rubella (MMR) vaccine, and Mycobacterium w vaccine) has been tried for the treatment of common warts with encouraging results.[7],[8]

Immunotherapy aims to achieve an HPV-targeted immune reaction and offers a theoretical advantage in the effective control of viral proliferation.[4] One theory suggests induction of a type IV hypersensitivity reaction another suggesting that the substance acts as a hapten to wart virus proteins to induce an immune reaction to HPV.[9] Both humoral and cell-mediated responses are stimulated during HPV infection, but warts are mostly cleared by cell-mediated immunity, in which dendritic cells, CD4+ T-helper cells, and CD8+ T-cells play predominant roles.[10] Intralesional immunotherapy has been shown to be associated with release of different cytokines such as IL-2, IL-4, IL-5, IL-8, Interferon-alpha INF-c, and tumor necrosis factor-alpha that stimulate a strong immune response against HPV.[11],[12] Antigen injection is associated with proliferation of peripheral blood mononuclear cells that promote Th1 cytokine responses which further activate cytotoxic T-cells and natural killer cells to eradicate HPV-infected cells.[11] This conceptualized intralesional immunotherapy uses different antigens to stimulate cell-mediated and humoral immunity to accelerate viral clearance of intralesionally treated and distant warts. Such therapy may be applied either topically or through intralesional injection or through systemic administration.

Cryotherapy acts by a complex mechanism; freeze and thaw cycles produce intracellular ice and extracellular ice formation and cellular destruction, which ultimately result in apoptosis of virus-infected cell. However, rapid freeze-thaw cycles in widespread area are most destructive as it produces ischemic necrosis, which can lead to side effects such as blister formation and hypopigmentation. Therefore, cryotherapy as alone as a treatment modality is not advisable in patients with multiple warts.

Taking advantage of the vaccination schedule in our country including the MMR vaccine, we designed the present study to evaluate the efficacy and safety of this antigen combination in the treatment of common warts.In our short study, most of the patients belonged to the adult age group. Hand and foot involvement was commonly seen in our study group, possibly because of more exposure and susceptible to trauma, pricks, and inoculation. Most of the patients were students, farmers, and nursing staff.

In this study, the MMR-treated group gave significantly better results compared with the cryotherapy group with higher rates of complete response. There was a 63.33% reduction in the number of warts in the MMR group at the end of the final visit as compared with only 33.33% reduction in the cryotherapy group. All patients in this study experienced injection site pain and swelling lasting for initial 1 or 2 days that did not warrant discontinuation of treatment. Erythema and pigmentary changes were frequently observed in the cryotherapy group. There was no recurrence at the end of the study period, and cured patients rated their treatment very much satisfactory.

In a similar study by Khozeimeh et al., MMR vaccine was given in the treatment of cutaneous warts in 30 patients and cryotherapy in 30 patients. This study showed a complete clearance rate of 76.7% compared with 56.7% of the control group. Complete remission was observed with fewer sessions in immunotherapy compared to cryotherapy, but no statistically significant difference was shown between the groups.[13]

Similarly, various other immunotherapies have been compared with cryotherapy in the treatment of warts with variable results.

Dhope et al. conducted a study on 40 patients using MMR and placebo (normal saline), three injections at 3 weekly intervals were given and reported higher rates of complete response (65% vs. 5%, respectively), and but as regards partial response, it was 10% versus 25%, respectively, and as regards no response, it was 5% versus 60%, respectively, with pain being the most common side effect observed.[4]

Johnson et al., conducted a study on 115 patients with warts using immunotherapy(mumps or candida sera) and cryotherapy, which showed 74% clearance rate with immunotherapy compared to 55% with cryotherapy.[14]

A study conducted by Choi et al. compared the clearance rate of viral warts treated with topical diphencyprone therapy which included 72 patients in Group A and cryotherapy with 75 patients in Group B. In all, 45 patients (62.5%) of Group A and 38 patients (50.8%) of Group B, respectively, showed complete clearance. After 12-month follow-up, 93.3% (42/45) of Group A and 76.3% (29/38) of Group B presented sustained clearance.[15]

Smaller sample size and shorter duration of followup were the limitations of this study requiring further studies to validate our results.


  Conclusion Top


Although cryotherapy is one of the most commonly used treatment modalities, it invariably requires multiple sittings, and the results might be slow and inadequate. Intralesional MMR vaccine immunotherapy appears effective and safe treatment for warts in children/adolescents with the advantage of single-lesion infiltration and resolution of even untreated distant warts, low recurrence, and without scarring or pigmentary changes commonly seen with destructive warts therapies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Naseem R, Aamir S. The efficacy of intralesional measles, mumps, rubella (MMR) antigen in treatment of common warts. PJMHS 2013;7:1130-3.  Back to cited text no. 1
    
2.
Chauhan PS, Mahajan VK, Mehta KS, Rawat R, Sharma V. The efficacy and safety of intralesional immunotherapy with measles, mumps, rubella virus vaccine for the treatment of common warts in adults. Indian Dermatol Online J 2019;10:19-26.  Back to cited text no. 2
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3.
Vender R, Bourcier M, Bhatia N, Lynde C. Therapeutic options for external genital warts. J Cutan Med Surg 2013;17 Suppl 2:S61-7.  Back to cited text no. 3
    
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Dhope A, Madke B, Singh AL. Effect of measles mumps rubella vaccine in treatment of common warts. Indian J Drugs Dermatol 2017;3:14-9.  Back to cited text no. 4
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Stanley M. Immune responses to human papillomavirus. Vaccine 2006;24:S16-22.  Back to cited text no. 5
    
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Maronn M, Salm C, Lyon V, Galbraith S. One-year experience with candida antigen immunotherapy for warts and molluscum. Pediatr Dermatol 2008;25:189-92.  Back to cited text no. 7
    
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Brunk D. Injection of Candida antigen works on warts. Skin Allergy News 1999;30:5.  Back to cited text no. 8
    
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Gupta R, Gupta S. Topical adapalene in the treatment of plantar warts; randomized comparative open trial in comparison with cryo-therapy. Indian J Dermatol 2015;60:102.  Back to cited text no. 9
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Gamil H, Elgharib I, Nofal A, Abd-Elaziz T. Intralesional immunotherapy of plantar warts: Report of a new antigen combination. J Am Acad Dermatol 2010;63:40-3.  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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Gupta S, Malhotra AK, Verma KK, Sharma VK. Intralesional immunotherapy with killed Mycobacterium w vaccine for the treatment of ano-genital warts: An open label pilot study. J Eur Acad Dermatol Venereol 2008;22:1089-93.  Back to cited text no. 12
    
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Khozeimeh F, Jabbari Azad F, Mahboubi Oskouei Y, Jafari M, Tehranian S, Alizadehsani R, et al. Intralesional immunotherapy compared to cryotherapy in the treatment of warts. Int J Dermatol 2017;56:474-8.  Back to cited text no. 13
    
14.
Johnson SM, Roberson PK, Horn TD. Intralesional injection of mumps or Candida skin test antigens: A novel immunotherapy for warts. Arch Dermatol 2001;137:451-5.  Back to cited text no. 14
    
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Choi MH, Seo SH, Kim IH, Son SW. Comparative study on the sustained efficacy of diphencyprone immunotherapy versus cryotherapy in viral warts. Pediatr Dermatol 2008;25:398-9.  Back to cited text no. 15
    


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